WO2026030525A1

WO2026030525A1 - Zilvetrigine dosage forms and dosing regimens for treating pain

Info

Publication number: WO2026030525A1
Application number: PCT/US2025/040023
Authority: WO
Inventors: Siying Liu; Brian J. Hare; Isabel A. ZACHARIAS
Original assignee: Vertex Pharmaceuticals Inc
Current assignee: Vertex Pharmaceuticals Inc
Priority date: 2024-07-31
Filing date: 2025-07-31
Publication date: 2026-02-05
Anticipated expiration: 2027-01-31

Abstract

Disclosed herein are methods of treating pain, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof.

Description

ZILVETRIGINE DOSAGE FORMS AND DOSING REGIMENS FOR TREATING PAIN

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U .S. Provisional Application No. 63/677,665, filed July 31, 2024, which is incorporated by reference in its entirety.

BACKGROUND

[0002] Pain is a protective mechanism that enables healthy persons and animals to avoid tissue damage and to prevent further damage to injured tissue. Managing pain in tire clinical setting, in both acute and chronic clinical settings, remains a high unmet need. In addition to acute pain, there are many conditions where chronic pain persists beyond its protective role (neuropathic pain) where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al ., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories: pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. Tire metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain. Neuropathic pain is a major cause or disability worldwide, negatively affecting patient’s sleep, mood, and functionality. Clin. Then 2018 40(6): p. 828-49.

[0003] Current pain therapies suffer from poor efficacy and a high risk of adverse events (AEs). For example, lidocaine (a nonselective sodium channel blocker) may effectively reduce pain, but its utility is limited because of prominent side effects when given at dose levels required for pain relief. Opioid pain medications have a high abuse liability, leading to frequent deaths due to overdose. In addition, opioid- induced hyperalgesia also limits the long term use of opioids. Opioid-induced hyperalgesia is encountered regularly in clinical practice and creates significant challenges in pain management.

[0004] Antidepressants and anticonvulsants remain the first line treatment for neuropathic pain despite not being designated for such purpose. Their use is often limited by an arsenal of side effects or inadequate pain relief. Clinical development has exhibited a considerable lack of recent progress and innovation of new medications to treat both acute and chronic pain. Over the last decades, most approved analgesic drugs for the treatment of neuropathic pain either act on the serotonin-norepinephrine system (such as the serotonin-norepinephrine reuptake inhibitor duloxetine) or on voltage-gated calcium channels (such as the gabapentinoid pregabalin). Given the limited treatment options for pain, combined with a growing awareness of the risks and relative ineffectiveness of the current standards of care, the development of analgesics targeting specific pathophysiology mechanisms with improved efficacy and safety profiles is vital for better pain management and patient health outcomes.

[0005] Voltage-gated sodium channels (Navs) are involved in pain signaling. Navs are biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types (e.g., neurons, skeletal myocytes, cardiac myocytes). Support for the assertion that Navs play a critical and central role in pain signaling arises from (1) evaluation of the role Navs plays in normal physiology, (2) pathological states arising from mutations in the Navi .8 gene (SCN10A). (3) preclinical work in animal models, and (4) pharmacology of known Navl.8-modulating agents. In addition, because Navi.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., tire dorsal root ganglia), Navi.8 inhibitors are less likely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse liability associated with opioid therapies. Therefore, targeting the underlying biology of pain through selective Navi.8 inhibition represents a novel approach to analgesic drug development that has the potential to address an urgent unmet need for safe and effective acute and chronic pain therapies (Rush, A.M. and T.R. Cummins, Painfiil Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nayl.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008); Krafte. D. S. and Bannon, A. W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Because of the role Navs play in the initiation and propagation of neuronal signals, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels have been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Na_v channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B.. Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002): Wang, G. K._ Mitchell, J., and Wang. S. Y., Block of persistent late Na⁺ currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

[0006] The Navs form a subfamily of tire voltage-gated ion channel super-family and comprises 9 isoforms, designated Navl.l - Navi.9. Tire tissue localizations of the nine isoforms vary. Nav 1.4 is the primary sodium channel of skeletal muscle, and Nav 1.5 is the primary sodium channel of cardiac myocxtes. Navi.7, Navi.8 and Navi.9 are primarily localized to the peripheral nervous system, while Navl.l, Navi.2, Navi.3, and Navi.6 are neuronal channels found in both the central and peripheral nervous systems. Tire functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman. S. G.. International Union of Pharmacology. XL VII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4). p. 397 (2005)).

[0007] Upon their discovery, Nav 1.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, Navi.8 has been shown to be a carrier of tire sodium current that maintains action potential firing in small DRG neurons, supporting its potential as a target for multiple indications or across multiple pain types (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX) -sensitive Na+ current. TTX -resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Navi.8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al.. The tetrodotoxin-resistant Na⁺ channel Nav 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective Nav 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Set. U S A, 2007. 104(20): p. 8520-5; Joshi. S.K., et al.. Involvement of the TTX- resistant sodium channel Navi .8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82; Lai, J., et aL, Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NavL8. Pain, 2002. 95(1-2): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown ofNa(v)L8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21; Huang. H.L., et al., Proteomic profding of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J.A., et al.. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008. 64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain. 2000. 85(1-2): p. 41-50; Yiangou, Y ., et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBSLett, 2000. 467(2-3): p. 249-52; Ruangsri, S.. et al.. Relationship of axonal voltage-gated sodium channel 1.8 (Navi .8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47). The small DRG neurons where NavL8 is expressed include the nociceptors involved in pain signaling. Nav 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na⁺ current. TTX- resistant Na⁺ current, and Ca²⁺ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Navi.8 is necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons (Choi, J.S. and S.G. Waxman, Physiological interactions between Navi.7 and Navi.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al.. The tetrodotoxin-resistant Na⁺ channel Navi.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na_v1.8 appears to be a driver of hyper-excitablility (Rush, A.M., et al., A single sodium chamrel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Set. USA, 2006. 103(21): p. 8245-50). In some animal pain models. Navi.8 mRNA expression levels have been shown to increase in tire DRG (Sun. W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of Navl.7, Navi.8 and Navi.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72; Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels Navi.8 and Navi.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.. 512(2): p. 61-6).

SUMMARY

[0008] In one aspect, the disclosure relates to a method of treating pain in a subject, comprising administering to the subject Compound 1:

(Compound 1), or a pharmaceutically acceptable salt thereof, in amounts specified herein.

[0009] In another aspect, the disclosure relates to a pharmaceutical composition comprising Compound 1, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate in amounts specified herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 Form A. [0011] Figure 2 provides the ¹³C solid-state NMR (SSNMR) spectrum of Compound 1 Form A.

[0012] Figure 3 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 Methanol Solvate Form C.

[0013] Figure 4 provides the ¹³C solid-state NMR (SSNMR) spectrum of Compound 1 Methanol Solvate Form C.

[0014] Figure 5 provides the X-ray powder diffraction (XRPD) pattern of Compound 1 2-MeTHF Solvate Form D.

[0015] Figure 6 provides the ¹³C solid-state NMR (SSNMR) spectrum of Compound 1 2-MeTHF Solvate Form D.

DETAILED DESCRIPTION

Definitions

[0016] The chemical elements are identified herein in accordance with the Periodic Table of tire Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry/’ Thomas Sorrell. University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5^th Ed., Ed.: Smith, M B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0017] As used herein, the term “amorphous” refers to a solid material having no long-range order in the position of its molecules. The molecules in an amorphous solid are generally arranged in a random manner with no well-defined arrangement. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.

[0018] As used herein, the tenn “substantially crystalline" refers to a solid material having little or no amorphous molecules. For example, substantially crystalline materials have less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term "substantially crystalline" includes the descriptor "cry stalline." which refers to materials that are 100% crystalline form.

[0019] As used herein, a crystalline form is "substantially pure" when it accounts for an amount byweight equal to or greater than 90% of the sum of all solid fonn(s) in a sample as determined by a method in accordance with the art. such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample. [0020] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," "XRPD spectrum" interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate).

[0021] A "signal" or "peak" as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. An XRPD peak is identified by its angular value as measured in degrees 20 (°20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed, for example, as "a signal at ... degrees two-theta," "a signal at [a] two-theta value(s) of ... " and/or "a signal at at least ... two-theta value(s) selected from .... "

[0022] The repeatability of the measured angular values is in the range of ±0.2° 20. i.e., tire angular value can be at the recited angular value +0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0023] One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[0024] The temis "signal intensities" and "peak intensities" interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0025] As used herein, an X-ray powder diffractogram is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%. at least 98%. or at least 99%. of the signals in the two diffractograms overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same cry stalline form. Thus, those of ordinary' skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta) generally mean that value is identified as ±0.2 degrees two-theta of the reported value, an art-recognized variance.

[0026] As used herein, the term “Compound 1,” and the structure and chemical name corresponding to the “Compound 1,” refer to a collection of molecules having identical chemical structures, namely the structure corresponding to the “Compound 1,” except that there may be isotopic variation among the constituent atoms of the molecules. The term “Compound 1” includes such a collection of molecules without regard to the purity of a given sample containing tire collection of molecules. Thus, the term ‘'Compound 1” includes such a collection of molecules in pure form or in a mixture (e.g., solution, suspension, or colloid) with one or more other substances.

[0027] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in Compound 1 is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0028] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory. Table of Nuclides (January 1980).

[0029] As used herein, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen and, therefore, a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0030] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, includes each constituent atom at approximately the natural abundance isotopic composition of the specified element. [0031] In some embodiments. Compound 1, or a pharmaceutically acceptable salt thereof, includes one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labelled” compound or salt). Examples of stable isotopes which are commercially available and suitable for tire invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example ²H. ¹³C, ¹³N, ¹⁸O, ¹⁷O, and ³¹P, respectively.

[0032] The terms “Compound 1” and “pharmaceutically acceptable salt thereof’ include the Compound 1 and any pharmaceutically acceptable salt thereof in any form, including any solid form thereof (including any amorphous or crystalline form thereol), any solvate, hydrate, or cocrystal form thereof, and any solution or suspension thereof.

[0033] As used herein, the term “about.” when used in relation to a specified amount, refers to a range encompassing that specified amount that provides a pharmacological effect equivalent to that obtained from the specified amount. The term “about” may refer to an acceptable error for the specified amount as determined by one of skill in the art, which may depend in part on how the amount is measured or determined. In some embodiments, the term “about” means within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% or 0.5% of the specified amount. In some embodiments, the term '‘about” means within 20% of the specified amount. In some embodiments, the term “about” means within 15% of the specified amount. In some embodiments, the term “about” means within 10% of the specified amount. In some embodiments, the term “about” means within 5% of the specified amount. In some embodiments, the temi “about” means within 1% of the specified amount. In some embodiments, the term “about” means within 0.5% of the specified amount.

[0034] As used herein in connection with a medical condition (e.g., chronic pain or acute pain), the term “treating” includes both providing full relief from the condition (e.g., providing full pain relief) and providing partial relief from the condition (e.g., providing partial pain relief or lessening the severity of the pain).

[0035] As used herein, the term “subject” or “patient” means an animal, preferably a mammal, and most preferably a human.

[0036] As used herein, the term “amount,” when referring to an amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a subject, refers to the mass of an equimolar amount of 2-(4-/e/7-biityl-5-chloro-2-mcthyl-phcnyl)-4-oxo- 1H- 1 ,6-naphthyridine-5-carboxamide, regardless of the actual mass of any salt, solvate, hydrate, or cocry stal form that may be administered. [0037] As used herein, the term “course of treatment.” when referring to Compound 1, or a pharmaceutically acceptable salt thereof, refers to the administration of one or more doses of the compound or salt during a period of time that is separate from any earlier or later administration of the compound or salt. Typically, Compound 1 and any metabolites thereof are substantially eliminated from a subject’s systemic circulation between courses of treatment.

[0038] As used herein, the tenn “dose,” when referring to the administration of Compound 1, or a phannaceutically acceptable salt thereof, refers to an amount of the compound or salt administered in a discrete period of time, separate from other amounts of the compound or salt that may be administered at other times during the same day or course of treatment. When a dose is administered orally, the dose may be administered in a single tablet, capsule, or other oral dosage form, or in multiple such dosage forms. [0039] As used herein, the term “first dose” refers to the first dose of Compound 1, or a phannaceutically acceptable salt thereof, that is administered in a given course of treatment. When the “first dose” is larger than the “subsequent dose” (defined below) administered in a given course of treatment, the “first dose” is sometimes referred to as a “loading dose.”

[0040] As used herein, the term “subsequent dose” refers to any dose of Compound 1, or a pharmaceutically acceptable salt thereof, that is administered after the first dose in a given course of treatment. [0041] As used herein, the term “baseline pain score” refers to a subject’s pain score, such as a score on the 11 -point Numeric Pain Rating Scale or Verbal Categorical Rating Scale, prior to beginning a course of treatment with Compound 1, or a pharmaceutically acceptable salt thereof.

[0042] As used herein, the term “11-point Numeric Pain Rating Scale” (also known as “NPRS”) refers to a pain rating scale on which a subject rates his or her pain intensity on a scale of 0 to 10, where a score of 0 denotes no pain, and a score of 10 denotes the worst pain intensity imaginable.

[0043] As used herein, the term “Verbal Categorical Rating Scale” refers to a pain rating scale on which a subject rates his or her pain intensity as none, mild, moderate, or severe.

Medical Uses of Compound 1 or a Pharmaceutically Acceptable Salt Thereof

Methods of Treatment

[0044] In one aspect, the disclosure relates to a method of treating pain in a subject, comprising administering to the subject Compound 1:

(Compound 1), or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours; (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[0045] In another aspect, the disclosure relates to a method of treating pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours; (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [0046] In some embodiments, the pain treated in the foregoing method is chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0047] In some embodiments, the pain treated in the foregoing method is chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

[0048] In some embodiments, the pain treated in the foregoing method is gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain.

[0049] In some embodiments, the pain treated in the foregoing method is neuropathic pain. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the tenn “diabetic peripheral neuropathy” includes painful diabetic peripheral neuropathy.

[0050] In some embodiments, the pain treated in the foregoing method is neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, antiretroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

[0051] In some embodiments, the pain treated in the foregoing method is musculoskeletal pain. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0052] In some embodiments, the pain treated in the foregoing method is musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, bum pain or dental pain.

[0053] In some embodiments, the pain treated in the foregoing method is inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia.

[0054] In some embodiments, the pain treated in the foregoing method is inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain.

[0055] In some embodiments, the pain treated in the foregoing method is idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

[0056] In some embodiments, the pain treated in the foregoing method is idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain.

[0057] In some embodiments, the pain treated in the foregoing method is pathological cough.

[0058] In some embodiments, the pain treated in the foregoing method is acute pain. In some aspects, the acute pain comprises acute post-operative pain.

[0059] In some embodiments, the pain treated in the foregoing method is postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain).

[0060] In some embodiments, the pain treated in the foregoing method is bunionectomy pain.

[0061] In some embodiments, the pain treated in the foregoing method is shoulder arthroplasty pain or shoulder arthroscopy pain.

[0062] In some embodiments, the pain treated in the foregoing method is herniorrhaphy pain.

[0063] In some embodiments, the pain treated in the foregoing method is abdominoplasty pain.

[0064] In some embodiments, the pain treated in the foregoing method is visceral pain. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0065] In some embodiments, the pain treated in the foregoing method is neurodegenerative disease. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0066] In some embodiments, the pain treated in the foregoing method is acute pain, sub-acutc and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus. Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration/hemiation pain, radiculopathy, facet joint syndrome, failed back surgery' syndrome, bums, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary’ tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury’, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

[0067] In some embodiments, the pain treated in the foregoing method is femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis: osteoarthritis; spinal stenosis; neuropathic low back pain: myofascial pain symdrome: fibromyalgia: temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain: IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV- associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury: painful neuromas; ectopic proximal and distal discharges; radiculopathy: chemotherapy induced neuropathic pain: radiotherapy-induced neuropathic pain: persistent/chronic post-surgical pain (e g., post amputation, post-thoracotomy, post-cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain;joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, bum pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type 1, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina- induced pain.

[0068] In some embodiments, the pain treated in the foregoing method is trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain.

[0069] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even- 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0070] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0071] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even’ 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0072] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0073] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[0074] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0075] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0076] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg. followed by subsequent doses of 35 mg every 12 hours.

[0077] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0078] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject: wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0079] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0080] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0081] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0082] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SP1D48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0083] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours: wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0084] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even’ 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain: wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0085] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0086] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0087] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0088] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[0089] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every’ 12 hours; wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0090] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0091] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0092] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[0093] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0094] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7. optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0095] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0096] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0097] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale, hi some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0098] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[0099] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00100] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SP1D48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00101] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00102] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00103] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00104] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00105] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00106] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg. followed by subsequent doses of 35 mg every 12 hours.

[00107] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00108] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even' 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00109] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00110] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00111] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00112] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every' 12 hours.

[00113] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours. [00114] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg every 12 hours.

[00115] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ’ 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00116] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject: wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SP1D48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00117] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00118] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00119] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00120] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an

11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00121] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00122] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00123] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00124] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00125] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00126] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00127] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[00128] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3. optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[00129] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00130] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an

11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensitydifference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[00131] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00132] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11 .2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours. [00133] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00134] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an

[00135] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00136] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00137] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00138] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7. optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00139] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00140] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00141] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve - 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00142] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours. [00143] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00144] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00145] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00146] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00147] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00148] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00149] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00150] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00151] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in tire subject. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00152] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00153] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute postoperative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00154] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute postoperative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every⁷ 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every⁷ 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00155] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00156] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00157] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours.

[00158] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy' pain, abdominoplasty' pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00159] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00160] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31 .2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00161] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00162] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty⁷ pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally⁷ 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00163] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every⁷ 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every⁷ 12 hours.

[00164] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty⁷ pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00165] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, follow ed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00166] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0. optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-w'eighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00167] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00168] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00169] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg. followed by subsequent doses of 90 mg even' 12 hours.

[00170] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every- 12 hours.

[00171] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every- 12 hours.

[00172] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. folloyved by subsequent doses of about 90 mg every 12 hours; yvherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; yvherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-yveighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00173] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00174] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain): wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity' difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2. optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00175] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00176] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00177] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00178] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00179] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, follow ed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00180] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein tire acute pain is lessened in the subject; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally' 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time- weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[00181] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaccutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00182] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve - 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even- 12 hours; wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00183] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 w t % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00184] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00185] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00186] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00187] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00188] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments.

Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire pharmaceutical composition comprises about 35 mg of Compound 1: about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every' 12 hours.

[00189] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251 .3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00190] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours. [00191] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00192] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00193] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours: wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00194] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium: and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00195] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00196] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even- 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00197] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours.

[00198] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate: wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or

(b) a difference from placebo in time-weighted sum of pain intensity’ difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours. [00199] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00200] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00201] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of nncrocrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium: and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251 .3 mg of lactose: about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00202] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251 .3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00203] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystallinc cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00204] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

[00205] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00206] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmcllosc sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00207] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 ^?t % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00208] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystallinc cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, tire pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00209] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; w herein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00210] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00211] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours. [00212] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00213] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours. [00214] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an

11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00215] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00216] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, tire phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00217] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every’ 12 hours.

[00218] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium: and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 2 1.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00219] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00220] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00221] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00222] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 \vt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 t % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, follow ed by subsequent doses of 5 mg even’ 12 hours.

[00223] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose: 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even’ 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00224] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[00225] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours. [00226] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00227] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00228] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(a) a first dose of 180 mg, follow ed by subsequent doses of 90 mg every 12 hours.

[00229] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; w'herein the acute pain is moderate to severe acute pain; w'herein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00230] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71 .5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours. [00231] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00232] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose: about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

[00233] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00234] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 \vt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, follow ed by subsequent doses of 5 mg even’ 12 hours.

[00235] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; w herein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 w4 % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00236] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00237] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every’ 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcry stalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00238] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours: or (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[00239] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscanncllosc sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg ever}’ 12 hours.

[00240] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00241] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00242] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

[00243] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2. -3.2 wt % of croscannellose sodium: and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1: about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00244] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystal I inc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00245] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours: wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00246] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; w herein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein tire acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, tire phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose: about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

[00247] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00248] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2. -3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg even’ 12 hours.

[00249] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00250] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate: wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium: and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00251] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every' 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every’ 12 hours. [00252] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve ' 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00253] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 w't % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every' 12 hours. [00254] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00255] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours. [00256] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg even' 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity' difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00257] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00258] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, tire phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00259] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every’ 12 hours.

[00260] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcr stalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11 .2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 2 1.3 mg of rnicrocrystallinc cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00261] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microciy stallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of rnicrocrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00262] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium: and 0.9-1. 1 wt % of magnesium stearate: wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11- point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00263] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00264] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; w herein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 w t % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00265] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; w herein the acute pain is acute postoperative pain or postsurgical pain (e.g.. bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 w t % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00266] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg even’ 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute postoperative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 . 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every’ 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00267] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscanncllosc sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg ever}’ 12 hours.

[00268] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours: wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3. optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00269] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg even' 12 hours.

[00270] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

[00271] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(b) a first dose of about 70 mg, follow ed by subsequent doses of about 35 mg every' 12 hours; w herein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, tire phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251 .3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00272] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2. optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00273] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00274] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire pharmaceutical composition comprises about 35 mg of Compound 1: about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

[00275] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 w t % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00276] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0. optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1 .0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00277] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein tire acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every⁷ 12 hours.

[00278] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy' pain, abdominoplasty⁷ pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein tire subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcry stallinc cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00279] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[00280] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every’ 12 hours; or (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium: and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours; (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours; or (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours. [00281] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00282] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every⁷ 12 hours.

[00283] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg eve - 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11-point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00284] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (a) a first dose of about 180 mg, follow ed by subsequent doses of about 90 mg eve ’ 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3. optionally 19.3 to 29.3 or about 24.3. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (a) a first dose of 180 mg, followed by subsequent doses of 90 mg every 12 hours.

[00285] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00286] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5. optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11 .2 to 31.2, optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose: about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose: about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, followed by subsequent doses of 35 mg every 12 hours.

[00287] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg, follow'ed by subsequent doses of 35 mg every 12 hours.

[00288] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 11.2 to 31.2. optionally 16.2 to 26.2 or about 21.2. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (b) a first dose of 70 mg. followed by subsequent doses of 35 mg every 12 hours.

[00289] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments.

Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg. followed by subsequent doses of 5 mg every 12 hours.

[00290] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a phannaccutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; w herein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every' 12 hours.

[00291] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein the subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00292] In another aspect, the disclosure relates to a method of treating acute pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every 12 hours; wherein the acute pain is moderate to severe acute pain; wherein tire subject has a baseline pain score of >4 on an 11- point Numeric Pain Rating Scale (NPRS) and/or a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale; wherein the acute pain is acute post-operative pain or postsurgical pain (e.g., bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain); wherein the acute pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate; wherein the subject experiences (a) a time-w eighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) a first dose of 10 mg, followed by subsequent doses of 5 mg every 12 hours.

[00293] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00294] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00295] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00296] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00297] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00298] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00299] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) 70 mg once per day. [00300] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00301] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00302] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00303] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00304] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00305] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00306] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(d) 140 mg once per day.

[00307] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00308] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of:

(e) 70 mg once per day.

[00309] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00310] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of:

(f) 10 mg once per day.

[00311] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00312] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00313] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, tire method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (1) 10 mg once per day; or (g) 5 mg every 48 hours. [00314] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every' 48 hours.

[00315] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00316] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00317] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00318] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein tire chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00319] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00320] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00321] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even' 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00322] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even’ 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00323] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day: (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is moderate to severe chronic pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00324] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day: or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day: (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00325] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00326] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00327] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day: wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00328] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00329] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00330] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in tire subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00331] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even' 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS). In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00332] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even’ 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00333] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day: (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours. [00334] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day: (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00335] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00336] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00337] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00338] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00339] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein tire chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00340] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00341] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00342] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours: wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00343] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (!) 10 mg once per day: or (g) 5 mg every 48 hours.

[00344] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day: or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-hcrpctic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00345] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00346] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00347] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00348] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00349] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00350] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00351] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00352] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even’ 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00353] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day: (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00354] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g.. post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, tire method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day: (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00355] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00356] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00357] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00358] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00359] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00360] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day. [00361] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00362] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00363] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00364] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00365] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00366] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00367] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00368] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00369] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy , diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00370] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a phannaccutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00371] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain. In some embodiments, the method comprises administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00372] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours: wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein the chronic pain is lessened in the subject. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00373] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day: (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystal line cellulose; 44-46 wt % of lactose: 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00374] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a phamiaccutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00375] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00376] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00377] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00378] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 w t % of Compound 1; 44- 46 wt % of microcry stallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00379] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00380] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; w'herein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystallinc cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day. [00381] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose: 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00382] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours: wherein the chronic pain is lessened in the subject: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00383] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (c) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44- 46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg eveiy 48 hours.

[00384] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00385] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00386] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00387] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00388] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00389] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00390] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day: wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00391] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1 .1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00392] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00393] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [00394] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline w eekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 .1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscanncllosc sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00395] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00396] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wl % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmcllosc sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00397] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00398] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, tire pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) 70 mg once per day. [00399] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00400] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00401] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaccutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00402] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1 .1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 w t % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00403] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every' 48 hours.

[00404] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in tire subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [00405] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00406] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00407] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline w eekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose: about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00408] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00409] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9- 1. 1 wt % of magnesium stearate. In some embodiments, tire phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystallinc cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00410] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium: and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day. [00411] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg even' 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00412] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00413] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of rmcrocrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00414] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every' 48 hours.

[00415] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00416] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00417] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) 70 mg once per day. [00418] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is neuropathic pain (e.g., postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00419] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g.. osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the phamraceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00420] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein tire chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00421] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g.. postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00422] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is neuropathic pain (e.g.. postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, tire pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00423] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1 .1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours.

[00424] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [00425] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00426] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00427] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00428] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcry stalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially cry stalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00429] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g.. post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; yvherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00430] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00431] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain: wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomr A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00432] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00433] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [00434] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every' 48 hours.

[00435] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g.. substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00436] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is lessened in the subject; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g.. osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00437] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00438] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the phannaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (c) 70 mg once per day. [00439] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00440] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g.. lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium: and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day.

[00441] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1: about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg eve ' 48 hours. [00442] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS): wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00443] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose: about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1. or a phannaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day: (e) 70 mg once per day: (f) 10 mg once per day: or (g) 5 mg every 48 hours.

[00444] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; (e) about 70 mg once per day; (f) about 10 mg once per day; or (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day; (e) 70 mg once per day; (f) 10 mg once per day; or (g) 5 mg every 48 hours. [00445] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystallinc cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fomi A). In some embodiments, tire pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day.

[00446] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) about 140 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, small- fibcr neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystallinc cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (d) 140 mg once per day. [00447] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments. Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, tire method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00448] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a phannaccutically acceptable salt thereof, in an amount of: (e) about 70 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day. [00449] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1. or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain: wherein the subject has a baseline w eekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (e) 70 mg once per day.

[00450] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to tire subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) about 10 mg once per day; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in tire subject; wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Fonn A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1: about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (f) 10 mg once per day. [00451] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain: wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11-point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain: wherein Compound 1 is administered in a phannaceutical composition comprising: 5-7 wt % of Compound 1: 44-46 wt % of microcrystalline cellulose: 44-46 wt % of lactose: 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystallinc cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a phannaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours.

[00452] In another aspect, the disclosure relates to a method of treating chronic pain in a subject, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) about 5 mg every 48 hours; wherein the chronic pain is moderate to severe chronic pain; wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS); wherein the chronic pain is neuropathic pain (e.g., post-herpetic neuralgia, smallfiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy), pain caused by radiculopathy (e.g., lumbosacral radiculopathy), musculoskeletal pain (e.g., osteoarthritis pain), or visceral pain; wherein the chronic pain is lessened in the subject; wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscannellose sodium; and 0.9-1. 1 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscannellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, Compound 1 is substantially crystalline (e.g., substantially pure Form A). In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscannellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the method comprises administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of: (g) 5 mg every 48 hours. [00453] In another aspect, the disclosure relates to a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with Compound 1, or a phannaceutically acceptable salt thereof. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

Compound, Pharmaceutically Acceptable Salts, and Compositions for Use

[00454] In another aspect, the disclosure relates to Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating pain in a subject in accordance with the methods described herein (including any embodiment thereof). Manufacture of Medicaments

[00455] In another aspect, the disclosure relates to the use of Compound 1, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for tire manufacture of a medicament for treating pain in a subject in accordance with the methods described herein (including any embodiment thereof).

Pharmaceutically Acceptable Salts. Pharmaceutical Compositions. Dosage Forms and Routes of Administration

Pharmaceutically Acceptable Salts

[00456] The methods described and claimed herein comprise administering to a subject Compound 1, or a pharmaceutically acceptable salt thereof. As used herein, the temr “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” of Compound 1 includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, Compound 1 or an inhibitorily active metabolite or residue thereof (e.g., the parent compound of a prodrug). The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

[00457] Pharmaceutically acceptable salts are well known in tire art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, buty rate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide. 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations fonned using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

Pharmaceutical Compositions

[00458] In the methods described and claimed herein, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered in the form of a pharmaceutical composition comprising Compound 1, or a phannaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. [00459] The term “phannaceutically acceptable carrier, adjuvant, or vehicle"’ includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating phannaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with Compound 1, or a pharmaceutically acceptable salt thereof, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the phannaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as phannaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose, starches such as com starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil, glycols, such a propylene glycol or polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogcn-frcc water, isotonic saline, Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of tire fonnulator.

Dosage Forms and Routes of Administration

[00460] The methods described and claimed herein may involve the administration of Compound 1. or a pharmaceutically acceptable salt thereof, by any route of administration effective for treating one or more of the pain diseases recited herein. Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated in dosage unit form for ease of administration and uniformity of dosage. The term “dosage unit form." as used herein, refers to a physically discrete unit of agent appropriate for the subject to be treated.

[00461] Compound 1, or pharmaceutically acceptable salt thereof, can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the condition being treated.

[00462] Liquid dosage forms for oral administration include, but are not limited to, phannaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to Compound 1, or a pharmaceutically acceptable salt thereof, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com. genn, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00463] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution. U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglyccridcs. In addition, fatty acids such as oleic acid arc used in the preparation of injcctablcs. [00464] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00465] In order to prolong the therapeutic effect of Compound 1, it may be desirable to slow the absorption of the compound, or a pharmaceutically acceptable salt thereof, from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and cry stalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00466] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing Compound 1, or a pharmaceutically acceptable salt thereof, with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00467] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, Compound 1, or a pharmaceutically acceptable salt thereof, is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, I) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00468] Solid compositions of a similar type may also be employed as fdlcrs in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00469] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g.. tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[00470] Dosage forms for topical or transdermal administration of Compound 1, or a pharmaceutically acceptable salt thereof, include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled deliver}' of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. Tire rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00471] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1.1 wt % of magnesium stearate. In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate.

[00472] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystalline cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate.

[00473] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate.

[00474] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate.

[00475] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1 .1 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein tire pharmaceutical composition is a tablet core composition. In some embodiments, tire pharmaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium: and 1.0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition.

[00476] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein the phannaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscanuellose sodium; and about 0.8 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystallinc cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition. [00477] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition.

[00478] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition. In some embodiments, the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition. In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition.

[00479] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1. 1 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the phamraceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1 .0 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous fomr).

[00480] In another aspect, the phannaceutical composition comprises about 5 mg of Compound 1: wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcry stalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; w herein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcr stalline cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium: and 0.8 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form).

[00481] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form).

[00482] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form).

[00483] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g.. less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of rnicrocrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein tire pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose: 3.0 wt % of croscarmellose sodium; and 1 .0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). [00484] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose: about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystalline cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). [00485] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose: about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form).

[00486] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially cry stalline (e.g., less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose: about 33.6 mg of croscannellose sodium; and about 11.2 mg of magnesium stearate: wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g.. less than 15% of Compound 1 is in amorphous form). In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form).

[00487] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein Compound 1 is Fonn A, as described and characterized below (e.g.. substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid forms of Compound 1 in the phamraceutical composition). In some embodiments, the pharmaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microct stall inc cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00488] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; wherein Compound 1 is Form A. as described and characterized below (e.g.. substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystalline cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate; wherein Compound 1 is Fomi A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid fomrs of Compound 1 in the pharmaceutical composition).

[00489] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the phamraceutical composition). In some embodiments, the phamraceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid fonns of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00490] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A. such as wherein Fonn A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein Compound 1 is Fonn A, as described and characterized below (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid fonns of Compound 1 in the pharmaceutical composition).

[00491] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1 .1 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in tire phannaceutical composition). In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Fonn A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the phannaceutical composition). In some embodiments, the phannaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1 .0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00492] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below' (e.g., substantially pure Form A, such as w'herein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystalline cellulose; 35.9 mg of lactose; 2.4 mg of croscannellose sodium; and 0.8 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00493] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein the phannaceutical composition is a tablet core composition; wherein Compound 1 is Fonn A, as described and characterized below (e.g.. substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below' (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid fonns of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscannellose sodium; and 5.6 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition; wherein Compound 1 is Fomi A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00494] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid fonns of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00495] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3 2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A. such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the phannaceutical composition). In some embodiments, the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form) ; wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Fonn A, such as wherein Fonn A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1 .0 wt % of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous fonn) ; wherein Compound 1 is Form A, as described and characterized below (e g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00496] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A. such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous fomi); wherein Compound 1 is Form A, as described and characterized below (e.g.. substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1: 35.9 mg of microcrystallinc cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A. as described and characterized below (e.g., substantially pure Fonn A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00497] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein Compound 1 is substantially cry stalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the phannaceutical composition). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystalline cellulose; 251.3 mg of lactose; 16.8 mg of croscarmellose sodium; and 5.6 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). [00498] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in tire phannaceutical composition). In some embodiments, the pharmaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11.2 mg of magnesium stearate; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00499] In one aspect, the disclosure relates to a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9- 1 .1 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in tire pharmaceutical composition). In some embodiments, the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous fonn); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid fomrs of Compound 1 in the pharmaceutical composition). In some embodiments, the phamraceutical composition comprises 6.25 wt % of Compound 1; 44.875 wt % of microcrystalline cellulose; 44.875 wt % of lactose; 3.0 wt % of croscarmellose sodium; and 1.0 wt % of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous fonn); wherein Compound 1 is Fonn A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00500] In another aspect, the pharmaceutical composition comprises about 5 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g.. substantially pure Form A. such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A. as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 5 mg of Compound 1; 35.9 mg of microcrystalline cellulose; 35.9 mg of lactose; 2.4 mg of croscarmellose sodium; and 0.8 mg of magnesium stearate; wherein the phannaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00501] In another aspect, the pharmaceutical composition comprises about 35 mg of Compound 1; wherein the phannaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g.. substantially pure Form A. such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A. as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises 35 mg of Compound 1; 251.3 mg of microcrystallinc cellulose; 251.3 mg of lactose; 16.8 mg of croscannellose sodium; and 5.6 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition: wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00502] In another aspect, the pharmaceutical composition comprises about 70 mg of Compound 1; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition). In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g., substantially pure Form A, such as wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in tire pharmaceutical composition). In some embodiments, the phannaceutical composition comprises 70 mg of Compound 1; 502.6 mg of microcrystalline cellulose; 502.6 mg of lactose; 33.6 mg of croscarmellose sodium; and 11 .2 mg of magnesium stearate; wherein the pharmaceutical composition is a tablet core composition; wherein Compound 1 is substantially crystalline (e.g., less than 15% of Compound 1 is in amorphous form); wherein Compound 1 is Form A, as described and characterized below (e.g.. substantially pure Form A, such as wherein Fonn A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition).

[00503] In some aspects, the disclosure relates to pharmaceutical compositions comprising Compound 1 Form A.

[00504] In some embodiments, Compound 1 Fomr A is substantially pure. In some embodiments, Compound 1 Form A is substantially crystalline (i.e., wherein less than 15% of Compound 1 is in amorphous form, wherein less than 10% of Compound 1 is in amorphous form, wherein less than 5% of Compound 1 is in amorphous form). In some embodiments, Compound 1 Form A is substantially 100% crystalline. In some embodiments. Compound 1 Form A is 100% crystalline.

[00505] In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Form A is characterized by an X- ray powder diffractogram having a signal at 5.5 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffractogram having a signal at 9.0 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffractogram having a signal at 10.4 ± 0.2 degrees two-theta.

[00506] In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two- theta, and 10.4 ± 0.2 degrees two-theta; and (b) one, two, orthree signals selected from 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, and 20.4 ± 0.2 degrees two-theta.

[00507] In some embodiments, Compound 1 Form A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two- theta, and 10.4 ± 0.2 degrees two-theta; (b) one, two, orthree signals selected from 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, and 20.4 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 8.0 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two-theta.

[00508] In some embodiments, Compound 1 Fomr A is characterized by an X-ray pow der diffractogram having signals at 5.5 ± 0.2 degrees two-theta, 8.0 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 11.1 ± 0.2 degrees two-theta, 11.7 ± 0.2 degrees two-theta, 12.8 ± 0.2 degrees two-theta. 16.0 ± 0.2 degrees two-theta. 17.3 ± 0.2 degrees two-theta. 18.7 ± 0.2 degrees two- theta, 20.4 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.9 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, 27.7 ± 0.2 degrees two-theta, 29.5 ± 0.2 degrees two-theta, and 29.9 ± 0.2 degrees two- theta.

[00509] In some embodiments, Compound 1 Fonn A is characterized by an X-ray pow der diffractogram substantially similar to FIG. 1.

[00510] In some embodiments, Compound 1 Form A is characterized by a ¹³C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8

± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7

± 0.2 ppm, 145.6 ± 0.2 ppm. 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0

± 0.2 ppm, 129.7 ± 0.2 ppm. 116.3 ± 0.2 ppm. 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4

± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm. 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm. In some embodiments, Compound 1 Form A is characterized by a ¹³C SSNMR spectrum having peaks at

179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm,

155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm,

147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm.

[00511] In some embodiments, Compound 1 Fomr A is characterized by a ^k’C SSNMR spectrum substantially similar to FIG. 2.

[00512] In some embodiments, Compound 1 Form A is characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu K_a radiation (1=1.54178 A) of: a 11.0 ± 0.1 A a 98.0 ± 0.1 b 11.2 ± 0.1 A 93.1 ± 0.1 c 15.9 ± 0.1 A y 95.8 ± 0.1

In some embodiments, the diffractometer is a Bruker diffractometer.

Solid Forms

[00513] In some aspects, the disclosure relates to a substantially crystalline Compound 1, wherein the substantially crystalline Compound 1 is selected from Compound 1 Methanol Solvate Form C and Compound 1 2-MeTHF Solvate Fonn D.

[00514] In some embodiments, the substantially crystalline Compound 1 is Compound 1 Methanol Solvate Form C. In some embodiments, Compound 1 Methanol Solvate Form C is substantially pure. In some embodiments, Compound 1 Methanol Solvate Form C is substantially 100% crystalline. In some embodiments, Compound 1 Methanol Solvate Fonn C is 100% crystalline.

[00515] In some embodiments, Compound 1 Methanol Solvate Form C is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Methanol Solvate Fonn C is characterized by an X-ray powder diffractogram having a signal at 5.8 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Methanol Solvate Fonn C is characterized by an X-ray powder diffractogram having a signal at 9.8 ± 0.2 degrees two-theta. In some embodiments, Compound 1 Methanol Solvate Form C is characterized by an X-ray powder diffractogram having a signal at 21.3 ± 0.2 degrees two-theta.

[00516] In some embodiments. Compound 1 Methanol Solvate Form C is characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, or eight signals selected from 5.8 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta. 9.8 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two- theta, 15.7 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, 19.8 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta. [00517] In some embodiments, Compound 1 Methanol Solvate Form C is characterized by an X-ray powder diffractogram having signals at 5.8 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two- theta, 19.8 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta.

[00518] In some embodiments, Compound 1 Methanol Solvate Form C is characterized by an X-ray powder diffractogram substantially similar to FIG. 3.

[00519] In some embodiments. Compound 1 Methanol Solvate Form C is characterized by a ¹³C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 177.2 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.0 ± 0.2 ppm, 157.3 ± 0.2 ppm, 152.7 ± 0.2 ppm, 151.7

± 0.2 ppm, 150.7 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.6 ± 0.2 ppm, 145.3 ± 0.2 ppm, 134.1 ± 0.2 ppm, 133.3

± 0.2 ppm, 132.6 ± 0.2 ppm. 131.2 ± 0.2 ppm, 130.3 ± 0.2 ppm, 115.4 ± 0.2 ppm, 114.5 ± 0.2 ppm, 113.9

± 0.2 ppm, 111.2 ± 0.2 ppm. 50.1 ± 0.2 ppm, 36.4 ± 0.2 ppm, 31.0 ± 0.2 ppm. 29.3 ± 0.2 ppm, 19.9 ± 0.2 ppm, and 18.3 ± 0.2 ppm.

[00520] In some embodiments. Compound 1 Methanol Solvate Form C is characterized by a ^ljC SSNMR spectrum having peaks at 177.9 ± 0.2 ppm, 177.2 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.0 ± 0.2 ppm, 157.3 ± 0.2 ppm, 152.7 ± 0.2 ppm. 151.7 ± 0.2 ppm, 150.7 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.6 ± 0.2 ppm, 145.3 ±

0.2 ppm, 134.1 ± 0.2 ppm. 133.3 ± 0.2 ppm. 132.6 ± 0.2 ppm, 131.2 ± 0.2 ppm, 130.3 ± 0.2 ppm, 115.4 ±

0.2 ppm, 114.5 ± 0.2 ppm. 113.9 ± 0.2 ppm. 111.2 ± 0.2 ppm. 50.1 ± 0.2 ppm, 36.4 ± 0.2 ppm, 31.0 ± 0.2 ppm, 29.3 ± 0.2 ppm, 19.9 ± 0.2 ppm, and 18.3 ± 0.2 ppm.

[00521] In some embodiments. Compound 1 Methanol Solvate Form C is characterized by a ^ljC SSNMR spectrum substantially similar to FIG. 4.

[00522] In some embodiments, the substantially crystalline Compound 1 is Compound 1 2-MeTHF Solvate Form D. In some embodiments, Compound 1 2-MeTHF Solvate Form D is substantially pure. In some embodiments. Compound 1 2-MeTHF Solvate Form D is substantially 100% crystalline. In some embodiments, Compound 1 2-MeTHF Solvate Form D is 100% crystalline.

[00523] In some embodiments. Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.4 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, and 17.0 ± 0.2 degrees two-theta. In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram having a signal at 5.4 ± 0.2 degrees two-theta. In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram having a signal at 8.6 ± 0.2 degrees two-theta. In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram having a signal at 17.0 ± 0.2 degrees two-theta. [00524] In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram having one, two, three, four, five, six, or seven signals selected from 5.4 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 17.0 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, and 22.1 ± 0.2 degrees two-theta.

[00525] In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-raypowder diffractogram having signals at 5.4 ± 0.2 degrees two-theta, 8.6 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 17.0 ± 0.2 degrees two-theta, 17.9 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two- theta, and 22.1 ± 0.2 degrees two-theta.

[00526] In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by an X-ray powder diffractogram substantially similar to FIG. 5.

[00527] In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by a ¹³C SSNMR spectrum having one, two. three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.6 ± 0.2 ppm, 177.0 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.3 ± 0.2 ppm, 169.5 ± 0.2 ppm, 169.1 ± 0.2 ppm, 157.1

± 0.2 ppm, 156.4 ± 0.2 ppm, 152.9 ± 0.2 ppm, 151.8 ± 0.2 ppm, 150.4 ± 0.2 ppm, 149.7 ± 0.2 ppm, 148.6

± 0.2 ppm, 147.3 ± 0.2 ppm, 145.3 ± 0.2 ppm, 144.6 ± 0.2 ppm, 134.6 ± 0.2 ppm, 133.7 ± 0.2 ppm, 133.0

± 0.2 ppm, 132.5 ± 0.2 ppm. 131.1 ± 0.2 ppm, 130.2 ± 0.2 ppm, 116.4 ± 0.2 ppm, 115.4 ± 0.2 ppm, 114.4

± 0.2 ppm, 113.5 ± 0.2 ppm. 112.9 ± 0.2 ppm. 111.5 ± 0.2 ppm, 110.9 ± 0.2 ppm, 75.1 ± 0.2 ppm. 68.9 ± 0.2 ppm, 36.3 ± 0.2 ppm, 32.3 ± 0.2 ppm, 29.8 ± 0.2 ppm. 29.2 ± 0.2 ppm, 25.0 ± 0.2 ppm, 23.2 ± 0.2 ppm, 19.4 ± 0.2 ppm, and 17.6 ± 0.2 ppm.

[00528] In some embodiments. Compound 1 2-MeTHF Solvate Form D is characterized by a ¹³C SSNMR spectrum having peaks at 177.6 ± 0.2 ppm, 177.0 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.3 ± 0.2 ppm, 169.5 ± 0.2 ppm, 169.1 ± 0.2 ppm. 157.1 ± 0.2 ppm, 156.4 ± 0.2 ppm, 152.9 ± 0.2 ppm, 151.8 ± 0.2 ppm, 150.4 ±

0.2 ppm, 149.7 ± 0.2 ppm. 148.6 ± 0.2 ppm. 147.3 ± 0.2 ppm, 145.3 ± 0.2 ppm, 144.6 ± 0.2 ppm, 134.6 ±

0.2 ppm, 133.7 ± 0.2 ppm. 133.0 ± 0.2 ppm. 132.5 ± 0.2 ppm. 131.1 ± 0.2 ppm. 130.2 ± 0.2 ppm, 116.4 ±

0.2 ppm, 115.4 ± 0.2 ppm, 114.4 ± 0.2 ppm, 113.5 ± 0.2 ppm, 112.9 ± 0.2 ppm, 111.5 ± 0.2 ppm, 110.9 ±

0.2 ppm, 75.1 ± 0.2 ppm, 68.9 ± 0.2 ppm, 36.3 ± 0.2 ppm, 32.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 29.2 ± 0.2 ppm, 25.0 ± 0.2 ppm, 23.2 ± 0.2 ppm, 19.4 ± 0.2 ppm, and 17.6 ± 0.2 ppm.

[00529] In some embodiments, Compound 1 2-MeTHF Solvate Form D is characterized by a ¹³C SSNMR spectrum substantially similar to FIG. 6.

Additional Therapeutic Agents

[00530] It will also be appreciated that Compound 1, pharmaceutically acceptable salts of Compound 1, and pharmaceutically acceptable compositions of Compound 1 can be employed in combination therapies, that is, the compounds, salts, and phannaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of tire desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin, naphthylalkanones such as Nabumetone, oxicams such as Piroxicam, para-aminophenol derivatives, such as Acetaminophen, propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin, salicylates such as Aspirin, Choline magnesium tri salicylate, Diflunisal, fenamates such as meclofenamic acid, Mefenamic acid, and pyrazoles such as Phenylbutazone), or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone. Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition. Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[00531] In another embodiment, additional appropriate therapeutic agents are selected from the following: [00532] (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[00533] (2) a nonsteroidal antiinflammator drug (NS AID), e.g. aspirin, diclofenac, diflunisal, etodolac, fcnbufcn, fenoprofen, flufcnisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[00534] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental: [00535] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[00536] (5) a histamine (Hi) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[00537] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[00538] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[00539] (8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3- fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3.4-dihydro-2(lH)-quinolinone:

[00540] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5- (2 -pyridyl) quinazoline;

[00541] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[00542] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vim pat ®) or valproate:

[00543] (12) a tachykinin (NK) antagonist, particularly an NK.-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,l 1 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H- [l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4- triazol-3-one (MK-869). aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]- methylamino J -2-phenylpiperidine (2 S, 3 S) ;

[00544] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[00545] (14) a COX-2 selective inhibitor, e.g. cclccoxib, rofccoxib, parccoxib, valdccoxib, dcracoxib, etoricoxib, or lumiracoxib; [00546] (15) a coal-tar analgesic, in particular paracetamol;

[00547] (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone. amisulpride, balaperidone, palindore. eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

[00548] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC- 15300);

[00549] (18) a beta-adrenergic such as propranolol;

[00550] (19) a local anesthetic such as mexiletine;

[00551] (20) a corticosteroid such as dexamethasone;

[00552] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_]B/ID agonist such as eletriptan. sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[00553] (22) a 5-HT₂A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL- 100907);

[00554] (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[00555] (24) Tramadol®¹, Tramadol ER (Ultram ER®)), IV Tramadol, Tapentadol ER (Nucynta®)); [00556] (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)- 2,3,6,7,12.12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',r:6,l]-pyrido[3,4-b]indole- 1,4-dione (IC-351 or tadalafil). 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo[5.1-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l- ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-cf]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)- 3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7E7-pyrazolo[4,3- ]pyrimidin-7-one, 5-[2-ethoxy-5-(4- ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7-oxo-3-propyl-6,7-dihydro-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; [00557] (26) an alpha-2 -delta ligand such as gabapentin (Neurontin®)), gabapentin GR (Gralise®)), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3 -methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-mcthyl-bicyclo[3.2.0]hcpt-3-yl)-acctic acid, (3S,5R)-3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)- 4H-[l,2,4]oxadiazol-5-one, C-[ l-( 1 H-tctrazol-5-ylmcthyl)-cycloheptyl ] -methylamine, (3S,4S)-(1- aminomethyl-3 ,4-dimethyl-cyclopentyl)-acetic acid, (3 S,5R)-3 -aminomethyl-5 -methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid. (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3- amino-4,5-dimethyl-heptanoic acid and (3R,4R.5R)-3-amino-4,5-dimethyl-octanoic acid;

[00558] (27) a cannabinoid such as KHK-6188;

[00559] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[00560] (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram. d,l-fenfluramine, femoxetine. ifoxetine, cyanodothiepin. litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[00561] (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

[00562] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine. clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[00563] (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l-iminoethyl)amino]ethyl]- L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l- iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5- heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S- pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5- (trifluoromethyl)phenyl]thio] -5 -thiazolebutanol, 2-[[(lR,3S)-3-amino-4- hydroxy-l-(5-thiazolyl) butyl ]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4- hydroxy-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3- chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide;

[00564] (33) an acetylcholinesterase inhibitor such as donepezil:

[00565] (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as 7V-[( {2-[4-(2-ethyl-4,6- dimethyl-lH- imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(15)-l- ({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl]amino)ethyl]benzoic acid; [00566] (35) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-yhnethyl-4-hydroxy-chroman-7-yl)- cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[00567] (36) a 5 -lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro- 2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3- pyridylmethyl)-l,4-benzoquinone (CV-6504);

[00568] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;

[00569] (38) aNavl.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ- 00432979. FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011/140425 (US2011/306607); WO2012/106499 (US2012196869); WO2012/112743 (US2012245136); WO2012/125613 (US2012264749), WO2012/116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, W02013/109521 (US2015005304), CN111217776, W02020/117626, WO2021/252822, WO2021/252818, WO2021/252820, W02014/201173, WO2012/125973, WO2013/086229, WO2013/134518, WO2014/201206, or W02016/141035 the entire contents of each application hereby incorporated by reference;

[00570] (38a) a Navl.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[l,2-a]pyrazine-1.4'- piperidine]-l'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-l-[l'-[3-methoxy-4-[2- (trifluoromethoxy)ethoxy]benzoyl]-2,4-dimetliyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'- piperidine]-6-yl]ethanone, [8-fhioro-2-methyl-6-(trifhroromethyl)spiro[3,4-dihydropyrrolo[l,2- a]pyrazine- 1 ,4'-piperidine] - 1 '-yl] -(4-isobutoxy-3 -methoxy-phenyl)methanone. 1 -(4-bcnzhydry Ipipcrazin- 1 -y 1) -3 - [2-(3 ,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3 -methoxy-phenyl)-[2 -methyl -6- (trifluoromethyl)spiro [3 ,4-dihydropyrrolo [ 1 ,2-a]pyrazine- 1.4'-piperidine] - 1 '-yl]methanone, [8-fluoro-2- methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-l'-yl]-(5-isopropoxy- 6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-( 1,1, 2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[ 1 ,2-a]pyrazine- 1 ,4'-piperidine]- l'-yl] methanone, 5-[2-methyl- 4-[2-metliyl-6-(2,2,2-trifluoroacetyl)spiro[3.4-dihydropyrrolo[1.2-a]pyrazine-l,4'-piperidine]-r- carbonyl]phenyl]pyridine-2 -carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4- dihydro-2H-pyrrolo [ 1.2-aJpyrazine- 1.4'-piperidine] - 1 '-yljmethanone, 2.2.2-trifluoro- 1 -[ 1 '-[3-methoxy-4- [2-(trifhioromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]- 6-yl]ethanone, 2,2,2-trifluoro-l-[r-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo| 1 ,2-a]pyrazinc- 1 ,4'-pipcridinc]-6-yl]cthanonc, 2,2,2-trifluoro- 1 -[ 1 '-(5- isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6- yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo [ 1 ,2-a]pyrazine- 1 ,4'-piperidine] - 1 '-yl]methanone, 2,2,2-trifluoro- 1 -[ 1 '-(5- isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]- 6-yl]ethanone, l-[(3S)-2,3-dimethyl-r-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[ 1 ,2-a]pyrazine- 1 ,4'-piperidine] -6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6- (trifluoromethylJspirofS^-dihydropyrrolofl^-alpyrazine-l.d'-piperidinel-r-yll-FS-methoxy-d-f lR)-!- mcthylpropoxy Iphcnyl |mcthanonc. 2,2,2-trifluoro- 1 -[ 1 '-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)- 2,4-dimethyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]ethanone, l-[l'-[4-methoxy-3- (trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]-2,2- dimethyl-propan-l-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[ 1 ,2-a]pyrazine- 1 ,4'-piperidine] - 1 '-yl]methanone, [2-methyl-6-( 1 - methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-l'-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(l-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-( 1,1, 2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[ 1 ,2 -a] pyrazine- 1 ,4'-piperidine]- 1 '-yl]methanone .

[00571] (39) a Navi .8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008/135826 (US2009048306), W02006/011050 (US2008312235), W02013/061205 (US2014296313). US20130303535. W02013131018. US8466188, WO2013114250 (US2013274243), W02014/120808 (US2014213616), W02014/120815 (US2014228371) W02014/120820 (US2014221435), W02015/010065 (US20160152561), WO2015/089361 (US20150166589), WO2019/014352 (US20190016671), WO2018/213426, WO2020/146682, WO2020/146612, W02020/014243, W02020/014246, W02020/092187, W02020/092667 (US2020140411), WO2020/144375, W02020/261114, W02020/140959, WO2020/151728, WO2021/032074, WO2021/047622 (CN112479996), WO2021/113627, WO2021/257490. WO2021/257420, WO2021/257418, WO2022/263498, WO2022/235558, WO2022/235859, WO2022/256622, WO2023/138599, WO2023/205463, WO2023/205465, WO2023/205468, WO2023/205778, WO2023/211990, WO2023/238065, WO2024/041613, WO2024/046253, W02024/046409, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each application hereby incorporated by reference:

[00572] (39a) a Navi.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4- (pcrfluorocthyl)bcnzamidc, 4,5-dichloro-2-(4-fluorophcnoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamide, N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide. 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4- yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzamide, 5- chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)benzarnide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo- 1.2- dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo- l,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(2- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-lH- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4- (trifluoromethyl)benzoyl] amino] -2-oxo- 1 -pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl- d3)phenoxy)-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl- d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate, 3-(4- fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4- fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2 -carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N- (3 -sulfamoylphenyl)quinoxaline-2 -carboxamide, 3 -(4-chloro-2-methoxyphenoxy)-N-(3 - sulfamoylphenyl)quinoxaline-2 -carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid. 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2- (4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)- N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4- (trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2 -carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2 -carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid. 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2.3-dihydro-lH- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2 -carboxamide, N-(3-cyanophcnyl)-3-(4-fluoro-2-mcthoxyphcnoxy)quinoxalinc-2 -carboxamide, N-(4-carbamoylphcnyl)- 3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy )phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2- methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4.5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(te77-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5 -(4,5 -dichloro-2-(4- (trifluoromethoxy)plienoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5 -(4,5 -dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4.5-dichloro-2-(2-chloro-4-fluorophenoxy (benzamide (picolinic acid, 5-(4,5-dichloro-2-(4-fluoro- 2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N- (3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide. 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4.5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl (benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromcthyl)bcnzamidc, 2-(4-fluoro-2-mcthylphcnoxy)-N-(3-sulfamoylphcnyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-mcthoxyphcnoxy)-N-(3-sulfamoylphcn l)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4- fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3- sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- [2-methoxy-4-(trifluorometlroxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3 -carbamoyl -4-fluoro- phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-

(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-| |3-chloro-2-fliioro-6-|2-mcthoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2 -carboxamide, 4-[[2-fluoro-6-[2-

(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy )plienoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-

(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-

(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-

(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4- trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5- [2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2- (difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-

(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-

(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6- [2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)pheiioxy]-4-(trifluorometliyl)benzoyl]amino]pyridiiie-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide. N-(3-carbamoyl-4-fluoro-phenyl)-2-|2-methoxy-4-

(trifluoromethoxy)phenoxy] -5-( 1 , 1 ,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro- 6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2 -carboxamide, N-(3-carbamoyl-4- fluoro-phcnyl)-2-fluoro-6-[2-fluoro-4-(trifluoromcthoxy)phcnoxy]-3-(trifluoromcthyl)bcnzamidc, 4-[[4- cyclopropyl-2 -fluoro-6-[2 -methoxy -4-(tri fluoromethoxy )phenoxy]benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fhioro-phenyl)-2-fluoro-6- (4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4- (trifluoromethoxy)plienoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2 -carboxamide;

[00573] (40) a combined Navi. and Navi.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[00574] (41) a 5-HT3 antagonist, such as ondansetron;

[00575] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[00576] (43) a nicotinic receptor antagonist, such as varenicline;

[00577] (44) an N-type calcium channel antagonist, such as Z-160;

[00578] (45) a nerve growth factor antagonist, such as tanezumab:

[00579] (46) an endopeptidase stimulant, such as senrebotase;

[00580] (47) an angiotensin II antagonist, such as EMA-401 ;

[00581] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®)); [00582] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[00583] (50) bupivacaine and meloxicam combination (e g., HTX-01 l/Zynrelef™).

[00584] In one embodiment, the additional appropriate therapeutic agents are selected from V-l 16517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®), AVP-923. Perampanel (E-2007), Ralfmamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

[00585] In another embodiment, the additional appropriate therapeutic agents are selected from N-(6- amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-l-methyl-lH-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-lH-imidazol-2-yl)methyl)oxetan-3-amine.

[00586] In another embodiment, the additional therapeutic agent is selected from a GlyT2/5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008. CMX-020, NEO6860, FTABS.

CNTX4975. MCP101, MDR16523. or MDR652, a EGR1 inhibitor such as Bnvoglide (AYX1). an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

[00587] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590). [00588] In another embodiment, the additional therapeutic agent is a Navi.7 blocker such as ST-2427, ST-2578 and those disclosed in WO2010/129864, WO2015/157559, WO2017/059385, WO2018/183781, WO2018/183782, W02020/072835, and/or WO2022/036297 the entire contents of each application hereby incorporated by reference.

[00589] In another embodiment, the additional therapeutic agent is selected from ASP18071, CC-8464, ANP-230. ANP-231, NOC-100. NTX-1175. ASN008, NW3509, AM-6120. AM-8145, AM-0422, BL- 017881, NTM-006, Opiransenn (Unafra™), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC- 17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, and XT-150.

[00590] In another embodiment, tire additional therapeutic agent is selected from Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant. TRV045. RTA901. NRD1355-E1, MT-8554. LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, 1N1011-N17, JMKX000623/ODM-111, ETX-801, OLP-1002, ANP-230/DSP-2230, 1N1011-N17, DSP-3905 and ACD440.

[00591] In another embodiment, the additional therapeutic agent is selected from HRS4800, ODM- 111/JMKX 000623, LX9211, LY3556050, LY3857210, CFTX01554/CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, OLP-1002, ATX01, ANP230, CC-8464, 1N1011-N17, ST-2427, MSD199. FZ008. VYNAV-01. BL-017881, Profervia (Cilnidipine), LS-04, vixotrigine, FX30I/PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[00592] The amount of additional therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Tire amount of additional therapeutic agent in tire presently disclosed compositions may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

EXAMPLES

Abbreviations

[00593] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings:

General Experimental Details

Solid State NMR

[00594] Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO: rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using ’H MAS TI saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹³C cross-polarization (CP) MAS experiments. The CP contact time of carbon CPMAS experiments was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Halin match was optimized on external reference sample (glycine). All carbon spectra were recorded with proton decoupling using TPPM15 or SPINAL64 decoupling sequence with the field strength of approximately 100 kHz.

X-ray Powder Diffraction

[00595] X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel ID Medipix-2 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 A). The powder sample was placed in a back filled sample holder and loaded into the instrument. The sample was scanned over the range of about 3° to about 40° 20 with a step size of 0.0131303° and 49.725s per step.

Example 1

Preparation of 2-(4-tert-butyl-5-chloro-2-methyl-phenyl)-4-oxo-lH-1.6-naphthyridine-5-carboxamide (Compound 1)

(Compound 1)

[00596] Compound 1 can be prepared by methods known in the art, including the methods described in International Publication No. WO 2023/205778 (Example 5), which is incorporated by reference in its entirety. Preparation of Compound 1 Form A

[00597] Compound 1 amorphous material (40 mg) was added to a 2 mL glass vial and the vial was crimped. The solids were diluted and suspended in methanol (400 pL). A stir bar was added and the vial was placed on a shaker block (20 °C, 800 rpm) for 1 hour. The solids were filtered and dried in an oven overnight (40 °C, under vacuum, nitrogen bleed).

X-Ray Powder Diffraction

[00598] The XRPD pattern for Compound 1 Fonn A fonn was recorded using the procedure described in the General XRPD Method. Tire XRPD diffractogram for Compound 1 Form A is provided in FIG. 1, and the data are summarized in the following table:

Solid-State ¹³ C NMR

[00599] The ¹³C SSNMR of Compound 1 Form A was acquired using the procedure described in the

General SSNMR Method. The ^ljC SSNMR spectrum for Compound 1 Form A is provided in FIG. 2, and the data are summarized in the following table:

Single Crystal Elucidation of Compound 1 Form A

[00600] Single crystals having the Compound 1 Form A structure were grown by making a slurry of Compound 1 n-propanol solvate B in 70% propanol/water at 60 °C. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu K_a radiation (1=1.54178 A) and a CPAD detector.

The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122), and results are summarized in the following table:

Preparation of Compound 1 n-Propanol Solvate B

[00601] Compound 1 amorphous material (40 mg) was added to a 2 mL glass vial and the vial was crimped. Compound 1 was diluted and suspended in w-propanol (400 pL). A stir bar was added and the vial was placed on a shaker block (20 °C, 800 rpm) for 24 hours. The solids were filtered and dried in an oven overnight (40 °C, under vacuum, nitrogen bleed).

Preparation of Compound 1 Methanol Solvate Form C

[00602] Compound 1 Metiianol Solvate Form C was obtained by exposing Compound 1 Neat Form B to methanol vapors for two days. Compound 1 Neat Form B can be prepared by methods known in the art, including the methods described in International Publication No. WO 2025/090516 (Example 2), which is incorporated by reference in its entirety.

[00603] The XRPD pattern for Compound 1 Methanol Solvate Form C was recorded using the procedure described in the General XRPD Method. The XRPD diffractogram for Compound 1 Methanol Solvate Fonn C is provided in FIG. 3, and the data are summarized in the following table:

[00604] The ¹³C SSNMR of Compound 1 Methanol Solvate Fonn C was acquired using the procedure described in the General SSNMR Method. The ¹³C SSNMR spectrum for Compound 1 Methanol Solvate Form C is provided in FIG. 4, and the data are summarized in tire following table: Preparation of Compound 1 2-MeTHF Solvate Form D

[00605] Compound 1 2-MeTHF Solvate Form D was obtained by slow drying of Compound 1 2-MeTHF solvate Form C at ambient temperature and pressure for 1 hour. Compound 1 2-MeTHF solvate Form C is described in WO 2025/090516 (Example 14), which is incorporated by reference in its entirety.

[00606] The XRPD pattern for Compound 1 2-MeTHF Solvate Form D was recorded using the procedure described in the General XRPD Method. The XRPD diffractogram for Compound 1 2-MeTHF Solvate Form D is provided in FIG. 5, and the data are summarized in the following table:

[00607] Tire ¹³C SSNMR of Compound 1 2-MeTHF Solvate Form D was acquired using the procedure described in the General SSNMR Method. Tire ¹³C SSNMR spectrum for Compound 1 2-MeTHF Solvate Form D is provided in FIG. 6. and the data are summarized in the following table:

[00608] Compound 1 Form A also can be prepared by the following method.

[00609] Synthesis of Bi

[00610] Step 1: Synthesis of 4-(tert-butyl)-5-chloro-2-methylphenol (BM)

^Cl\^s/^OH f-BuOH (3.0 eq)

|| | cone. H₂SO₄ (2.0 eq)^ n-heptane (10 V)

5-chloro-2methylphenol 18-25 C, 16 h

B-1-3

[00611] 5 -chloro-2 -methylphenol (40.4 kg, 1.0 eq.) (B1.3) was charged to a clean and dry reactor, n- Heptane (275.7 kg, 10 V) and t-BuOH (63.02 kg, 3 eq.) were charged to the reactor followed by cone. H2SO4 (55.75 kg, 2 eq). The reaction mixture was stirred at 18-25 °C. After reaction completion, as determined by HPLC. the reaction mixture was cooled to 0-10 °C. H2O (282.8 kg. 7 V) was charged and the layers were separated. The organic layer was collected in a clean container. The aqueous layer was back extracted with n-heptane (55.3 kg, 2 V). The combined organic layers were washed with 10% NaCl (81 kg) and the organic layer was dried over anhydrous MgSCfi (22.2 kg). The organic layer was filtered. The filtrate was concentrated under reduced pressure to afford 4-(tert-butyl)-5-chloro-2 -methylphenol (Bi.

2) as a brown oil (78.1 kg, 92% isolated yield, 93% pure by HPLC). H NMR (400 MHz, CDCT) 5 1.44 (s, 9 H), 2.20 (s, 3 H), 6.80 (s, 1 H), 7.13 (s, 1 H). The crude 4-(tert-butyl)-5-chloro-2-methylphenol (BI.₂) was used directly in the next step without further purification.

[00612] Step 2: Synthesis of 4-(/e/7-butyl)-5-chloro-2-methylphenyl trifluoromethanesulfonate (BM)

Tf O (1 2 e ) 0-25 C, 1 h

[00613] 4-(tert-butyl)-5-chloro-2-methylphenol (BI.₂) (53 kg, 1.0 eq.) and toluene (401.21 kg) were charged to a reactor. Pyridine (42.4 kg, 2 eq.) and Tf₂O (90.63 kg, 1.2 eq.) were charged to the resulting mixture at 0-10 °C. The reaction mixture was stirred at 0-10 °C. After reaction completion, as determined by HPLC, the mixture was treated with 1 M HC1 (107.4 kg). The layers were separated. The organic layer was washed with 10% KHCOs (530 kg). The organic phase was washed with 10% NaCl (106 kg) and then treated with activated carbon (8.48 kg). The charcoal was filtered off and the filtrate was concentrated to afford 4-(tert-butyl)-5-chloro-2-methylphenyl trifluoromethane sulfonate (B ) as a lightyellow oil (89 kg, 100% yield, 92.4% purity by HPLC). 'HNMR (400 MHz, CDC1₃) 5 1.47 (s, 9 H), 2.35 (s, 3 H), 7.25 (s, 1 H), 7.33 (s, 1 H); ¹⁹F NMR (376 MHz, CDCL) 5 -73.75. The crude 4-(tert-butyl)-5- chloro-2 -methylphenyl trifluoromethanesulfonate (BM) was used directly in the next step without further purification.

[00614] Step 3: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (Bi)

[00615] 4-(tert-butyl)-5-chloro-2 -methylphenyl trifluoromethanesulfonate (BM) (89.3 kg, 1.0 eq.) and 1,4-dioxane (92 kg) were charged to a reactor. Bic(pinacolato)diboron (79.05 kg, 1.1 eq.) and KOAc (66.28 kg, 3.0 eq.) were charged, and the mixture was degassed with nitrogen. PdCl₂(dppf) (6.43 kg, 0.03 eq.) was charged to the reactor and the resulting mixture was stirred at 100-105 °C. After reaction completion, as determined by HPLC analysis, the mixture was cooled to 20 °C. Activated carbon (17.86 kg) and ^-heptane (807.82 L) were charged and the reaction mixture was stirred at 20 °C. The mixture was filtered, and tire filtrate was concentrated. A-heptane (131.35 L) was charged, and the mixture was concentrated. MeOH (113.06 L) was charged, and the mixture was concentrated. The methanol solution was heated to about 50 to about 55 °C and stirred for 2~3 h, and then slowly cooled to about 15 to about 20 °C. Hie resulting slurry was filtered, and the wet cake was dried under vacuum to afford 2-(4-(tert- butyl)-5-chloro-2-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Bi) as a white solid (72.8 kg, 88% yield), m/z = [M+H]⁺ 309.1; 'H NMR (400 MHz, CDC13) 5 1.35 (s, 12 H), 1.49 (s, 9 H), 2.51 (s, 3 H), 7.22 (s, 1 H), 7.74 (s, 1 H).

[00616] Synthesis of 2,4-dichloro-l,6-naphthyridine-5-carbonitrile (A₂)

[00617] Step 1: Synthesis of methyl 4-aminonicotinate (AI_₄)

[00618] 3-bromopyridin-4-amine (A1.5) (60 kg, 346.8 mol. 1 eq.), EtsN (36.77 kg, 364.1 mol, 1.05 eq.), DPPF (317.2 g, 0.57 mol, 0.00165 eq.) and MeOH (225 L) were charged to an autoclave and agitation was started. Pd(OAc)₃ (85.6 g, 0.38 mol, 0.0011 eq) was then charged and the mixture was stirred under CO (100 psi) at 80 °C. Afterthe reaction was completed, as determined by HPLC analysis, the mixture was concentrated in vacuo to give the crude product. H₂O (3.5 V) was charged, and the resulting mixture was stirred at 20 °C. The resulting suspension was filtered, and the wet cake was dried under reduced pressure to give methyl 4-aminonicotinate (A2.4) (42 kg. 276.3 mol, 79.6% yield) as an off-white solid, m/z = [M+H] ' 153.1; H NMR (400 MHz. DMSO-de) 5 8.66 (s. 1H), 8.07 (s, 1H), 7.27 (s, 2H), 6.68 (d. J = 4.0 Hz, 1H), 3.81 (s, 3H). [00619] Step 2: Synthesis of ethyl 4-hydroxy-2-oxo-l,2-dihydro-l,6-naphthyridine-3-carboxylate (AI-₃)

[00620] Methyl 4-aminonicotinate (A1.4) (42 kg, 276.3 mol, 1 eq) and diethyl malonate (53.1 kg, 331.5 mol, 1.2 eq.) were charged to a reactor at 25 °C followed by EtOH (294 L) and EtONa (24.4 kg. 359.2 mol. 1.3 eq.). The mixture was stirred at 90 °C. After the reaction was completed, as detennined by HPLC analysis, the reaction mixture was acidified with HC1 (1.5 M) to pH 3~4. The mixture was then concentrated in vacuo. The slurry was cooled to 25 °C and filtered. The filter cake was dried under vacuum to afford crude ethyl 4-hydroxy-2-oxo-l,2-dihydro-l,6-naphthyridine-3-carboxylate (A1.3) (~65 kg), which was used directly in the next step without further purification, m/z = [M-OEt]⁺ 189.0; ^]H NMR (400 MHz, DMSO-cL): 8 10.02 (s. 1H), 8.78 (s, 1H), 8.20 (d, J= 5.4 Hz, 1H), 6.87 (d, J = 6.1 Hz, 1H), 4.03 (q, J= 1A Hz, 2H). 1.19 (t. J= 7.0 Hz. 3H).

[00621] Step 3: Synthesis of 4-hydroxy-l,6-naphthyridin-2(lH)-one (Ai.₂)

[00622] Crude ethyl 4-hydroxy-2-oxo-l,2-dihydro-l,6-naphthyridine-3-carboxylate (A1.3) (64.8 kg) and toluene (32 L) were charged to a reactor followed by HC1 (453 L, 27% w/w% in H₂O). Tire mixture was stirred at 90 °C. After the reaction was completed, the mixture was cooled to 25 °C and the layers were separated. Tire aqueous layer was cooled to 0 °C and basified with 30% NaOH to pH 5-6. Tire resulting slurry was filtered and the filter cake was triturated with MeCN (5 V). The wet cake was dried under vacuum to afford 4-hydroxy-l,6-naphthyridin-2(lH)-one (Ai.₂) (33.5 kg) as an off-white solid, m/z = [M+H]⁺ 163.0; ’H NMR (400 MHz, DMSO-d₆) 8 11.97 (s, 1H), 8.97 (s, 1H), 8.53 (d../ - 8.0 Hz. 1H), 7.36 (d, J= 8.0 Hz, 1H). 5.91 (s, 1H).

[00623] Step 4: Synthesis of 2,4-dichloro-l,6-naphthyridine (A₂.i)

[00624] 4-Hydroxy-l,6-naphthyridin-2(lH)-one (AI.₂) (33.5 kg, 206.6 mol, 1.0 eq.) and toluene (67 L) were charged to a reactor followed by POCI3 (88 kg, 574.3 mol, 2.78 eq.). The mixture was stirred at 110 °C. After the reaction was completed, as determined by HPLC analysis, the mixture was concentrated in vacuo. The residue was diluted with CH2CI2 (5 V), quenched into ice water (5 V), and then the resulting mixture was poured into sat. NaHCOv The resulting mixture was filtered, and the layers of the bi-phasic filtrate were separated. The aqueous phase was extracted with EtOAc. All organic phases were combined, washed with brine, dried over anhydrous Na₂SC>4, filtered, and concentrated under vacuum. The residue was triturated with MTBE (2 V) to afford 2,4-dichloro-l,6-naphthyridine (A2-1) (33.6 kg, 168.8 mol, 81.7% yield) as a yellow solid, m/z = [M³⁵C1³⁵C1+H]⁺ 199.0; [M³⁵C1³⁷C1+H]⁺ 201.0; [M³⁷C1³⁷C1+H]⁺ 203.0 (9:6: 1 ratio); 'HNMR (400 MHz, DMSO-de) 3 9.57 (s, 1H), 8.91 (d, 4.0 Hz, 1H), 8.12 (s, 1H),

7.94 (d, J = 4.0 Hz, 1H). [00625] Step 5: Synthesis of 2,4-dichloro-l,6-naphthyridine-5-carbonitrile (A₂)

[00626] 2,4-Dichloro-l,6-naphthyridine (A₂-I) (33.6 kg, 168.8 mol, 1 eq.) and CH2CI2 (336 L) were charged to a reactor. The solution was cooled to -10 °C. Tf₂O (50 kg, 177.2 mol, 1.05 eq.) was charged. After complete addition. TMSCN (17.5 kg, 177.2 mol, 1.05 eq.) was charged followed by EtsN (22.2 kg, 219.4 mol, 1.3 eq.). After reaction completion, as determined by HPLC analysis, the reaction mixture was diluted with CH2CI2 (7.5 V) and basified to pH 7 with sat. NaHCCL. The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 x 5 V). The combined organic layers were washed with water (2 x 5 L) and brine and dried over with anhydrous Na₂SO₄. The organic solution was concentrated under vacuum and the residue was triturated with MeOH (4 V). Tire slurry was filtered, and the wet cake was dried under vacuum to afford 2, 4-dichloro-l,6-naphthyridine-5 -carbonitrile (A₂) as a yellow solid (31.21 kg), m/z = [M+H]⁺ 223.9; 'HNMR (400 MHz, DMSO-d₆) 5 9.01 (d, J= 5.6 Hz, 1H), 8.32 (s. 1H), 8.29 (d, J= 5.6 Hz, 1H).

[00627] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6-naphthyridine-5- carbonitrile (C₂)

[00628] 2,4 -dichloro-l,6-naphthyridine-5-carbonitrile (A₂) (30 g, 1 eq.), 2-(4-(tert-butyl)-5-chloro-2- mcthylphcnyl)-4,4,5,5-tctramcthyl-l,3,2-dioxaborolanc (Bi) (42.2 g, 1.02 eq.), dichlorobis(triphenylphosphine)-palladium (0.64 g, 0.68 mol%), and THF (270 mL, 9 vol) were charged to a reactor. Tire mixture was evacuated and purged with nitrogen. The reaction was heated to 45 °C and an aqueous solution of potassium phosphate (71.1 g, 2.5 eq, in 138 ml, 4.6 vol of water) was added to the mixture. After reaction completion, as determined by HPLC analysis, THF (180ml, 6 vol) was added, and the aqueous layer was separated from the batch. The organic layer was treated with SiliaMetS Thiol resin (6 g, 20 vvt%) and stirred for 16 hours at 45 °C. Tire mixture was cooled to 25 °C and the resin was filtered off. Water was added (60 mL, 2 vol) and the resulting mixture w as filtered. Hie filter cake was isolated and dried under vacuum at 50 °C to afford 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro- L6-naphthyridine-5 -carbonitrile (C₂) as a white solid (39.7 g, 80% yield), m/z = [M+H]⁺ 370.10; H NMR (400 MHz, DMSO) 5 8.99 (d, J = 5.7 Hz, 1H), 8.38 - 8.30 (m, 2H), 7.66 (s, 1H), 7.47 (s, 1H), 2.44 (s, 3H), 1.49 (s, 9H).

[00629] Alternate Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6- naphthyridine-5-carbonitrile (C2)

[00630] 2,4-dichloro-l,6-naphthyridine-5-carbonitrile (A2) (20 kg. 1 eq.), 2-(4-(tert-butyl)-5-chloro-2- methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Bi) (28.10 kg, 1.02 eq.), dichlorobis(triphenylphosphine)-palladium (0.22 g, 0.4 mol%), and THF (180 L, 9 vol) were charged to a reactor. Tire mixture was evacuated and purged with nitrogen. The reaction was heated to 35 ± 5 °C and an aqueous solution of potassium phosphate (47.37 kg, 2.5 eq. in 92 L, 4.6 vol of water) was added to tire mixture, and the reactor content was stirred. After reaction completion, THF (120 L, 6 vol) was added, the reactor content was stirred at 45 ± 5 °C, the phases were allowed to separate, the aqueous layer was separated from the batch, and the organic layer was filtered, washing with THF (40 L, 2 vol). The organic layer distilled down to 6.5 volumes at an internal batch temperature below' 50 °C. THF (30 L, 1.5 vol) was added to the reactor, the reactor was heated to an internal temperature of 50 ± 5 °C and was then cooled to 20 ± 5 °C over 6 hours. Water (49 L, 2.5 vol) was added over 2 hours, and the reactor content was held at 20 °C. The mixture was cooled to 25 °C and the resin was filtered off. Water was added (60 mL. 2 vol) and the resulting mixture was filtered. The resulting slurry was filtered, and the filter cake was washed with THF (20 L, 1 vol) and water (20 L, 1 vol). The wet filter cake was dried under vacuum at 50 °C to afford 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6-naphthyridine-5-carbonitrile (C2) as an off-white solid.

[00631] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide n-propanol solvate (Compound 1 1-propanol solvate) Compound 1 (1-propanol solvate)

[00632] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6-naphthyridine-5-carbonitrile (C2) (22 g, 1 eq.), trifluoroacetic acid (132 mL, 6 vol) and water (7 mL, 0.3 vol) were charged to the reactor. Tire mixture was heated to 60 °C. After reaction completion, as determined by HPLC, the reaction was concentrated and treated with aqueous sodium hydroxide (154 g, 6.5 eq. in 660 mL, 30 vol of water), sodium chloride (116.6 g, 33.6 eq.) and 2-MeTHF (880 ml, 40 vol). The organic layer was isolated and washed with aqueous sodium chloride (15 wt%). The organic layer was then concentrated and swapped into n-propanol. The n-propanol solution was seeded with Formula 1 n-propanol solvate form B and the resulting slurry filtered. Tire isolated solid was dried under vacuum at 45 °C to afford 2-(4-(tert-butyl)-5- chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5-carboxamide n-propanol solvate (Compound 1 n-propanol solvate) as a white solid (23.0 g, 90% yield). H NMR (400 MHz, DMSO-de) 8 12.01 (bs, 1H), 8.51 (d, J= 5.8 Hz, 1H), 7.55 (bs, 1H), 7.49 (s, 2H), 7.46 (d, J= 5.8 Hz, 1H), 7.33 (bs, 1H), 6.13 (s, 1H), 4.37 (t, J = 4.0 Hz, 1H), 3.3-3.4 (m, 2H), 2.31 (s, 3H), 1.48 (s, 9H), 1.35-1.45 (m, 2H), 0.83 (t, J = 4.0 Hz, 3H).

[00633] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide n-Propanol Solvate Form B Seeds

[00634] Compound 1 was charged to a vessel controlled at 20 +/- 5 °C. 1 -propanol (4 L/kg based amount of Compound 1) was charged and the slurry mixture was stirred at 20 °C for at least 24 h. The solids were filtered and dried in an oven overnight (40 °C, under vacuum, nitrogen bleed) prior to use as seed material in the crystallization.

[00635] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide Form A

Compound 1 (1 -propanol solvate) Compound 1 (Neat Form A)

[00636] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5-carboxamide n-propanol solvate (Compound 1 n-propanol solvate) (3800 g, 1 cq.) and methanol (20.6 L, 5.5 vol) were charged to a reactor and the slurry was stirred at 25 °C. The slurry was filtered, washed with methanol (7.6L, 2 vol) and the isolated solid material was dried at 50 °C under vacuum to afford 2-(4-(tert-butyl)-5- chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5 -carboxamide (Compound 1 Form A) as a white solid (2909 g, 89% yield). HRMS m/z = [M+H]⁺ 370.1304; ’H NMR (500 MHz, DMSO-de) 5 12.01 (bs, 1H), 8.51 (d, J= 5.8 Hz, 1H), 7.55 (bs, 1H), 7.49 (s, 2H), 7.46 (d, J= 5.8 Hz, 1H), 7.33 (bs, 1H), 6.13 (s, 1H), 2.31 (s, 3H), 1.48 (s, 9H). [00637] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carbonitrile (C4)

[00638] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6-naphthyridine-5-carbonitrile (C2 60 g, 162 mmol, 1.0 eq) and AcOH (480 mL) were charged to a reactor at 25 °C. Stirring was started and the mixture was heated to 100 °C. The mixture was stirred at 100 °C for 5 h, and then cooled to 20 °C over 5 h. Tire batch was stirred at 20 °C for 12 hours and then the batch was filtered, and the cake was rinsed with AcOH (120 mL). The wet cake was dried under vacuum at 50 °C to afford 2-(4-(tert-butyl)-5-chloro- 2-methylphenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5-carbonitrile (C4) HC1 salt, AcOH solvate as an off-white solid (67.8 g, 93% yield).

[00639] Alternate Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carbonitrile (C4)

[00640] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-l,6-naphthyridine-5-carbonitrile (C?; 1.0 kg, 1.0 eq) and AcOH (8 L, 8.0 vol) were charged to a reactor at 25 ± 5 °C. Hie reactor contents were heated to 100 °C, stirred for 5 h, and then cooled to 20 ± 5 °C over 5 h. The resulting slurry was filtered, and the filter cake was washed with acetic acid (2 L, 2.0 vol). The batch was stirred at 20 °C for 12 hours and then the batch was filtered, and the cake was rinsed with AcOH (120 mL). The wet filter cake was dried at 50 °C with an N2 sweep to afford 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5 -carbonitrile (C4) HC1 salt, AcOH solvate as a yellow solid.

[00641] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide (Compound 1), Neat Form C [00642] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-L4-dihydro-l,6-naphthyridine-5-carbonitrile (C4) HC1 salt, AcOH solvate (55 g, 123 mmol, 1.0 eq), water (2.25 g, 1.02 equiv), and TFA (132 mL) were charged to the reactor at 25 °C. Stirring was started and the mixture was heated to 60 °C. The reaction mixture was stirred at 60 °C for 16 h, and then cooled to 20 °C over 2 h. The batch was transferred to a second reactor containing a mixture of NaOH (75.13 g), water (864 mL), and MeTHF (33 mL) at 50 °C. An additional solution of NaOH (1.92 g) in water (22 mL) was added to the batch, followed by MeTHF (1078 mL) and NaCl (56.1 g). The mixture was stirred for 1 hour at 50 °C and then stirring was stopped and the aqueous phase was removed. A solution of NaCl (22.3 g) in water (429 mL) was charged to tire organic phase and the mixture was stirred for 1 hour at 50 °C. After 1 hour, the stirring was stopped, and the aqueous phase was removed. A solution of NaCl (22.3 g) in water (429 mL) was charged to the organic phase and the mixture was stirred for 1 hour at 50 °C. After 1 hour, the stirring was stopped, and the aqueous phase was removed. The mixture was distilled under reduced pressure to a volume of 214.5 mL and MeTHF (1166 mL) was charged to the batch. The mixture was heated to 50 °C and the resulting solution was filtered. The mixture was then distilled under reduced pressure to a volume of 302.5 mL. The batch was heated to 75 °C and then slowly cooled to 20 °C over 10 hours. The batch was stirred at 20 °C for 8 h and then filtered. Tire cake was rinsed with MeTHF (88 mL) and then dried under vacuum at 80 °C to afford Compound 1, neat form C, as an off-white solid (32.3 g, 71% yield).

[00643] Alternate Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide (Compound 1), Neat Form C

[00644] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5-carbonitrile (C4) HC1 salt, AcOH solvate (15 g, 33.5 mmol, 1.0 eq), water (633 mg, 1.05 equiv), and TFA (30 mL) were charged to a reactor with the jacket controlled at 25 ± 5 °C, while keeping the internal batch temperature at no more than 40 °C. Stirring was started, and the mixture was heated to 60 ± 5 °C. Tire reaction mixture was stirred at 60 ± 5 °C for 15 h, and then cooled to an internal temperature of 20 ± 5 °C over 2 h. The batch was transferred to a second reactor containing a mixture of K3PO4 (82.5 g), water (150 mL), and 2-MeTHF (105 mL) at 50 ± 5 °C, while maintaining an internal batch temperature of no more than 60 °C and a pH in the range of 8-9. Tire pH was maintained using trifluoroacetic acid and K3PO4 as needed. Tire reaction vessel was rinsed with an additional 120 mL of 2-MeTHF, which was then added to the batch. The batch was then stirred at 60 ± 5 °C until the quench was complete. The phases were allowed to separate, and the aqueous phase was removed. A solution of potassium chloride (1.5 g) in water (150 mL) was added to the organic layer, the batch was stirred for about 1 hour at 60 ± 5 °C, the phases were allowed to separate, and the aqueous phase was removed. The mixture was distilled at ~55 °C under reduced pressure (~500 mbar) to a volume of 5 mL/g (75 mL), 2-MeTHF (150 mL) was added, the mixture was distilled again to a volume of 5 mL/g (75 mL), and 2-MeTHF (165 mL) was added. The mixture was heated to 60 °C, stirred to ensure dissolution, and filtered. The filter was washed with 2-Me THF (30 mL), and the rinse was added to tire batch. The mixture was then distilled under reduced pressure to 5 volumes. The batch was heated to 78 °C, slowly cooled to 20 °C over 10 hours, stirred at 20 °C for 8 h, and then filtered. The cake was rinsed with 2-MeTHF (30 mL) and then dried under at 80 °C to afford Compound 1. neat form C.

[00645] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-l,4-dihydro-l,6- naphthyridine-5-carboxamide (Compound 1), Form A

[00646] Compound 1 (67.7 kg, 183 mol, 1 eq, Neat Form C) and methanol (406 L) were charged to the reactor at 25 °C. Hie batch was stirred at 25 °C for 13h and then filtered. The cake was rinsed with methanol (135 L) and then dried under vacuum at 45 °C to afford Compound 1 as a white solid (58.5 kg, 158 mol, 86.4% yield, Form A).

Example 2 Preparation of Compound 1 Tablets

[00647] Compound 1 tablets (5 mg dosage strength) were prepared as follows. Compound 1 Form A, microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium were each passed through a 20-mesh screen and combined in a 40 L Bohle Blender. The mixture was blended for about 8 minutes at 24 rpm. Magnesium Stearate was passed through a 60-mesh screen and added to the blended mixture, and the mixture was further blended for about 2 minutes at 24 rpm.

[00648] The resulting mixture was then compressed into tablets using a PICCOLA tablet press to yield tablets with each containing 5 mg of Compound 1. The press had a 6 mm standard round concave tooling and paddle feeder. The turret speed was set to 50 rpm and the paddle speed was set to 10 rpm.

[00649] Compound 1 tablets (35 mg and 70 mg dosage strengths) were prepared by analogous methods, except that capsule shaped tooling and suitable turret and paddle speeds were used.

[00650] Tire compositions of all three tablet dosage strengths are provided in the following table:

„ Amount per Amount per Amount per „

Component Component _{g mg Tabkt 3g mg Tab|et 70 mg Tab|et} Content f unction _{(mg) (mg) (mg)} ( /o w/w)

Compound 1 Form A Active 5.0 35.0 70.0 6.250

Microcrystallinc „ „ . Filler 35.9 251.3 302.6 44.875

Cellulose

Lactose Monohydrate Filler 35.9 251.3 502.6 44.875 „ . Amount per Amount per Amount per „ . .

Component Component _{5 m Tablet 35 m Tabkt 70 m Tabkf} Content

Ooscarmellose _{Dlsintegrant 2 4 l 6 8} 33 ,₆ 3.000

Sodium

Magnesium Stearate Lubricant 0.8 5.6 11.2 1.000

Total - 80.0 560.0 1120.0 100.0

Example 3

A Study Evaluating Efficacy and Safety of Compound 1 for Acute Pain After a Bunionectomy

[00651] A randomized, double-blind, placebo-controlled, dose-ranging, 5-arm, parallel study design evaluating tire efficacy and safety of Compound 1 doses in treating acute pain after a bunionectomy is conducted. Bunionectomy is a well-established, multi-dose, surgical, acute pain model. A randomized, double-blind study design was used to avoid observer bias and reduce symptoms or outcomes arising from the subjects’ knowledge of treatment. A parallel design is considered most appropriate given the acute nature of bunionectomy surgery.

Study Subjects

[00652] Male and female subjects. 18 through 75 years of age (inclusive), with pain that is moderate or severe on the verbal categorical rating scale (VRS) and >4 on the NPRS after a bunionectomy are included in the study.

Study Drugs

[00653] Investigational Drug: Compound 1. The investigational drug is administered orally in 5 mg, 35 mg, and 70 mg tablets. Tablets are prepared according to Example 2.

[00654] Reference Drug: HB/APAP. Tire reference drug is administered orally in 5 mg/325 mg capsules, supplied as over-encapsulated 5 mg/325 mg tablets.

Study Protocol

[00655] The schedule for the study is summarized in Table 1. On Day -1, subjects undergo a primary unilateral bunionectomy with distal first metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo and popliteal sciatic block) and may be coupled with intravenous sedation anesthesia for comfort. A continuous popliteal sciatic block infusion

(0.2% ropivacaine) is started after surgery , remains in place until after midnight, and is removed by approximately 5 AM on Day 1. After removal of the popliteal sciatic block, a subject is randomized to 1 of 5 treatment groups if: (1) the subject requests the first dose of study drug for pain relief, (2) the subject’s pain is moderate or severe on the VRS, and (3) the subject’s pain is >4 on the NPRS. If a subject does not meet the VRS and NPRS criteria within 9 hours after removal of the popliteal sciatic block, the subject is not included in the study.

Table 1. Study Schedule

[00656] Approximately 355 subjects are randomized 1: 1: 1: 1: 1 to 5 treatment groups: Compound 1 (180 mg loading dose/90 mg q 12h); Compound 1 (70 mg loading dose/35 mg q 12h); Compound 1 (10 mg loading dose/5 mg ql2h); HB/APAP (active reference); or placebo (Table 2). Randomization is stratified by site and baseline NPRS (<8 versus >8). To maintain the blind, all subjects receive the same number of tablets ql2h and/or capsules every 6 hours (q6h) in a double-dummy design.

Table 2. Treatment Groups

> , , . _ Number of Subjects

Treatment Active Dose

(planned)

Compound 1 180 mg loading dose90 mg ql2h 71

Compound 1 70 mg loading dose/35 mg ql2h 71

Compound 1 10 mg loading dose/5 mg ql2h 71

HB/APAP 5 mg/325 mg q6h 71

Placebo 71

[00657] To maintain the blind, all subjects receive the same number of tablets and/or capsules q6h in a double-dummy design. Compound 1 active or Compound 1 placebo tablets are administered to all subjects ql2h as follows: 0 hours (first dose) and at 12, 24, and 36 hours after the first dose of study drug. HB/APAP active or HB/APAP placebo capsules are administered to all subjects q6h as follows: 0 hours (first dose) and at 6, 12, 18, 24, 30, 36, and 42 hours after the first dose of study drug. [00658] Thus, in the Compound 1 arms. Compound 1 is administered every 12 hours (ql2h). The final dose of Compound 1 is given 36 hours after the first dose. HB/APAP placebo capsules are administered every 6 hours (q6h).

[00659] In tire HB/APAP Arm, HB/APAP is administered every 6 hours (q6h) at a dose of 5 mg/325 mg. The final dose of HB/APAP is given 42 hours after the first dose. Compound 1 placebo capsules are administered every 12 hours (ql2h).

[00660] In the Placebo Arm, Compound 1 placebo capsules are administered every 12 hours (ql2h), and HB/APAP placebo capsules are administered every 6 hours (q6h).

[00661] Ibuprofen (400 mg orally q6h as needed [pm]) is permitted as a rescue medication for pain relief upon the subject’s request starting any time after the first dose of study drug through 48 hours after the first dose of study drug. Subjects are encouraged to wait 90 minutes after the first dose of study drug to request rescue medication, and subjects should generally not receive rescue medication unless their NPRS score is >4.

Efficacy and Safety Assessments

[00662] 4-point Verbal Categorical Rating Scale: Subjects report their pain on tire 4-point VRS (none, mild, moderate, or severe) upon request for the first dose of study drug for pain relief after removal of the popliteal sciatic block (baseline VRS). A 4-point VRS is included as part of tire pain threshold inclusion criterion to ensure that all subjects have moderate or severe pain at baseline, which ensures subjects have sufficient pain to determine if the study drug is effective.

[00663] 11-point (0 to 10) Numeric Pain Rating Scale: NPRS scores are frequently used in bunionectomy studies and are recognized by the FDA as a valid pain intensity measure. On the 11 -point NPRS, a score of 0 denotes no pain, and a score of 10 denotes the worst pain intensity imaginable. Pain rated >4 at baseline ensures subjects have sufficient pain to determine if the study drug is effective. Subjects report their pain intensity on the NPRS after VRS (if the subject’s pain is rated moderate or severe on the VRS) and at each scheduled time point through 48 hours after the first dose of study drug (0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after the first dose of study drug). In addition, pain intensity is recorded on the NPRS immediately before each administration of rescue medication.

[00664] Use of rescue medications: The use of rescue medications is an important covariate in pain studies and provides additional information on the analgesic effect.

[00665] Patient Global Assessment: The PGA of study drug is a single-item assessment of patient perceptions of tire method of pain control with the study drug and is evaluated on a 4-point Likert scale (poor, fair, good, or excellent). The PGA of study drug provides subjects the ability to state their perceptions of the treatment that may not be captured by measuring pain intensity alone.

[00666] Safety: Adverse events, clinical laboratory assessments, clinical evaluation of vital signs, standard 12-lead ECGs, and physical examinations

Endpoints

[00667] Time-weighted sum of the pain intensity difference (SPID) as recorded on the numeric pain rating scale (NPRS) from 0 to 48 hours (SPID48)

[00668] Proportions of subjects with >30%, >50%, and >70% reduction in NPRS at 48 hours

[00669] Pharmacokinetic parameter estimates of Compound 1 and its metabolite(s)

[00670] Safety and tolerability based on the incidence and type of adverse events (AEs). changes from baseline in clinically significant laboratory test results, vital signs, and ECGs

[00671] Time-weighted SPID as recorded on the NPRS from 0 to 24 hours (SPID24)

[00672] Time to >2 -point reduction in NPRS from baseline

[00673] Time to >1 -point reduction in NPRS from baseline

[00674] Proportions of subjects with >30%, >50%, and >70% reduction in NPRS at 24 hours

[00675] Proportion of subjects reporting good or excellent on the Patient Global Assessment (PGA) at 48 hours

[00676] Proportion of subjects using rescue medication, and total rescue medication usage, from 0 to 48 hours

[00677] Time to first use of rescue medication

Example 4

Evaluation of Efficacy and Safety of Compound 1 for Pain Associated With Diabetic Peripheral Neuropathy

[00678] A randomized, double-blind, active -controlled, dose-ranging, 5-arm, parallel-design study to evaluate the safety and efficacy of Compound 1 in treating subjects with painful diabetic peripheral neuropathy (DPN) is conducted.

Study Subjects

[00679] Male and female subjects 18 through 80 years of age, inclusive, with presence of bilateral pain in lower extremities due to DPN for at least 1 year, and weekly average NPRS score of >4 and <9 with limited variation in the Run-in Period arc included in the study. Study Drugs

[00680] Investigational Drug: Compound 1. The investigational drug is administered orally in 5 mg and 70 mg tablets. Tablets are prepared according to Example 2.

[00681] Reference Drug: Pregabalin. The reference drug is administered orally in 50 mg and 100 mg capsules. A pregabalin reference arm is included as an active control, as it is approved for the treatment of DPN and is considered a first-line treatment in most international clinical guidelines for neuropathic pain.

Study Design

[00682] Subjects who meet eligibility criteria during screening visits enter a 7-day Run-in Period to establish their baseline NPRS score. Subjects with a weekly average NPRS score of >4 and <9 with limited variation (SD <25% of mean) in the Run-in Period are eligible for the 12-week Treatment Period followed by a Safety Follow-up Visit.

[00683] A total of approximately 300 subjects are randomized equally (l: l: l: l: l) to 5 treatment groups: 4 Compound 1 dose levels (140, 70, or 10 mg once daily [qd] and 5 mg every 48 hours [q48h] for 12 weeks) or pregabalin reference (50 mg 3 times per day [tid] for tire first week of dosing, then 100 mg tid for 11 weeks, followed by the 7-day taper regimen). Randomization is stratified by geographic region (US or ex-US), creatinine clearance (<80 or >80 mL/min), and baseline NPRS score (<7 or >7). To maintain tire blind, all subjects receive the same number of tablets qd in the morning and the same number of capsules tid in a double-dummy design for the 12-week Treatment Period.

[00684] After the 12-week Treatment Period, subjects enter a 7-day period to allow⁷ for capsule (pregabalin or matching placebo) study drug taper. The recommended capsule taper regimen is 4 days of dosing 1 capsule even⁷ 12 hours, then 3 days of dosing 1 capsule qd. The Safety Follow-up Visit occurs 14 (± 2) days after the last dose of tablet (Compound 1 or matching placebo) study drug.

[00685] Subjects stop taking pain medications (including pregabalin, if applicable), except acetaminophen (paracetamol; up to 500 mg every 4 to 6 hours as needed [pm]), for at least 14 days before the first dose of study drug.

[00686] Acetaminophen (paracetamol) is pennitted as a pain rescue medication pm throughout tire study. Subjects are permitted to take up to 500 mg every 4 to 6 hours pm, up to a maximum of 2500 mg in any 24-hour period. Subjects record NPRS pain score immediately before each administration and record date, time, and dose (in mg) of administration. Efficacy and SafetyAssessments

[00687] 11-point (0 to 10) Numeric Pain Rating Scale (NPRS): Pain intensity is the FDA recommended efficacy endpoint for studies of pain drugs. This evaluation is a standard pain assessment scale used in many pain registration studies. The 11 -point scale ranges from 0 (no pain) to 10 (worst imaginable pain).

[00688] Each morning from Day -7 through Week 12. subjects report their average pain intensity on the NPRS over the previous 24 hours. The NPRS scores reported during the Run-in Period (days -7 to -1) establish the baseline NPRS pain score. During the Treatment Period, the NPRS score is recorded before the first daily dose. Subjects also report their current pain score before each administration of rescue medication. Daily NPRS scores are averaged over a weekly period to reduce the impact of individual high or low pain scores on the analyses.

[00689] Use of rescue medication: Data on the use of rescue medications are collected to provide additional information on the analgesic effects.

[00690] SF-36v2: The SF-36v2 is a 36-item scale, which measures 8 domains of general health status: physical functioning, role limitations due to physical problems, social functioning, bodily pain, mental health, role limitations due to emotional problems, vitality, and general health perception. Physical and mental component summary scores (PCS and MCS, respectively) are calculated based on weighting the scores of the 8 domains.

[00691] BPI-SF: The BPI-SF is widely used in clinical and research settings with patients who have chronic pain. Tire BPI-SF questionnaire assesses both pain severity (pain severity index) and the impact of pain on daily life, such as its interference with walking and sleep, (pain interference index) in 2 separate index scores.

[00692] SF-MPQ-2: The SF-MPQ-2 is designed to measure the multidimensional qualities of pain as well as total pain by assessing the major symptoms of both neuropathic and non-neuropathic pain. It assesses 15 specific sensory and affective pain descriptors and provides a total score and sensory and affective subscale scores.

[00693] NPSI: Tire NPSI is a well-characterized method for quantifying distinct symptoms experienced by a diversity of neuropathic pain patients as well as treatment effects. The instrument characterizes neuropathic pain symptom severity and is comprised of 5 subscales: superficial spontaneous pain, deep (or pressing) spontaneous pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia. A total severity score and scores for each subscale may be evaluated.

[00694] PGA: The PGA captures subjects’ perceptions of the study drug using a single-item questionnaire measured using a validated Likert scale. PGAs arc generic measures that have precedence in clinical studies for chronic pain conditions. [00695] POMS-2-SF: The POMS-2-SF was developed to measure the effects of mood on various therapeutic approaches. The domains measured are tension-anxiety, depression, anger-hostility, vigoractivity, fatigue, and confusion. Total mood disturbance is a function of these six domain scores and reported as a total score. Tire short fomr has been validated for patients under stress and pain.

[00696] WPAI-NP: The WPAI-NP v2.0 is a validated and broadly used 6-item instrument to measure the impact of an individual’s health status on their work and daily activities. It measures the impact of neuropathic pain on absenteeism, presenteeism and overall work impairment as a function of these 2 domains. Tire WPAI:NP also measures impairments in daily activities other than work at a job and reports this as a separate domain.

[00697] Safety: Adverse events, clinical laboratory assessments, clinical evaluation of vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale

[00698] Columbia Suicide Severity Rating Scale (C-SSRS): The FDA recommends the evaluation of suicidality in clinical studies involving drugs with CNS activity. The C-SSRS evaluates this through a series of questions about suicidal thoughts and behaviors.

Endpoints

[00699] Change from baseline in the weekly average of daily pain intensity on the numeric pain rating scale (NPRS) at Week 12

[00700] Proportions of subjects with >30%, >50%, and >70% reductions from baseline in the weekly average of daily pain intensity on the NPRS at Week 12

[00701] Safety and tolerability based on adverse events (AEs), laboratory' test results, vital signs, and ECGs

[00702] Change from baseline in tire weekly average of the daily NPRS score at each week

[00703] Change from baseline in Medical Outcomes Study 36-item Short-form Health Status (SF-36v2) Physical Component Summary and Mental Component Summary scores at Week 12

[00704] Change from baseline in pain severity and pain interference indices on the Brief Pain Inventory' - Short Form (BPI-SF) at Week 12

[00705] Change from baseline in tire Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) total score at Week 12

[00706] Change from baseline in the Neuropathic Pain Symptom Inventory (NPS1) total score at Week 12 [00707] Proportion of subjects reporting good, very good, or excellent at Week 12 on the Patient Global Assessment (PGA)

[00708] Change from baseline in total mood disturbance score on Profile of Mood States (POMS-2-SF) at Week 12 [00709] Change from baseline in overall work impairment on Work Productivity and Activity Impairment - Neuropathic Pain (WPAI-NP) at Week 12

[00710] Proportion of subjects using rescue medication and total rescue medication usage [00711] Pharmacokinetic parameter estimates of Compound 1 and its metabolite(s)

Example 5

A Study Evaluating Efficacy and Safety of Compound 1 for Acute Pain After a Bunionectomv

[00712] A randomized, double-blind, placebo-controlled, dose-ranging, 5-arm, parallel study design evaluating the efficacy and safety of Compound 1 doses in treating acute pain after a bunionectomy was conducted. Bunionectomy is a well-established, multi-dose, surgical, acute pain model. A randomized, double-blind study design was used to avoid observer bias and reduce symptoms or outcomes arising from the subjects’ knowledge of treatment. A parallel design was considered most appropriate given the acute nature of bunionectomy surgery.

[00713] The objectives of the study included: evaluating the efficacy of Compound 1 in treating acute pain after a bunionectomy, evaluating the safety and tolerability of Compound 1, evaluating the pharmacokinetics of Compound 1 and its metabolite(s), and evaluating the dose-response and exposureresponse relationships.

Study Subjects

[00714] Male and female subjects, 18 through 75 years of age (inclusive), with pain that is moderate or severe on the verbal categorical rating scale (VRS) and >4 on the NPRS after a bunionectomy were included in the study.

Study Drugs

[00715] Investigational Drug: Compound 1. The investigational drug was administered orally in 5 mg, 35 mg, and 70 mg tablets. Tablets were prepared according to Example 2.

[00716] Reference Drug: HB/APAP. Hie reference drug was administered orally in 5 mg/325 mg capsules, supplied as over-encapsulated 5 mg/325 mg tablets.

Study Protocol

[00717] Excluding the Screening Visit, each subject participated in the study for 3 days (from Day 1 to Day 3) plus a Safety Follow-up Visit 14 ± 2 days after the last dose of study drug. [00718] The schedule forthe study is summarized in Table 3. On Day 1, subjects underwent a primary unilateral bunionectomy with distal first metatarsal osteotomy (i.e., Austin procedure) and internal fixation under regional anesthesia (Mayo block), coupled in some cases with intravenous sedation anesthesia for comfort. After surgery completion, subjects were randomized to 1 of 5 treatment groups if: (1) the subject requested the first dose of study drug for pain relief, (2) the subject’s pain was moderate or severe on the VRS, and (3) the subject's pain was >4 on the NPRS. If a subject did not meet the VRS and NPRS criteria within 9 hours after surgery completion on Day 1, the subject was not included in the study.

Table 3. Study Schedule

[00719] Approximately 355 subjects were randomized 1: 1: 1: 1: 1 to 5 treatment groups: Compound 1 (180 mg loading dosc/90 mg ql2h); Compound 1 (70 mg loading dosc/35 mg ql2h); Compound 1 (10 mg loading dose/5 mg ql2h); HB/APAP (active reference); or placebo (Table 4). Randomization was stratified by site and baseline NPRS (<8 versus >8). To maintain the blind, all subjects received the same number of tablets ql2h and/or capsules every 6 hours (q6h) in a double-dummy design.

Table 4. Treatment Groups

Number of Number of

Treatment Active Dose Subjects Subjects

(planned) (actual)

Compound 1 180 mg loading dose/90 mg 71 71 ql2h

Compound 1 70 mg loading dose/35 mg ql2h 71 77

Compound 1 10 mg loading dose/5 mg ql2h 71 73

HB/APAP 5 mg/325 mg q6h 71 75

Placebo 71 71

[00720] To maintain the blind, all subjects received the same number of tablets and/or capsules q6h in a double-dummy design. Compound 1 active or Compound 1 placebo tablets were administered to all subjects q!2h as follows: 0 hours (first dose) and at 12, 24, and 36 hours after the first dose of study drug. HB/APAP active or HB/APAP placebo capsules were administered to all subjects q6h as follows: 0 hours (first dose) and at 6, 12, 18, 24, 30, 36, and 42 hours after the first dose of study drug.

[00721] Ibuprofen (400 mg orally q6h as needed [pm]) was pennitted as a rescue medication for pain relief upon the subject’s request starting any time after the first dose of study drug through 48 hours after the first dose of study drug. Subjects were encouraged to wait 90 minutes after the first dose of study drug to request rescue medication, and subjects generally did not receive rescue medication unless their NPRS score was >4.

Efficacy and Safety Assessments

[00722] 4-point Verbal Categorical Rating Scale: Subjects reported their pain on the 4-point VRS (none. mild, moderate, or severe) upon request for the first dose of study drug for pain relief after surgery (baseline VRS). A 4-point VRS was included as part of the pain threshold inclusion criterion to ensure that all subjects have moderate or severe pain at baseline, which ensures subjects have sufficient pain to determine if the study drug is effective.

[00723] 11-point (0 to 10) Numeric Pain Rating Scale: NPRS scores are frequently used in bunionectomy studies and are recognized by the FDA as a valid pain intensity measure. On the 11 -point NPRS, a score of 0 denotes no pain, and a score of 10 denotes the worst pain intensity imaginable. Pain rated >4 at baseline ensures subjects have sufficient pain to determine if the study drug is effective. Subjects reported their pain intensity on the NPRS after VRS (if tire subject’s pain was rated moderate or severe on the VRS) and at each scheduled time point through 48 hours after the first dose of study drug (0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 hours after the first dose of study drug). In addition, pain intensity was recorded on the NPRS immediately before each administration of rescue medication.

[00724] Use of rescue medications: The use of rescue medications is an important covariate in pain studies and provides additional information on the analgesic effect.

[00725] Patient Global Assessment: The PGA of study drug is a single-item assessment of patient perceptions of the method of pain control with the study drug and is evaluated on a 4-point Likert scale (poor, fair, good, or excellent). The PGA of study drug provides subjects the ability to state their perceptions of the treatment that may not be captured by measuring pain intensity alone.

[00726] Safety: Adverse events, clinical laboratory assessments, clinical evaluation of vital signs, standard 12-lead ECGs, and physical examinations Endpoints

[00727] Time-weighted sum of the pain intensity difference (SPID) as recorded on the numeric pain rating scale (NPRS) from 0 to 48 hours (SPID48)

[00728] Proportions of subjects with >30%, >50%, and >70% reduction in NPRS at 48 hours

[00729] Pharmacokinetic parameter estimates of Compound 1 and its metabolite(s)

[00730] Safety and tolerability based on the incidence and type of adverse events (AEs). changes from baseline in clinically significant laboratory test results, vital signs, and ECGs

[00731] Time-weighted SPID as recorded on the NPRS from 0 to 24 hours (SPID24)

[00732] Time to >2 -point reduction in NPRS from baseline

[00733] Time to >1 -point reduction in NPRS from baseline

[00734] Proportions of subjects with >30%, >50%, and >70% reduction in NPRS at 24 hours

[00735] Proportion of subjects reporting good or excellent on the Patient Global Assessment (PGA) at

48 hours

[00736] Proportion of subjects using rescue medication, and total rescue medication usage, from 0 to

48 hours

[00737] Time to first use of rescue medication

Efficacy Results

[00738] SPID48 Scores. The SPID scores for the subjects in the five treatment groups listed in Table 4 appear in Table 5 below.

Table 5. Efficacy Results - SPID48 Scores Safety Results

[00739] Compound 1 was generally safe and well-tolerated at all doses studied in the trial. The majority of the adverse events were mild or moderate in severity. There were no serious adverse events related to Compound 1 in the study. No patients treated with Compound 1 discontinued study drag due to adverse events.

[00740] The most common adverse events (incidence >5% in either combined Compound 1. HB/APAP or placebo group, respectively) were nausea (4.1%, 14.7%, 11.3%), headache (2.7%, 6.7%. 1.4%), dizziness (1 .4%, 5.3%, 1 .4%) and vomiting (1.4%, 5.3%, 2.8%). Adverse events were generally consistent with the post-surgical setting.

Example 6

[00741] A randomized, double-blind, active -controlled, dose-ranging, 5-arm, parallel-design study to evaluate the safety and efficacy of Compound 1 in treating subjects with painful diabetic peripheral neuropathy (DPN) is conducted.

[00742] The objectives of the study included: evaluating the efficacy of Compound 1 in treating subjects with pain associated w ith DPN, evaluating the safety and tolerability of Compound 1. evaluating the pharmacokinetics of Compound 1 and its metabolite(s), and evaluating the dose-response relationship of Compound 1.

Study Subjects

[00743] Male and female subjects 18 through 80 years of age, inclusive, with presence of bilateral pain in lower extremities due to DPN for at least 1 year, and weekly average NPRS score of >4 and <9 with limited variation in the Run-in Period were included in the study.

Study Drugs

[00744] Investigational Drug: Compound 1. The investigational drug was administered orally in 5 mg and 70 mg tablets. Tablets were prepared according to Example 2.

[00745] Reference Drug: Pregabalin. The reference drag was administered orally in 50 mg and 100 mg capsules. A pregabalin reference arm w as included as an active control, as it is approved for the treatment of DPN and is considered a first-line treatment in most international clinical guidelines for neuropathic pain. Study Design

[00746] Excluding the Screening Period (which included a 7-day Run-in Period), each subject participated in the study for approximately 16 weeks: a 12-week Treatment Period and Safety Follow-up Visits 14 (± 2) and 28 (± 2) days after the last dose of tablet study drug.

[00747] Subjects who met eligibility criteria during screening visits entered a 7-day Run-in Period to establish their baseline NPRS score. Subjects with a weekly average NPRS score of >4 and <9 with limited variation (SD <25% of mean) in the Run-in Period were eligible for the 12-week Treatment Period followed by two Safety Follow-up Visits.

[00748] A total of approximately 300 subjects were randomized equally (l:l: l:l: l) to 5 treatment groups: 4 Compound 1 dose levels (140, 70, or 10 mg once daily [qd] and 5 mg every 48 hours [q48h] for 12 weeks) or pregabalin reference (50 mg 3 times per day [tid] for the first week of dosing, then 100 mg tid for 11 weeks, followed by the 7-day taper regimen). Randomization was stratified by geographic region (US or ex-US), creatinine clearance (<80 or >80 mL/min), and baseline NPRS score (<7 or >7). To maintain the blind, all subjects received the same number of tablets qd in the morning and the same number of capsules tid in a double-dummy design for the 12-week Treatment Period.

[00749] After the 12-week Treatment Period, subjects entered a 7-day period to allow for capsule (pregabalin or matching placebo) study drug taper. The recommended capsule taper regimen was 4 days of dosing 1 capsule every 12 hours, then 3 days of dosing 1 capsule qd. The Safety Follow-up Visits occured 14 (± 2) and 28 (± 2) days after the last dose of tablet (Compound 1 or matching placebo) study drug.

[00750] Subjects stopped taking pain medications (including pregabalin, if applicable), except acetaminophen (paracetamol; up to 500 mg every 4 to 6 hours as needed [pm]), for at least 14 days before the first dose of study drug.

[00751] Acetaminophen (paracetamol) was permitted as a pain rescue medication pm throughout the study. Subjects were permitted to take up to 500 mg every 4 to 6 hours pm, up to a maximum of 2500 mg in any 24-hour period. Subjects recorded NPRS pain score immediately before each administration and recorded date, time, and dose (in mg) of administration.

Efficacy and SafetyAssessments

[00752] 11-point (0 to 10) Numeric Pain Rating Scale (NPRS): Pain intensity is the FDA recommended efficacy endpoint for studies of pain dmgs. This evaluation is a standard pain assessment scale used in many pain registration studies. The 11 -point scale ranges from 0 (no pain) to 10 (worst imaginable pain). [00753] During the Run-in Period and Treatment Period, subjects were instructed to record their average pain intensity every morning on the NPRS over the previous 24 hours via e-diary. The NPRS scores reported during the Run-in Period (days -7 to -1) established the baseline NPRS pain score. During the Treatment Period, the NPRS was completed in the morning, before the first daily dose of study drug. Subjects also reported their current pain score before each administration of rescue medication. Daily NPRS scores were averaged over a weekly period to reduce the impact of individual high or low pain scores on the analyses.

[00754] Use of rescue medication: Data on the use of rescue medications were collected to provide additional information on the analgesic effects.

[00755] SF-36v2: The SF-36v2 is a 36-item scale, which measures 8 domains of general health status: physical functioning, role limitations due to physical problems, social functioning, bodily pain, mental health, role limitations due to emotional problems, vitality, and general health perception. Physical and mental component summary' scores (PCS and MCS, respectively) were calculated based on weighting the scores of the 8 domains.

[00756] BPI-SF: Tire BPI-SF is widely used in clinical and research settings with patients who have chronic pain. The BPI-SF questionnaire assesses both pain severity (pain severity index) and the impact of pain on daily life, such as its interference with walking and sleep, (pain interference index) in 2 separate index scores.

[00757] SF-MPQ-2 : The SF-MPQ-2 is designed to measure the multidimensional qualities of pain as well as total pain by assessing the major symptoms of both neuropathic and non -neuropathic pain. It assesses 15 specific sensory and affective pain descriptors and provides a total score and sensory' and affective subscale scores.

[00758] NPSI: The NPSI is a well-characterized method for quantifying distinct symptoms experienced by a diversity of neuropathic pain patients as well as treatment effects. The instrument characterizes neuropathic pain symptom severity and is comprised of 5 subscales: superficial spontaneous pain, deep (or pressing) spontaneous pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia. A total severity' score and scores for each subscale may be evaluated.

[00759] PGA: The PGA captures subjects’ perceptions of the study drug using a single-item questionnaire measured using a validated Likert scale. PGAs are generic measures that have precedence in clinical studies for chronic pain conditions.

[00760] POMS-2-SF: The POMS-2-SF was developed to measure the effects of mood on various therapeutic approaches. The domains measured are tension-anxiety', depression, anger-hostility, vigoractivity, fatigue, and confusion. Total mood disturbance is a function of these six domain scores and reported as a total score. The short fonn has been validated for patients under stress and pain. [00761] WPAI-NP: The WPAI-NP v2.0 is a validated and broadly used 6-item instrument to measure the impact of an individual’s health status on their work and daily activities. It measures the impact of neuropathic pain on absenteeism, presenteeism and overall work impairment as a function of these 2 domains. Tire WPALNP also measures impairments in daily activities other than work at a job and reports this as a separate domain.

[00762] Safety: Adverse events, clinical laboratory assessments, clinical evaluation of vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale

[00763] Columbia Suicide Severity Rating Scale (C-SSRS): The FDA recommends the evaluation of suicidality in clinical studies involving drugs with CNS activity. The C-SSRS evaluates this through a series of questions about suicidal thoughts and behaviors.

Endpoints

[00764] Change from baseline in the weekly average of daily pain intensity on the numeric pain rating scale (NPRS) at Week 12

[00765] Proportions of subjects with >30%, >50%, and >70% reductions from baseline in the weekly average of daily pain intensity on the NPRS at Week 12

[00766] Safety and tolerability based on adverse events (AEs). laboratory test results, vital signs, and ECGs

[00767] Change from baseline in the weekly average of the daily NPRS score at each week

[00768] Change from baseline in Medical Outcomes Study 36-item Short-form Health Status (SF-36v2) Physical Component ummary and Mental Component Summary scores at Week 12

[00769] Change from baseline in pain severity and pain interference indices on the Brief Pain Inventory - Short Form (BPI-SF) at Week 12

[00770] Change from baseline in tire Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) total score at Week 12

[00771] Change from baseline in the Neuropathic Pain Symptom Inventory (NPSI) total score at Week 12 [00772] Proportion of subjects reporting good, ven good, or excellent at Week 12 on the Patient Global Assessment (PGA)

[00773] Change from baseline in total mood disturbance score on Profile of Mood States (POMS-2-SF) at Week 12

[00774] Change from baseline in overall work impairment on Work Productivity and Activity Impairment - Neuropathic Pain (WPAI-NP) at Week 12

[00775] Proportion of subjects using rescue medication and total rescue medication usage [00776] Phannacokinetic parameter estimates of Compound 1 and its metabolite(s) [00777] Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only.

Claims

CLAIMS What is claimed is:

1. A method of treating pain in a subject, comprising administering to the subject Compound 1:

(Compound 1), or a pharmaceutically acceptable salt thereof, in an amount of:

(a) a first dose of about 180 mg, followed by subsequent doses of about 90 mg every 12 hours:

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours;

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours;

(d) about 140 mg once per day;

(e) about 70 mg once per day;

(f) about 10 mg once per day; or

(g) about 5 mg every 48 hours.

2. Tire method of claim 1, wherein said pain is acute pain, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of:

(a) a first dose of about 180 mg. followed by subsequent doses of about 90 mg every 12 hours;

(b) a first dose of about 70 mg, followed by subsequent doses of about 35 mg every 12 hours; or

(c) a first dose of about 10 mg, followed by subsequent doses of about 5 mg every' 12 hours.

3. Tire method of claim 2, wherein the acute pain is lessened in the subject.

4. The method of claim 2 or 3. wherein the first dose is about 180 mg, and the subsequent doses are about 90 mg.

5. The method of claim 4, wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 49.5 to 99.5, optionally 69.5 to 79.5 or about 74.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 14.3 to 34.3, optionally 19.3 to 29.3 or about 24.3.

6. Tire method of claim 2 or 3, wherein the first dose is about 70 mg, and the subsequent doses are about 35 mg.

7. The method of claim 6, wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11 -point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 46.5 to 96.5, optionally 66.5 to 76.5 or about 71.5; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS). from 0 to 48 hours (SPID48) of 11.2 to 31.2, optionally 16.2 to 26.2 or about 21.2.

8. The method of claim 2 or 3, wherein the first dose is about 10 mg, and the subsequent doses are about 5 mg.

9. The method of claim 8, wherein the subject experiences (a) a time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 29.0 to 79.0, optionally 49.0 to 59.0 or about 54.0; and/or (b) a difference from placebo in time-weighted sum of pain intensity difference, relative to baseline, as recorded on an 11-point Numeric Pain Rating Scale (NPRS), from 0 to 48 hours (SPID48) of 1.7 to 5.7, optionally about 3.7.

10. The method of any one of claims 2-9, wherein the acute pain is moderate to severe acute pain.

11. The method of claim 10, wherein the subj ect has a baseline pain score of >4 on an 11 -point Numeric Pain Rating Scale (NPRS) or where the subject has a baseline pain level of moderate or severe on a Verbal Categorical Rating Scale.

12. The method of any one of claims 2-11, wherein the acute pain is acute post-operative pain or postsurgical pain.

13. The method of any one of claims 2-12, wherein the acute pain is bunionectomy pain.

14. The method of any one of claims 2-12, wherein the acute pain is abdominoplasty pain.

15. The method of claim 1, wherein said pain is chronic pain, and wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of:

(d) about 140 mg once per day;

(e) about 70 mg once per day;

(f) about 10 mg once per day; or

(g) about 5 mg every 48 hours.

16. Tire method of claim 15, wherein the chronic pain is lessened in tire subject.

17. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 140 mg once per day.

18. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 70 mg once per day.

19. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 10 mg once per day.

20. The method of claim 15 or 16, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 5 mg every 48 hours.

21. The method of any one of claims 15-20. wherein the chronic pain is moderate to severe chronic pain.

22. The method of claim 21, wherein the subject has a baseline weekly average pain score of >4 and <9 on an 11 -point Numeric Pain Rating Scale (NPRS).

23. The method of any one of claims 15-22. wherein the chronic pain is neuropathic pain, musculoskeletal pain, or visceral pain.

24. The method of any one of claims 15-23, wherein the chronic pain is diabetic peripheral neuropathy.

25. The method of any one of claims 1-24, wherein Compound 1 is administered in a pharmaceutical composition comprising: 5-7 wt % of Compound 1; 44-46 wt % of microcrystalline cellulose; 44-46 wt % of lactose; 2.8-3.2 wt % of croscarmellose sodium; and 0.9-1.1 wt % of magnesium stearate.

26. The method of claim 25, wherein Compound 1 is substantially cry stalline.

27. The method of claim 26, wherein Compound 1 is substantially pure Form A.

28. Tire method of any one of claims 25-27, wherein the pharmaceutical composition is a tablet core composition.

29. The method of any one of claims 25-28. wherein the phannaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose: about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

30. The method of any one of claims 25-29, wherein the phannaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate.

31. The method of any one of claims 25-29, wherein the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscannellose sodium; and about 5.6 mg of magnesium stearate.

32. The method of any one of claims 25-29. wherein the phannaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose: about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate.

33. A pharmaceutical composition comprising:

5-7 wt % of Compound 1:

(Compound 1); 44-46 wt % of microcrystalline cellulose:

44-46 wt % of lactose;

2.8-3.2 wt % of croscarmellose sodium; and

0.9- 1.1 wt % of magnesium stearate.

34. The pharmaceutical composition of claim 33, wherein Compound 1 is substantially crystalline.

35. The pharmaceutical composition of claim 34, wherein less than 15% of Compound 1 is in amorphous form.

36. The pharmaceutical composition of claim 34, wherein Compound 1 is substantially pure Form A.

37. The pharmaceutical composition of claim 36, wherein Form A accounts for at least 95% by weight of all solid forms of Compound 1 in the pharmaceutical composition.

38. The pharmaceutical composition of claim 36 or 37, wherein Fonn A is characterized by an X-ray powder diffractogram (XRPD).

39. The pharmaceutical composition of any one of claims 36-38, wherein Form A is characterized by ¹³C solid-state nuclear magnetic resonance (¹³C SSNMR) spectrum.

40. The pharmaceutical composition of any one of claims 33-39, wherein the pharmaceutical composition is a tablet core composition.

41. The pharmaceutical composition of any one of claims 33-40, wherein the pharmaceutical composition comprises about 6.25 wt % of Compound 1; about 44.875 wt % of microcrystalline cellulose; about 44.875 wt % of lactose; about 3.0 wt % of croscarmellose sodium; and about 1.0 wt % of magnesium stearate.

42. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 5 mg of Compound 1.

43. The pharmaceutical composition of claim 42, wherein the pharmaceutical composition comprises about 5 mg of Compound 1; about 35.9 mg of microcrystalline cellulose; about 35.9 mg of lactose; about 2.4 mg of croscarmellose sodium; and about 0.8 mg of magnesium stearate.

44. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 35 mg of Compound 1.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition comprises about 35 mg of Compound 1; about 251.3 mg of microcrystalline cellulose; about 251.3 mg of lactose; about 16.8 mg of croscarmellose sodium; and about 5.6 mg of magnesium stearate.

46. The pharmaceutical composition of any one of claims 33-41, wherein the pharmaceutical composition comprises about 70 mg of Compound 1.

47. Tire pharmaceutical composition of claim 46, wherein the pharmaceutical composition comprises about 70 mg of Compound 1; about 502.6 mg of microcrystalline cellulose; about 502.6 mg of lactose; about 33.6 mg of croscarmellose sodium; and about 11.2 mg of magnesium stearate.

48. The pharmaceutical composition of any one of claims 33-47 for use in treating pain in a subject.

49. Use of the pharmaceutical composition of any one of claims 33-47 in the manufacture of a medicament for treating pain in a subject.

50. A method of treating pain in a subject comprising administering the pharmaceutical composition of any one of claims 33-47 to the subject.

51. Tire pharmaceutical composition for use of claim 48, the use of claim 49, or tire method of claim 50, wherein said pain is acute pain.

52. The pharmaceutical composition for use, use, or method of claim 51, wherein the acute pain is bunionectomy pain.

53. Tire pharmaceutical composition for use, use, or method of claim 51, wherein the acute pain is abdominoplasty pain.

54. The pharmaceutical composition for use of claim 48, the use of claim 49, or the method of claim 50, wherein said pain is chronic pain.

55. The pharmaceutical composition for use, use, or method of claim 54, wherein the chronic pain is diabetic peripheral neuropathy.

56. A substantially crystalline Compound 1:

(Compound 1); wherein the substantially crystalline Compound 1 is selected from Compound 1 Methanol Solvate Form C and Compound 1 2-MeTHF Solvate Fonn D.

57. The substantially crystalline Compound 1 according to claim 56, where the substantially crystalline Compound 1 is Compound 1 Methanol Solvate Form C, optionally wherein Compound 1 Methanol Solvate Fonn C is characterized by:

(a) an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two- theta, 9.8 ± 0.2 degrees two-theta, and 21.3 ± 0.2 degrees two-theta; and/or

(b) an X-ray powder diffractogram substantially similar to FIG. 3; and/or

(c) a ^ljC SSNMR spectmm having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 177.2 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.0 ± 0.2 ppm, 157.3 ± 0.2 ppm, 152.7 ± 0.2 ppm, 151.7 ± 0.2 ppm, 150.7 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.6 ± 0.2 ppm, 145.3 ± 0.2 ppm, 134.1 ± 0.2 ppm, 133.3 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.2 ± 0.2 ppm, 130.3 ± 0.2 ppm, 115.4 ± 0.2 ppm. 114.5 ± 0.2 ppm, 113.9 ± 0.2 ppm, 111.2 ± 0.2 ppm. 50.1 ± 0.2 ppm, 36.4 ± 0.2 ppm, 31.0 ± 0.2 ppm, 29.3 ± 0.2 ppm, 19.9 ± 0.2 ppm, and 18.3 ± 0.2 ppm; and/or

(d) a ' ’C SSNMR spectmm substantially similar to FIG. 4.

58. The substantially crystalline Compound 1 according to claim 56, where the substantially crystalline Compound 1 is Compound 1 2-MeTHF Solvate Form D, optionally wherein Compound 1 2- MeTHF Solvate Form D is characterized by:

(a) an X-ray powder diffractogram having one, two, or three signals selected from 5.4 ± 0.2 degrees two- theta, 8.6 ± 0.2 degrees two-theta, and 17.0 ± 0.2 degrees two-theta; and/or

(b) an X-ray powder diffractogram substantially similar to FIG. 5; and/or

(c) a ^ljC SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.6 ± 0.2 ppm, 177.0 ± 0.2 ppm, 174.3 ± 0.2 ppm, 170.3 ± 0.2 ppm, 169.5 ± 0.2 ppm, 169.1 ± 0.2 ppm, 157.1 ± 0.2 ppm, 156.4 ± 0.2 ppm, 152.9 ± 0.2 ppm, 151.8 ± 0.2 ppm, 150.4 ± 0.2 ppm, 149.7

± 0.2 ppm, 148.6 ± 0.2 ppm, 147.3 ± 0.2 ppm, 145.3 ± 0.2 ppm, 144.6 ± 0.2 ppm, 134.6 ± 0.2 ppm. 133.7

± 0.2 ppm, 133.0 ± 0.2 ppm, 132.5 ± 0.2 ppm, 131.1 ± 0.2 ppm, 130.2 ± 0.2 ppm, 116.4 ± 0.2 ppm. 115.4

± 0.2 ppm, 114.4 ± 0.2 ppm, 113.5 ± 0.2 ppm, 112.9 ± 0.2 ppm, 111.5 ± 0.2 ppm, 110.9 ± 0.2 ppm, 75.1 ±

0.2 ppm, 68.9 ± 0.2 ppm, 36.3 ± 0.2 ppm, 32.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 29.2 ± 0.2 ppm, 25.0 ± 0.2 ppm, 23.2 ± 0.2 ppm, 19.4 ± 0.2 ppm, and 17.6 ± 0.2 ppm; and/or

(d) a ¹³C SSNMR spectrum substantially similar to FIG. 6.