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Baclofen

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis.[8][9] It may also be used for hiccups and muscle spasms near the end of life,[9] and off-label to treat alcohol use disorder[10][11] or opioid withdrawal symptoms.[12] It is taken orally (swallowed by mouth) or by intrathecal pump (delivered into the spinal canal via an implantable pump device).[8] It is also sometimes used transdermally (applied topically to the skin) in combination with gabapentin and clonidine prepared at a compounding pharmacy.[13]

Baclofen
Clinical data
Trade namesLioresal, Liofen, Gablofen, others
Other namesβ-(4-chlorophenyl)-γ-aminobutyric acid (β-(4-chlorophenyl)-GABA)
AHFS/Drugs.comMonograph
MedlinePlusa682530
License data
Pregnancy
category
  • AU: B3
Routes of
administration		oral, intrathecal, transdermal
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityWell-absorbed
Protein binding30%
Metabolism85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Elimination half-life1.5 to 4 hours
ExcretionKidney (70–80%)
Identifiers
  • (RS)-4-Amino-3-(4-chlorophenyl)butanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.013.170 Edit this at Wikidata
Chemical and physical data
FormulaC10H12ClNO2
Molar mass213.66 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • NCC(CC(=O)O)c1ccc(Cl)cc1
  • InChI=1S/C10H12ClNO2/c11-9-3-1-7(2-4-9)8(6-12)5-10(13)14/h1-4,8H,5-6,12H2,(H,13,14) checkY
  • Key:KPYSYYIEGFHWSV-UHFFFAOYSA-N checkY
  (verify)

Common side effects include sleepiness, weakness, and dizziness.[8] Serious side effects may occur if baclofen is rapidly stopped including seizures and rhabdomyolysis.[8] Use in pregnancy is of unclear safety while use during breastfeeding is probably safe.[14] It is believed to work by decreasing levels of certain neurotransmitters.[8]

The adverse effects and safety profile associated with baclofen when it is combined with sedative drugs (for example alcohol or benzodiazepines) range depending on the dose and the individual. The interaction may increase the sedative effects of all ingested sedatives and as such is not generally recommended.[15] In high doses the interaction can cause de novo seizures.[16]

Baclofen was approved for medical use in the United States in 1977.[8] It is available as a generic medication.[9][17] In 2022, it was the 104th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[18][19]

Medical uses

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Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis.[20] Use in people with stroke or Parkinson's disease is not recommended.[20] Intrathecal baclofen is used for severe spasticity of spinal cord origin that is refractive to maximum doses of oral antispasmodic agents or who experience intolerable side effects.[21][22] Baclofen is also used in the treatment of sleep-related painful erections.[23]

Baclofen is sometimes used off-label as a treatment for alcohol use disorder to reduce the risk of relapse and to increase the number of days that a person can go without drinking alcohol (abstinence days).[10] It is also sometimes used for the treatment of opioid withdrawal symptoms, and may be superior for this purpose to the more-commonly used clonidine.[11][12]

Adverse effects

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Adverse effects include drowsiness, dizziness, weakness, fatigue, headache, trouble sleeping, nausea and vomiting, poor concentration and recall (resembling dementia), urinary retention, or constipation.[3]

Withdrawal syndrome

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Discontinuation of baclofen can be associated with a withdrawal syndrome which resembles benzodiazepine withdrawal and alcohol withdrawal. Withdrawal symptoms are more likely if baclofen is administered intrathecally or for long periods of time (more than a couple of months) and can occur from low or high doses.[24] The severity of baclofen withdrawal depends on the rate at which it is discontinued. Thus to minimise withdrawal symptoms, the dose should be tapered down slowly when discontinuing baclofen therapy. Abrupt withdrawal is more likely to result in severe withdrawal symptoms. Acute withdrawal symptoms can be eased or completely reversed by re-initiating therapy with baclofen.[25]

Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, dizziness, nausea, inattention, memory impairments, perceptual disturbances, itching, anxiety, depersonalization, hypertonia, hyperthermia (higher than normal temperature without infection), formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia (fever), extreme muscle rigidity resembling neuroleptic malignant syndrome and rebound spasticity.[25][24]

Abuse

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Russian baclofen (trade name "Baclosan") 25 mg tablets with a warning: "Caution: the drug may suppress psychomotor reactions"

Baclofen, at standard dosing, does not appear to possess addictive properties, and has not been associated with any degree of drug craving.[26][27] Euphoria is however listed as a common to very common side-effect of baclofen in the BNF 75.[28] There are very few cases of abuse of baclofen for reasons other than attempted suicide.[26] In contrast to baclofen, another GABAB receptor agonist, γ-hydroxybutyric acid (GHB), has been associated with euphoria, abuse, and addiction.[29] These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor.[29] Baclofen possesses both sedative and anxiolytic properties.[27]

Overdose

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Reports of overdose indicate that baclofen may cause symptoms including vomiting, general weakness, sedation, respiratory insufficiency, seizures, unusual pupil size[clarification needed], dizziness,[3] headaches,[3] itching, hypothermia, bradycardia, cardiac conduction abnormalities, hypertension, hyporeflexia and coma sometimes mimicking brain death.[30] Overdose may require intubation and length of mechanical ventilation required may correlate with serum baclofen levels shortly after ingestion. Symptoms may persist even after the point at which serum baclofen levels are undetectable.[31]

Pharmacology

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Chemically, baclofen is a derivative of the neurotransmitter γ-aminobutyric acid (GABA). It is believed to work by activating (or agonizing) GABA receptors, specifically the GABAB receptors.[32]

Pharmacodynamics

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Baclofen produces its effects by selectively activating the GABAB receptor. Baclofen is postulated to block mono-and-polysynaptic reflexes by acting as an inhibitory ligand, inhibiting the release of excitatory neurotransmitters. Baclofen does not have significant affinity for the GHB receptor, and has no known abuse potential.[33] Agonism of GABAB receptors is thought to be responsible for baclofen's range of therapeutic properties, as GABAB knockout mice are unresponsive to the neurobiological effects of baclofen.[34]

Similarly to phenibut (β-phenyl-GABA), as well as pregabalin (β-isobutyl-GABA), which are close analogues of baclofen, baclofen (β-(4-chlorophenyl)-GABA) has been found to block α2δ subunit-containing voltage-gated calcium channels (VGCCs).[35] However, it is weaker relative to phenibut in this action (Ki = 23 and 39 μM for R- and S-phenibut and 156 μM for baclofen).[35] Moreover, baclofen is in the range of 100-fold more potent by weight as an agonist of the GABAB receptor in comparison to phenibut, and in accordance, is used at far lower relative dosages. As such, the actions of baclofen on α2δ subunit-containing VGCCs are likely not clinically relevant.[35]

For drug-reward and addiction, baclofen's mechanism of action is thought to be through its effect on the mesolimbic dopamine pathway, specifically leading to a decrease in dopamine release associated with alcohol.[10] GABAB receptor activation (GABAB receptor agonist activity) may decrease or inhibit alcohol's ability to activate or fire dopaminergic neurons following exposure to alcohol. Baclofen's mechanism of action when used to treat alcohol use disorder is not thought to be mediated through its muscle-relaxing or sedative properties, however there is evidence to suggest that the GABAB receptor-activation in the limbus may also reduce feelings of anxiety in people with alcohol use disorder.[10]

Pharmacokinetics

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The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low: the drug is predominantly excreted unchanged by the kidneys.[36] The half-life of baclofen is roughly 2–4 hours; it therefore needs to be administered frequently throughout the day to control spasticity appropriately.

Chemistry

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Baclofen is a white (or off-white) mostly odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

History

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Historically, baclofen was designed as a drug for treating epilepsy. It was first synthesized at Ciba-Geigy, by the Swiss chemist Heinrich Keberle, in 1962.[37][38] Its effect on epilepsy was disappointing, but it was found that in certain people, spasticity decreased. In 1971, it was introduced as a treatment for certain form of spasticity. It was approved by the US Food and Drug Administration (FDA) in 1977.[39]

Intrathecal baclofen was first introduced in 1984 to treat severe spinal spasticity. This administration route aimed to avoid supraspinal side effects.[40][41]

In his 2008 book, Le Dernier Verre (translated literally as The Last Glass or The End of my Addiction), French-American cardiologist Olivier Ameisen described how he treated his alcoholism with baclofen. Inspired by this book, an anonymous donor gave $750,000 to the University of Amsterdam in the Netherlands to initiate a clinical trial of high-dose baclofen, which Ameisen had called for since 2004.[42] The trial concluded, "In summary, the current study did not find evidence of a positive effect of either low or high doses of baclofen in AD patients. However, we cannot exclude the possibility that baclofen is an effective medication for the treatment of severe, heavy drinking AD patients not responding to or not accepting routine psychosocial interventions."[43]

Society and culture

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Routes of administration

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Baclofen 20 mg oral tablet

Baclofen can be administered, orally, intrathecally (directly into the cerebral spinal fluid) using a pump implanted under the skin, or transdermally as part of a pain-relieving and muscle-relaxing topical cream mix (also containing gabapentin and clonidine) prepared at a compounding pharmacy.[13][44]

Intrathecal pumps offer much lower doses of baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. A drug concentration in the cerebrospinal fluid more than 10 times greater than when given orally is achieved with this route. At the same time the blood concentration levels are almost undetectable, thus minimizing side effects.[44]

Besides those with spasticity, intrathecal administration is also used in patients with cerebral palsy[44] or multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen.[citation needed] With pump administration, a test dose is first injected into the spinal fluid to assess the effect, and if successful in relieving spasticity, a chronic intrathecal catheter is inserted from the spine through the abdomen and attached to the pump which is implanted under the abdomen's skin, usually by the ribcage.[citation needed] The pump is computer-controlled for automatic dosage and its reservoir can be replenished by percutaneous injection.[citation needed] The pump also has to be replaced every five to seven years or so.[45]

Other names

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Synonyms include chlorophenibut. Brand names include Beklo, Baclodol, Flexibac, Gablofen, Kemstro, Liofen, Lioresal, Lyflex, Clofen, Muslofen, Bacloren, Baklofen, Sclerofen, Pacifen and others.

Research

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Baclofen is being studied for the treatment of alcoholism.[26] Evidence as of 2019 is not conclusive enough to recommend its use for this purpose.[26][46] In 2014, the French drug agency ANSM issued a three-year temporary recommendation allowing the use of baclofen in alcoholism.[47] In 2018, baclofen received a Marketing Authorization for use in alcoholism treatment from the agency if all other treatments are not effective.[48]

It is being studied along with naltrexone and sorbitol for Charcot–Marie–Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy.[49] It is also being studied for cocaine addiction.[50] Baclofen and other muscle relaxants are being studied for potential use for persistent hiccups.[51][52]

From 2014 to 2017 baclofen misuse, toxicity and use in suicide attempts among adults in the US increased.[53]

References

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