LV11940B - APPLICATION OF MELATONINE TO TREATMENT OF PERSONS RESPONSIBLE FOR MEDICINAL PRODUCTS \ t - Google Patents

Description

1 LV 11940

USE 0F MELATONIN FOR TREATING PATIENTS SUFFERING ROM DRUG ADDICTION

The present invention relates to melatonin for use in the manufacture of a medicament for treating, or for preventing, synptoffls of dependence on, tolerance of, or addiction to 5 benzodiazepine drugs, for treating multidrug addicts and to a pharmaceutical formulation, for use iņ such treatoents

Dependence on benzodiazepines often develops in Insomnlacs who use thein for the lndūction of sleep and In multi-drug addicts who In the process of wlthdrawal from narcotics, 1Θ become addlcted to benzodiazepines to ease anxiety and convulslons. Moreover, chronlc benzodiazepine ādminis tration {where the benzodiazepines usually have long half-life values) may Inducē tolerance, expressed by an ineffective lncrease in dosage, by an unknown mechanism. Furthermore, rebound or 15 nwithdrawal" phenomena which often follow abrupt cessation of these drugs, as observed both in animals and humāns lead to addiction (Greenblatt, D.J., and Shader, R.I., Drug Hetab. Rev., 197S, 8: 13-28). In the 1990 US National Household Survey of the Use of Psychotherapeutic Medications, about 8% of the medical 20 users of hypnotics advanced a prescribed dose on their own, which is an lncrease of 25% as compared to former report in 1979· Taking into consideration that the survey found that 2.6% of the US population took benzodiazepine hypnotics (as compared to 2.k% in 1979) the number of individuāls in the US only who do 25 develop tolerance and dependence may be estimated at 580,000.

These values do not include substance use outside medical or social norms and multiple drug abuse. No method of rapid 2 withdrawal followed by an effective altemative treatoent has yet been reported in patlents who developed . dependence on benzodiazepine hypnoti.cs and this problem is a great obstacle in the rehabilitation and recovery of narcotic drug addicts.

It is well known that melatonin, an indole-derived hormone produced at night by the pineal gland, plays a major role in oediating the circadian sleep-wake cycle and in the regulation of sleep. There is also some evidence that melatonin can increase benzodiazepine efficacy, see, e.g., Cardinal!, O.P. et al, Adv. Biochem. Psychophara., 1986, 42: 155·" 164; Acuna Castroviejo, D., et al, J. Pineal Res., 1986, 3: 101-102; and Niles, L.P. et al, J. Neural Transm. 70: 117-124]. Also, melatonin can enhance the anxiolytic effects of diazepam in mice ' (Guardiola-Lemaitre, B. et al, Pharmacol. Biochem. Behav., 1992, 4l, 4O5~4O80). On the other hand, it has been suggested that benzodiazepines could, in some species including humāns, potentiate GABA-induced inhibition of melatonin synthesis and secretion (Mclntyre, I.H. et al, Biol. Psychiat., 1988, 24: 105-108) and that nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humāns, thus leading to distortion in the diurnal melatonin rhythm (Kabuto, M. et al, Endocr. Japon., 1986, 33. 405-414). Moreover, it has been observed that chronic treatment with oxazepam modified the diurnal variations in the density of melatonin receptors at night in the rat brain and that this effect was not observed in pinealectomized animals (Anis, Y. et al, J. Neural Transm., 1992, 89: 155”l66).

It has surprisingly been found in connection with the LV 11940 present invention that administrarion of melatonin concurrentlv with benzo-diazepine drugs can potentiaIly (1) wean a patient away from dependence on, addiction to, or tolerance of such drugs, and (2) in the case of a patient who has been diagnosed as requiring a benzodiazepine drug (where such undesired 5 svmptoms have not yet occurred), prevent the occurrence of such svmptoms. ACKNOVVLEDGMENT OF CITED PRIOR ART EP-A-513702 describes the use of melatonin and certain derivatives thereof in the therapv of sleep disorders and in pre-anaesthetic medication, 10 optionally in presence of a benzodiazepine. Tnis document States that the benzodiazepine can therebv be administered in a relativelv Iower dosage, and thus avoid effects (alteration of sleep rhvthms, rebound effect and development of tolerance) which are said to be related to administration of benzodiazepines in high dosages or for prolonged periods of time. This 15 document does not suggest that dosages of melatonin or the derivatives less than 10 mg could be used for the stated purpose, nsither does it suggest that melatonin might be useful when a patient has alreadv become dependent on, tolerant of, or addicted to a benzodiazepine drug. EP-A-518468 describes pharmaceutical controlled-release -20 formulations vvhich, briefly stated, release melatonin according to a profilē which simulates the profilē in plasma of a human having a normai endogenous melatonin profilē. The formulations, which oprionaIIy contain a melatonin receptor profilē modifier such as ojcazepam, are useful for treating conditions related to melatonin deficiency or distorrion, such as sudden infant death 25 svndrome and migraine. This document does not suggest use of melatonin to prevent or treat addiction to benzodiazepines.

DlALOG File Supplier PHIND. AN 00302794,13-03-92, reports that indole-3-pyruvic acid (IPA) increases sleep time in insomniacs, e.g. in benzodiazepine withdra%val, and that the effect of IPA on sleep is mainlv 30 3Α mediated by increased melatonin tumover in the pineal gland. This document does nor suggest use of melatonin to prevent or treat addiction to benzodiazepines. DESCRJPTION OF THE INVENTION The present invention thus proviaes use of melatonin in the manufacture of a medicament for treating addiction to benzodiazepines in a muhidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinicallv diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneouslv preventing the occurrence in the patient of svmptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, wherein said medicament contains at least an amount of 10 melatonin effective for any of said treatments, said amount being adapted for a dailv rāte of administration vn'thin the range of 0.01-100 mg, provided that, when said medicament is for treating a patient who has been clinicallv diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, then said medicament is a sustained release pharmaceurical formulation, which contains no more than 5 mg melatonin. 4 LV 11940

The said medicament may be a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal ādministration and which comprises at least one diluent, carrier or adjuvant, and may be additionally characterized by at least 5 one of the following features: (1) it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies within the range of 0.ΟΘ25-1ΘΟ mg; (ii) it is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rāte; (iii) it 10 comprises also at least one melatonin receptor modifier and/or melatonin profilē modifier. The medicament may comprise also, and the pharmaceutical formulation according to the invention comprises, at least one benzodiazepine drug, such as at least one of Alprazolam. Chlordiazepoxide, Clorazepate. Diazepam, 15 Flunitrazepam, Flurazepam, Halazepam, Lorazepam, 0xazepam, Prazepam, Temazepam and Triazolam. The formulation which comprises at least one benzodiazepine drug may also be characterized further by one or more of the features (i), (ii) and (iii) as described above. 20 In applying the present Invention to treating a multidrug addict or a patient who has symptoms of having becooe dependent on, tolerant of, or addicted to a benzodiazepine drug, ādminis tration of a benzodiazepine drug to the patient is continued, at least initially, and melatonin is concurrently 25 ādminis tered to the patient an amount which is effective to alleviate at least one of such symptoms.

In a particular embodiment of such treatoent, either 5 one of the benzodiazeplne drug and the melatonin may be In the forn of a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal ādministration and which comprises at least one diluent, carrier or adjuvant. Alternatively, benzodiazepine drug and melatonin may each be administered thus formulated, either separately, or may be combined into a single pharmaceutical formulation including both diazepine drug and melatonin. īn relation to the ādminis tration of the melatonin, whether administered separately from or together with one or more benzodiazepine drugs, administration may be effected at a daily dosage rāte which e.g. lies within the range of 0.01-100 mg; it may be administered in the form of a controlled release formulation. Illustratively, 1-2 mg melatonin in the form of a controlled release formulation may be administered at night. The melatonin may be administered together with a melatonin receptor modifier or a melatonin profilē modifler. Examples of melatonin receptor modifiers are short-acting benzodiazepines such as 0xazepam; examples of melatonin profilē modifiers are benzodiazepines, beta-blockers and serotonin uptake inhibitors. Instead of, or in addition to, use of such a profilē modifier, the melatonin profilē may be modifiēd by subjecting the patient to the effect of light, before, after or during administration of melatonin.

The benzodiazepine drugs referred to herein. may give rise to symptoms of dependence, tolerance and/or addiction. Without prejudice to this generality, such drug or drugs may be 6 LV 11940 one or more of, e.g., Alprazolam. Chlordiazepoxide, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, 0xazepam, Prazepam, Temazepam and Triazolam, as indicated above.

In one altemative embodiment of applying the lnvention to treating the above-mentioned symptoms. the benzodiazeplne drug(s) is(are) initially continued to be ādministered to the patient, concurrently with the melatonin, at a. daily rāte substantially the same as that received by the patient prior to coomencing treatment with melatonin. In another altemative embodiment of applying the invention in treating such symptoms, the benzodiazepine drug(s) is(are) ādministered to the patient, concurrently with the melatonin, at a'progressively decreasing daily rāte compared with that received by the patient prior to commencing treatment with melatonin. In this embodiment, the progressively decreasing daily rāte of administration may be continued, e.g., until a predetermined stabilized rāte of administration is achieved, or altematively, e.g., until the amount of benzodiazepine drug ādminis tered is zero.

In applying the invention for preventive purposes, i.e. in treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, a benzodiazepine drug is ādminis tered in an amount effective to alleviate said condition, while cohcurrently administering to the patient an amount of melatonin which is effective to prevent at least one of 7 such symptoos. The various embodiments described above as applicable to treating a patient having the stated symptom(s) are also correspondingly applicable to preventive purposes, except insofar as they wlll not be applicable for reasons which are 5 self-evident to a person of the art, e.g. in this instance treatment with a benzodiazeplne drug is a desideratum, so that evidently the amount of benzodiazepine administered. while possibly being reduced in any particular case as determined by a physician, will not be reduced to zero. 10 However, it will be within the scope of the preventive application of the invention, not only to administer, concurrently with melatonin, the benzodiazepine drug(s) at the conventional daily dosage rāte to achieve a particular purpose, but in the altemative to similarly administer such drug(s) at a 15 daily rāte which is less than that which is conventionally administered to a patient in order to alleviate said condition.

As stated above, the invention also extends to a pharmaceutical formulation which includes at least one a benzodiazepine drug and melatonin. Since benzodiazepine drugs 2G are usually administered 1-4 times daily, a daily rāte of 0.01-100 mg melatonin, administered typically at night, in the same formulation as the benzodiazepine (s), or even if administered separately therefrom, will illustratively be achieved by ādministering benzodiazepines as follows: 25 8 days unit dosage of benzodiazepines vvithin the range 1 0.01 -100 mg 2 0.05- 50 mg 0.033-33.3 mg 4 0.025- 25 mg

Thuš, when the pharmaceutical formulation of the invention is in unit dosage forrn, each unit dosage is preferablv admiriistered at night and preferably comprises an amount of melatonin within the range 0.0025-100 mg.

The follovving Table gives the amounts of benzodiazep'ine drugs used for treating the stated conditions in adults. For fiirther informātion, e.g. as to reservations, half-life, forms of administrarion and suitable dosages for children or infants, see Goodman & Gilman’s ‘The Pharmacological Basis of Therapeutics”, 7th Edition, 1985 (MacMillan Publishing Co.), the passages relating to use of benzodiazepines (e.g. pp. 352,437). 25 LV 11940 30 9

Benzodiazepine Content of unit oral dosage mg (xperday) Sedative Hypnotic Usual daily oral dose Anxiolytic Alprazolam 0.75-1.5 Chlordiazepoxide 10-100(1-3) 50-100 15-40 Clorazepate 3.75-15(2-4) 15-30 30 Diazepam 5- 10 (3-4) 5- 10 4-40 Flurazepam 15-30 Halazepam 60-160 Lorazepam 2- 4 2- 6 Oxazepam 15-30(3-4) 15-30 30-60 Prazepam 20-40 Temazepam 15-30 Triazolam 0.25-0.5 *mg; generallv divided into 2-i unit doses; for further informarion including parenteral dosage rātes, see Goodman & Giiman, loc cir

The preparation and release profilē of formulations for use for use in accordance with the invention or its applications are illustrated belovv. (a) There were compressed in a 7 mm cvlindrical punch at 2540 kg (2.5 tons), after diy mixing of the powdered materiāls, namelv 2 mg'tablet melatonin (Biosvnth Co., Switzerland) and acrvlic resin carrier (Rohm Pharma) which was Eudragit® RS100 (formulation SR-Msl or Eudragit® RSPO (formulation SR-Mfj, besides other components as noted: formulation SR-Ms: Eudragit® RS100 48.3%, lactose 50%, melatonin 1.2%: formulation SR-Mf: Eudragit® RSPO 36.3%, lactose 16.7%, calcium hvdrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%. SR-Ms and SR-Mf are sustained release formulations. A conventional dosage form (RM) \vas prepared similarlv to formulation SR-Mf, but using lactose instead of Eudragit® as carrier. 10 LV 11940 (b) The potential release profilē of the tablets prepared as described in paragraph (a), was first investigated by in vitro dissolution of melatonin therefrom in distilled water at 37 *C. The results in Table A show the % of the melatonin content (mean value of 6 tablets) which has dissolved at the stated intervāls of time.

Table A

Time(hours) 1 2 4 6 8 10 melatonin (X) released from: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100 (c) The iņ vivo profilē of the SR-Mf tablets prepared as described in paragraph (a), was investigated by oral ādministration twice to a healthy male (age 36) at 10 a.m.. i.e. when circulating melatonin Ievels are undetectable. The amount of melatonin released in vivo was determined by radioimmunoassay of its major metabolite, 6-sulphatoxymelatonin, in the urine. The amount of urinary 6-sulphatoxymelatonin closely reflects the blood Ievel of the hormone. The results in Table B show the melatonin determined as a % of the total melatonin ādministered (mean value of 2 tablets). 11

Table B

In vivo release of melatonin from SR-Mf

Time(hours) 1 2 4 6 8 10 % release at intervāls 10.7 25-7 40.6 14.0 7.0 1.9 cumulative release % 10.7 36.4 77.0 91.0 98.0 99.9

It is noted that the release of melatonin iņ vitro. illustrated in Table A, provides only an approximate indication of the iņ vivo release profilē due to the known phenomenon of the active 10 compound being absorbed by the tissues in the early stages of release.

The amount of melatonin in the sustained release formulations may be changed e.g. to 0.5» 1 or 5 mg/tablet, without affecting the release pattern found for the tablets 15 containing 2 mg/tablet melatonin.

Insofar as analogues of melatonin which substantially imitate the function of melatonin in the human body are known in the art, it will be appreciated that such analogues are deemed to be obvious Chemical eguivalents of melatonin, in the present 20 context.

In accordance with the present invention, one or more benzodiazepines may be incorporated in the above formulations, in amounts which have been described herein.

The invention will now be illustrated by the following 25 Examples. 12 LV 11940 EXAMPLE 1

The reciprocal effects of chronic benzodiazepine and melatonin ādministration on brain melatonin and benzodiazepine receptors and the ability of melatonin to reverse these effects were studied. Male rats were maintained on a daily 14 h light:10 h darkness schedule (lights-on G5.0Gh; cool white fluorescent illumination) at 24±2*C. Food and drinking water were supplied ad libitum. The animals (2 months old), were divided into 4 groups, 5 animals in each. The animals in one group (CON) were injected i.p. daily at l6:QG h with vehicle (200 μΐ saline). Those in the second group {VAL) were injected daily, i.p. at l6:GG h with diazepam {1 mg in 2GG μΐ vehicle; Roche). The animals of the third group (MEL) were injected daily at l6;GG h with vehicle; the drinking water of this group contained melatonin (4 mg dissolved in 10G μΐ ethanol and diluted to 1 liter). The animals in the fourth group (VAL/MEL) were injected daily at 16:00 h with diazepam (1 mg in 20G μΐ vehicle); the drinking vater of this group contained melatonin (4 mg dissolved in 1ΘΘ μΐ ethanol and diluted to 1 liter). After 21 days the treatment was stopped and the animals were weighed. The mean body weight values in the VAL (27^±20 g) and VAL/MEL groups (239*30 g) were found to be slightly lower than those in CON (292±30 g) or MEL groups (285*30 g).

The animals were decapitated between 18-19-00 h of the next day (at this time the density of 2-^5i_ļ0<j0meiatonin in the medulla pons should be maximal); their brains were rapidly removed and crude synaptosomal pellets were prepared as 13 described, and oelatonln receptors were assessed, as described by Laudon, M. and Zisapel, N.. FEBS Lett., 1986, 197: 9*12.

Benzodlazepine receptors were assessed by measurlng ^H-flunitrazepam (^H-FNZ) and ^H-RO 15*1788 binding as described by Amiri, Z. et al. BrainRes., 1991. 553: 155*158. Blnding parameters were calculated from the equilibrium blnding data. Bmax values represent the specific blnding of iodomelatonin, ^h-fNZ or ^h-RO 15*1788 at saturation, and Kd values are the apparent dissociation constants. Blnding parameters of the various groups were compared by analysis of Variance followed by Student-Newman-Keul's tēst for multiple comparisons. Differences were considered significant if P<0.05· Daily injections of diazepam (lmgi.patl6.GGh) to male rats for 3 weeks markedly reduced the density of 2-^5i-ļ0(jomeiatonin binding sites in the oedulla*pons (Table 1), whereas benzodiazepine binding was not signlficantly affected (Table 2). If melatonin receptors are related to the control of the sleep-wake cycle, the results suggest that chronic benzodiazepine ādministration results in the diminution of melatonin-responsive mechanisms and consequent physlological activities.

Melatonin, given orally via the drinking water for 3 weeks, significantly enhanced ^H-RO 15-1788 binding in the medulla pons (Tables 2,3). whereas 2-^^5x_i0(joinelatonin binding was not affected. The increase in benzodiazepine binding site density and apparent Kd in the medulla-pons induced by the melatonin treatment, is compatible with the augmentation observed previously in the rat cortex, and shown to be mediated by opioid 14 LV 11940 peptides (Gomar, M.D. et al, Neuroendocrinology 1993. 4:987-990). The fact that this enhancement persists even in diazepam-treated animals may rule out competition between melatonin and benzodiazepines on the benzodiazepine binding sltes. 5 Daily ādministration of both dlazepam and melatonin, enhanced ^H-RO 15-1788 binding in the-medulla pons, and reversed the diazepam-induced suppression of 2-^^5j-i0<jomelatonin binding in this area (Tables 1,2). These results are surprising since as previously shown (Anis, Y. et al, in melatonin binding sites in 10 the hamster brain: impact of melatonin. Molec. Celi.

Endocrinol., 1989. 67: 121-128; Oaknin-Bendahan. S. et al, J.

Basic Clin. Physiol. Pharmacol., 1992, 3: 253“268) and is also confirmed in the present study, ādministration of melatonin by morning or evening injections, or orally via the drinking water, 15 does not affect the density or diurnal variations in melatonin binding sites in most brain areas including medulla-pons.

Moreover, pinealectomy does not abolish the diurnal variations in 2-^5i-i0<jomeiatonin binding sites although it affects their phase position (Oaknin-Bendahan et al., 1992, ibid). Thus, 20 changes in melatonin binding site densities might not be due to autoregulation of the receptor by melatonin.

In the cerebral cortex, melatonin slightly reduced ^h-R0 15-1788 and %-FNZ binding. Diazepam treatment did not significantly affect 15-1788 and binding but 25 prevented the melatonin-mediated decrease (Tables 2,3). These data suggest firstly, that the· effects of melatonin on benzodiazepine binding sites are localized, rather than general 15 suppression or facilitation of the binding occurring, and secondly, that melatonin replacement therapy may counCeract some deleterious effects of chronic benzodiazepine treatment.

Table 1 shows equilibrium binding parameters of 5 iodomelatonin binding sites in synaptosomal preparations from the medulla-pons area of diazepam and/or melatonin-treated and untreated rats, in terms of mean and S.D. values of Kd (in nM) and Bmax (in pmol/mg protein). Values denoted by the same character In Table 1 do not differ significantly. (Codes having 10 the same significance are also used in Tables 2 and 3· below.)

Table 1 GROUP Kd±sd Bmax±sd CON 0.87*0.2 a 7.9*1.0 a MEL 1.16*0.3 a 7.7*1.0 a VAL 0.98*0.21 a 5.1*0.5 b VAL/MEL 2.27*0.75 b 12.5*2.0 c

Table 2 shows equilibrium binding parameters of ^H-RO 15-17^8 binding sites in synaptosomal preparations from the medulla-pons area of diazepam and/or melatonin-treated and 20 untreated rats, in terms of mean and S.D. values of Kd (in nM) and Bmax (in pmol/mg protein). 25 LV 11940

Table 2 GROUP Kd±sd Bmax*sd CON 2.3*0.4 a 310*22 a MEL 2.8*0.2 a 476*26 b VAL 2.5*0.4 a 295*34 a VAL/MEL 2.6*0.5 a 375*87 b Table 3 shows the effect of diazepam or melatonin on 3h-fnz and 3H-R0 15-1788 binding in rat cerebral cortex membranes , in terms of mean i and S.D. values (in pmol/mg protein). Table 3 GROUP 3H-FNZ 3h-ro 15-1788 CON 935*31 a 1354* 48 a MEL 765*78 b 1060* 26 b VAL 870*22 a 1264* 99 a VAL/MEL 980*16 a 1362*155 a EXAMPLE 2

Thls Exaaple illustrates the surprising action of melatonin in facilltating very rapld wlthdrawal from benzodiazeplne drug tolerance. A 43 year old female, marrled wlth 2 children has been suffering from sleep onset insoonia for the last 10 years accompanied by frequent and severe mlgralne attacks. A thorough neurological assessoent was negative. Psychiatric or other organic problems were also ruled out.

Throughout these years she had been treated with benzodiazepines, tricyclic antidepressants and neuroleptic drugs, 17 as well as by biofeedback and relaxation nethods, with no apparent relief. For the last year she has been using 4-8 mg Lorazepam every night. A thorough psychological assessment at the Sleep Laboratory of Tel Avlv University, did not disclose any Significant pathology. The quality of 'sleep was assessed by an actigraph tracing which automatically monitors the bedtioe sleep-wake pattem through a small device attached to the hand wrist. The tracing was recorded for 3 consecutive days and showed a deranged sleep pattern: reduced efficiency, long sleep latency and multiple waking episodes. Urine was collected every 3 hours (for 36 hours) and assayed for the major melatonin metabolite: 6-sulphatoxymelatonin, as an indicator for the diurnal secretion of plasma melatonin. Results showed that 6-sulphatoxymelatonin excretion Ievels were lower than for aged-matched individuāls, and lacked the typical circadian rhythm (TABLE 4),

Oral administration of a controlled-release melatonin formulation in the form of tablets containing 1 mg melatonin (Neurim Pharmaceuticals, īsrael) was initiated, in order to correct for the deficiency and distortion of the melatonin rhythm. One tablet was administered daily at 8:30 p.m. The patient was asked to gradually reduce the number of benzodiazepine tablets taken each night. Surprisingly, within 2 days, the patient stopped using the benzodiazepine hypnotics altogether, and claimed that her insomnia has improved remarkably. In addition, her headaches also subsided gradually. A repeated actigraph tracing after 3 weeks treatment showed marked 18 LV 11940 improvement in sleep pattern.

The treatment was stopped and 2 weeks. afterwards urine was collected again every 3 hours (for 36 hours) and assayed for 6-sulphatoxymelatonin. The results (Table 4) indlcated an 5 lncrease in amount and a clear nocturaal peak of urinary 6-sulphatoxymelatonin. A 5"®onth follow-up has confirmed that the patient stili maintains her quality of sleep and hardly suffers frotn headaches. After 6 months without treatment sleep quality began to deteriorate and melatonin therapy was resumed. 10 This case-report indicates potentially a breakthrough in relieving many patients whose quality of life has been impaired by addiction to benzodiazepine hypnotics. Ādministration of exogenous melatonin may moreover serve as a means of rapid and symptomless withdrawal from benzodiazepines in tolerant patients. 15 Table Urinary 6-sulphatoxymelatonin in benzodiazepine -dependent patient before and after melatonin therapy (pg/hour)

Time before treatment after treatment 15-00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11 24.00 0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.21 12.00 0.13 0.01 15.00 0.22 0.04 25 19 EXAMPLE 3

Thls example illustrates the effects of long term ādministration of melatonin in the treatment of insomnia in patients dependent on a benzodiazepine drug.

Two volunteers, Y.L., an 80 year old male, and E.L., a 73 year old female, had each suffered for a number of years from insomnia and/or frequent awakenings during the night . accompanied by difficulty in resuming sleep afterwards. Both were found to have low melatonin secretion, by determination of the amount of the metabolite 6-sulphatoxymelatonin, in the urine. Both patients had been taking 1-2 mg of flunitrazepam orally prior to retiring each evening.

Each patient was vreaned off the flunitrazepam by gradually reducing the dose and simultaneously administering melatonin orally (2 mg melatonin daily in controlled release form) over a two-month period. Since the end of that period, each patient has continued taking melatonin in the same form and at the same dosage rāte over approximately two years.

Each patient has subjectively reported good sleep inducement and a substantial improvement in sleep quality. Specifically, patient E.L. noted an improvement in sleep quality at the beginning of the «reaning period and Y.L. noted a similar effect about two «reeks into the weaning period. Each patient reported reduced fatigue during the daytime within several days after the beginning of the weaning period. and also indicated that the melatonin has caused neither residual tiredness in the moming, nor any hangover feeling. No side effects were reported 20 LV 11940 by either patient. EXAMPLE 4

This example, designed as a randomized, double-blind, crossover study, illustrates the ability of melatonin replacement 5 therapy to improve sleep maintenanee in chronic benzodiazepine drug-using elderly patients.

The group, of Dean age 78 (SD-9»7) conslsted of eight men and five wooen, ali of whom complained of long-term insomnia and used varlous benzodiazepines for sleep induction. Urine was 10 collected approxioately every 4 hours for 15 hours and the nocturnal excretlon of 6-sulphatoxymelatonin, the major urinary metabolite of melatonin, was assayed In duplicate by RIA. Urine analysls of these patients showed. low and delayed 6- sulphatoxymelatonin excretion (<l4 pg per night compared with 25 15 pg per minūte in young adults). The study protocol consisted of two treatment periods of three weeks each, with one week wash-out interval between the two treatment periods. Ouring the treatment periods, patients were ādministered orally either 2 mg controlled-release melatonin tablets, or placebo, two hours 20 before bedtime. Five patients continued the melatonin treatment for a period of two months beyond the initial experimental period.

Patients' sleep was objectlvely assessed at the end of each treatment period for three consecutive nights using a wrist-25 worn actigraph. Motion recordings were analysed using the Neurim algorithm to determine sleep latency, sleep efficiency, total slepp time, wake after sleep onset and number of awakenings, as 21 an average over three nights for each subject. Six Wilcoxon matched-palrs signed-ranks analyses revealed statistically significant dlfferences in sleep parameters between the melatonln and placebo treatment periods' ranks. The results are shown in Table 5·

Table 5'· Effect on sleep parameters of melatonln replacement of benzodiazepine drugs.

Parameter after 3 weeks' treatment after +two months melatonin placebo oelatonin treatment sleep } 82% 75% 852 efficiency) (z - -2.82, P - 0.005) sleep latency. 17 mins. » 39 mins. 7 mins. (z - -2.12, P - 0.03) wake after ) 59 mins. » 76 mins. 42 mins. sleep onset) (z - -2.00, P - 0.04) no. of awakenings 11 17 10 <z - -2.70, P - 0.007) total sleep time 386 mins. • 375 mins. 348 mins (z « -0.57. P - O.58)

From the above results, it is concluded that melatonin replacement therapy can improve sleep initiation and maintenance in benzodiazepine drug-using elderly patients having a low endogenous melatonin output. The benefits of melatonin treatment increase with time, suggesting that reorganisation of the circadian system has occurred. LV 11940 22

GLAIMS 1. Use of melatonin in the manufacture of a medicament for treating addiction to benzodiazepines in a multidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinicallv diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneouslv preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, wherein said medicament contains at least an amount of melatonin effective for any of said treatments, said amount being adapted for a daily rāte of administration within the range of 0.01-100 mg, provided that, when said medicament is for treating a patient vvho has been clinically diagnosed as having a condition susceptible to alleviation bv administration of a benzodiazepine drug, then said medicament is a,sustained release( pharmaceutical formulation, which contains no more than 5 mg melatonin. 2. Use of melatonin according to claim 1 in the manufacture of a medicament for treating addiction to benzodiazepines in a multidrug addict, or a patient vvho has svmptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug. 3. Use according to claim 2, vvherein said medicament is a sustained release medicament, which contains no more than 5 mg melatonin. 4. Use of melatonin according to claim 1 in the manufacture of a sustained release medicament for treating a patient who has been clinicallv diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneousIy preventing the occurrence in the patient of svmptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, vvherein said medicament contains at least an amount of melatonin effective for said treatment vvhich, said amount being adapted for a daily rāte of administration vvithin the range of 0.01-5 mg. 5. Use according to any one of claim 1 -4, wherein said medicament comprises a pharmaceutical formulation adapted for oral, rectal, parenteral or transdennal administrarioņ and vvhich comprises at least one diluent, carrier or adjuvant 6. Use according to claim 5, wherein said pharmaceutical formulation is additionally characterized bv ai least one of the following features: (i) · it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies vvithin the range of0.0025-100 mg when said formulation is not a sustained release formulation and vvithin the range of 0.0025-5 mg when said formulation is a sustained release formulation (ii) vvhen said formulation is a sustained release formulation it is a controlled release formulation, vvherein the melatonin is released at a predetermined controlled rāte; (iii) it comprises also at least one melatonin receptor modifier and/or melatonin profilē modifier. 7. Use according to any one of claims 1-6, vvherein said pharmaceutical formulation comprises also at least one benzodiazepine drug, which preferablv comprises at least one of Alprazolam, Chlordiazepoxide, Clorazepate, Diazepara, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam and Triazolam. 8. Use according to any one of claims 1-7, vvherein said treating includes administering the benzodiazepine drug(s) concurrentIy with melatonin, the benzodiazepine drug(s) being administered at a daily rāte vvhich is progressively decreased until a predetermined stabilized rāte of administration of benzodiazepine drug(s) is achieved. 24 24 LV 11940 9. Use according to any one of claims 1-7, wherein said treating includes admmistcring the benzodiazepine drug(s) concurrentiy with melatonin, the benzodiazepine drug(s) being administered at a daily rāte which is progressively decreased untū complete withdrawal of the patient from benzodiazepine drug(s) is achieved.

Claims (9)

Use of melatonin for the manufacture of medicaments for the treatment of patients with pharmaco-pharmaceuticals on a plurality of drugs, including adherence to benzodiazepines, for the treatment of patients with symptoms of addiction, tolerance or predisposition to benzodiazepine preparations, or For the treatment of patients with clinical signs of improvement after the use of benzodiazepine preparations, while preventing the occurrence of addiction, tolerance or predisposition symptoms to benzodiazepine preparations, these medicinal products contain at least the amount of melatonin effective in the treatment of the above conditions. at 0.01-100 mg, but if the medicine is for the treatment of patients who are clinically exposed to the condition after the benzodiazepine treatment, the medicine is dosed as a slow-release formulation, where the dose of melatonin does not exceed 5 mg. 2. The use of melatonin for the manufacture of a medicament according to claim 1, for use in the treatment of patients with pharmaco-pharmaceuticals on a plurality of drugs, including benzodiazepines, which exhibit symptoms of addiction, tolerance or tendency to benzodiazepine preparations. The use of melatonin according to claim 2, wherein said medicament is dosed as a slow-release preparation, wherein the dose of melatonin does not exceed 5 mg. 4. The use of melatonin according to claim 1 for the manufacture of a medicament for the treatment of patients with clinical manifestations of post-benzodiazepine improvement, while preventing the symptoms of addiction, tolerance or predisposition to benzodiazepine preparations, said medicament comprising at least melatonin. effective in treating the above conditions and the effective daily dose of melatonin is from 0.01 to 5 mg. 5. The use of melatonin according to any one of claims 1 to 4, wherein said medicament comprises a pharmaceutical composition for oral (oral), rectal, parenteral or transdermal use and contains at least one diluent, carrier or adjuvant. form preparation. 6. The use of melatonin according to claim 5, wherein said pharmaceutical composition is further characterized by at least one of the following features: (i) a dosage unit form, each dosage unit comprising an amount of melatonin in the range of 0.0025 to 100 mg, said the composition is not intended for long-term use and between 0.0025 and 5 mg when the composition is intended for long-term operation; (ii) when said composition is for a sustained, controlled action in which melatonin is involved in a pre-conditionally controlled dose; (iii) further comprising at least one melatonin receptor modifier and / or a melatonin profile modifier. 7. The use of melatonin according to claims 1 to 6, wherein said pharmaceutical composition also comprises at least one benzodiazepine, which consists primarily of at least one alprazolam, chlordiazepoxide, chlorazepam, diazepam, flunitrazepam, flurazepam, halazepam, lorazepam, oxazepam, prazepam, temazepam and triazolam. The use of melatonin according to claims 1 to 7, wherein said treatment includes the use of benzodiazepine (s) concomitantly with melatonin, the use of benzodiazepine (s) at a daily dose which progressively decreases until the dose of benzodiazepine (s) prescribed above is reached. The use of melatonin according to claims 1 to 7, wherein said treatment includes the use of benzodiazepine concomitantly with melatonin, the use of benzodiazepine (s) at a daily dose which progressively decreases until the patient is completely removed from the benzodiazepine.