138
Case Report
Misuse of Zopiclone and Convulsions during Withdrawal K. Aranko 1, M Henriksson 2, C. Hublin 3, A. M. Seppä/äinen 3 Departments of Clinical Pharmacology I, Psychiatry2 and Neurology 3, U niversity of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
It has been documented that benzodiazepines have the potential to cause dependence and withdrawal reactions, including convulsions. However, the available data concerning zopiclone, a nonbenzodiazepine hypnotic, are insufficient. The present study describes the case of a 36year-old man who repeatedly rnisused zopiclone, in daily doses of 60 - 90 mg. Furthermore, the patient sufTered from convulsion on two occasions following abrupt withdrawal of zopiclone. The concominant use of alcohol, trimiprarnine, and promazine may have contributed to the development of convulsions. It is concluded that zopiclone may cause problems associated with misuse and withdrawal reactions similar to those ofbezodiazepines.
Introduction
The dependence-inducing potential of benzodiazepines and withdrawal reactions, including convulsions, are well recognized (Hollister et al., 1961; Petursson and Lader, 1984; Cappell et al., 1986; Woocß et al., 1987). Zopiclone, a nonbenzodiazepine hypnotic, is one of their successors; its efficacy is well-established and it causes few side-effects (Goa and Hee/, 1986). Zopiclone, a cyclopyrrolone derivative, difTers in chemical structure from benzodiazepines, but resembles them very closely in pharmacological profile (lu/ou et al., 1983; Griffiths et al., 1986). It binds to sites on the benzodiazepine receptor complex linked to the GABAA"receptor and chloride-ion channel ("central type benzodiazepine receptors") (B/anchard et al., 1983), however, there are some dissimilarities between zopiclone and benzodiazepines as regards receptor-binding properties (Trift/etti and Snyder, 1984). In spite of experience with benzodiazepines, data on the 10ngterm efTects, dependence potential, and withdrawal reactions of zopiclone are incomplete (Editorial,
Pharmacopsychiat. 24 (1991) 138 - 140 lC> GeorgThieme Verlag Stuttgart·New York
Der Mißbraucb von Zopiclon und KrampfanfliUe während des Arzneimittelentzugs - Ein Fallbericbt
Es ist bekannt, daß der Mißbrauch von Benzodiazepinen Abhängigkeit und Entzugssymptome, einschließlich Konvulsionen, verursachen kann. Über Zopiclon, ein Non-Benzodiazepin-Hypnotikum, gibt es allerdings nur unzureichend Daten. Wir beschreiben einen Fall von einem 36jährigen Mann, der wiederholt Zopiclon mißbrauchte, wobei die tägliche Dosis 60 - 90 mg war. Der Patient hatte zweimal einen Krampfanfall, nachdem er plötzlich eine hohe Dosis Zopiclon abgesetzt hatte. Ein mäßiger Alkoholgebrauch sowie die Behandlung mit Trimipramin und Promazin zu der gleichen Zeit haben möglicherweise zur Auslösung von Konvulsionen beigetragen. Zusammenfassend läßt sich feststellen, daß Zopiclon Probleme wie Mißbrauch und Entzugssymptome ähnlich wie die Benzodiazepine verursachen kann.
1990). To the authors' knowledge, this is the first report of misuse and convulsions after abrupt withdrawal of zopiclone.
Case report The patient, a 36-year-old man with a masters degree in technology, had no history of cerebral or other somatic disease. He had been prone to perfectionism and preoccupation with the schedules of daily Iife. In Januar 1987 he was admitted to the psychiatric outpatient department of Helsinki University Central Hospital (HUCH) and diagnosed as sufTering from major depression and compulsive personality disorder. His physical examination, EEG, and routine laboratory screening aIl showed normal findings. A comprehensive psychiatric interview revealed no evidence of memory disturbances. Clomipramine (ad, 150 mg daily) and supportive psychotherapy were initiated. In autumm 1987 the patient's depression recurred and clomipramine was reintroduced together with 5 mg of nitrazepam to relieve the subjective distress caused by difficulties in falling asleep and early awakenings. The patient insisted on sleeping 10 hours per night to maintain his working capacity, and started to misuse ni-
Received: 28. 9. 1990 Revised version: 28.2. 1991 Accepted: 1.3. 1991
Downloaded by: Universite Laval. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Misuse ojZopiclone and Convulsions during Withdrawal
In autumm 1988 the next major depressive episode was again characterized by very distressing sleep difficulties. After trimipramine (ad, 150 mg for nights) and promazine (100 mg for nights) had failed to alleviate the patient's difficulties in falling asleep, 7.5 mg of zopiclone was added (zopiclone has been on the market in Finland since 1987). In August 1989, following an accumulation of psychosocial stress in his life, the patient experienced increased anxiety, and he began to suffer from being awake for several short periods every nigh1. He started to use an additional 15 - 30 mg ofzopiclone in the early morning hours so that he could meet his requirement of 10 hours ofuninterrupted sleep. According to the patient's diary written over the next two months, he gradually increased the dose of zopiclone to 60 - 90 mg per nigh1. He began to suffer from memory difficulties, but he was able to keep up with his normal daily activities. At the beginning of November he began to run out of zopiclone tablets, and before he discontinued taking them he had 7.5 mg on two nights. On the first day of total abstinence, he experienced a grand-mal-type convulsion observed by his sister (a nurse). One week later, at an appointment with his psychiatrist, he had marked difficulties in recalling the events of the past month. He also reported that while taking high doses of zopiclone he daily found hirnself in situations and places without remembering why and what to do there. The patient refused further examinations, and agreed to restrict the dose of zopiclone to 7.5 mg. In December, 1989, however, his diary documented daily use of 60 - 90 mg of zopiclone which was confirmed by the drug delivery data records in his prescriptions. The pattern of consumption of beer was unchanged (30 - 40 g of alcohol daily). In spite of the resulting daytime sleepiness, he had also increased the daily doses of trimipramine and promazine to 200 - 300 mg and 200 - 300 mg (600 mg once) respectively. Zopiclone tablets were now being taken throughout the whole night, usually two tablets immediateiy upon awakening. The nightly dose of zopiclone fluctuated, usually between a high dose (30 - 80 mg) one night and a low dose (15 mg) the nex1. In January 1990, after almost two months of high-dose zopiclone administration, he agreed to be hospitalized. A day before admission to the inpatient department of psychiatry (HUCH), he reduced the dose of zopiclone to 7.5 mg, and those of trimipramine and promazine to the prescribed doses (i. e., 150 mg and 100 mg respectively). Soon after his arrival at the hospital, on 19 January 1990, he was found in bed at noon with a grand-mal-type convulsion lasting about four minutes. Diazepam rectiole (10mg) was given within five minutes. Later in the afternoon the patient was anxious, dysphoric, and suffering from memory difficulties. Carbamazepine (100 mg 1. i. d.) was added to the medieation and zopiclone gradually withdrawn over a one-week period, starting from 15 mg per nigh1. Except for impairments in longterm memory storage and/or retrieval processes, the results of a detailed neurological examination (performed 21 January 1990) were normal. A neuropsychological examination performed two weeks after hospital admission and repeated testing two months later showed no obvious memory deficits, with slight improvement occurring over time (Wechsler Memory Scale land 11, MQ ~ 129 and 135 respectively). Extensive laboratory screening revealed no plausible cause for the patient's convulsion, nor did erythrocyte indices or liver tests indicate signs of alcohol toxicity. Five days after the convulsion, an EEG examination displayed a slight abnormality. Alpha activity was somewhat disorganized and slow transients were noted in the posterior areas; both abnormalities were possibly duc to overuse of drugs. No paroxysmal abnormalities were notcd. In March 1990, the patient's EEG was again normal; alpha activity was regular and resembled his EEG examination in January 1987. In addition, a brain er scan revealed no pathologie changes. Soon after discharge from the hospital in April 1990, the patient's fear of insomnia returned and he increased the doses of chlorprothixen and promazine to 200 mg and 300 mg per night respectively. In addition, he resumed his daily consumption ofbeer (30-
40 g of a1cohol). For the first two days after readmission to the hospital, he was only given 100 mg of promazine daily; no withdrawal symptoms were seen.
Discussion
Although there were several confoundings factors, the patient's compulsive use of high doses of zopiclone and concurrent reversible memory deficits, and the subsequent convulsions on abrupt withdrawal, were reasonably weil documented. It is evident that the regular misuse of zopiclone in doses ten times higher than those recommended was due to the patient's psychopathology; thc resulting neuropsychological consequences are the pharmacological efTects to be expected given the doses ingested. The patient's history and extensive examinations detected no reasons for a lowered convulsion threshold aside from zopiclone withdrawal. However, the concomitant use of antidepressants and neuroleptics, both of which are known to precipitate convulsions (Marks, 1985), the lack of drug concentration data, and the regular use of alcohol confound the conclusions. Alcohol is a known predisposing factor for both convulsions and benzodiazepine dependence (Petursson and Lader, 1984; Woods et al., 1987). Interestingly, the patient had previously misused nitrazepam in a similar pattern and, indeed, nitrazepam and zopiclone have been shown to have an equal dependence potential in rhesus monkeys (Yanagita, 1983). Furthermore, the withdrawal symptoms of nitrazepam and zopiclone were reported to be comparable. In contrast to diazepam withdrawal, however, no convulsions were manifested upon abrupt discontinuation of zopiclone (Yanagita. 1983). The results of two double-blind studies (Bechelli et al., 1983; Boiss! et al., 1983) suggest that the dependence-inducing potential of zopiclone may be slightly lower than that of triazolam. However, both drugs may produce efTects similar to those induced by alcohol in 60 to 70% of former alcoholics (Bechelli et al., 1983). Furthermore, when zopiclonc was tested with hcalthy volunteers, withdrawal symptoms manifested in a form of rebound insomnia or increased anxiety were documented after discontinuation of treatment lasting only up to three weeks at the recommended doses (Dorian et al., 1983; Lader and Frcka, 1987). The same symptoms were reported for insomniacs (van der Kleijn, 1989). The present patient had used high doses of zopiclone for months, and convulsions had occurred during two consecutive withdrawal periods. The short elimination half-life (t l / 2 ß = 5 - 6.5 hours) of zopiclone (Gaillot et al., 1983; Houghton et al., 1985) may partly explain the pattern of misuse, characterized by one "wash-out" day between high doses. In fact, this fluctuating pattern of intake may have contributed to the present patient's continuation of misuse: one is reminded here of the daily withdrawal syndromes described among users of triazolam, another hypnotic with a short halflife (Morgan and Oswald, 1982). This concept also correlates with the emergence of convulsions after more than six t l / 2ß have elapsed from the high dose and three t 1/ 2ß from the last small dose; i. e., after 98 % and 88 '% of the doses have been eliminated respectively (Rowland und Tozer, 1989). It is also worth recalling that abnormal anxiolytic or hypnotic doses of barbiturates (Isbell at al., 1950; Fraser et al., 1958) and benzodiazepines (Hollister et al. , 1961; Cappell et al., 1986) are
Downloaded by: Universite Laval. Copyrighted material.
trazepam (ad, 50 mg nightly). He also reported daily consumption of beer equivalent to 30 - 40 g of absolute alcohol. It took one week to taper down nitrazepam; no withdrawal symptoms occurred and attention was paid to the potential dangers of hypnotic misuse.
139
Pharmacopsychiat. 24 (1991)
usually needed for a prolonged period to induce convulsions upon withdrawal.
In conclusion, the authors would like to emphasize the problems, analogous to those associated with benzodiazepines, encountered by the patient during and upon withdrawal from high doses of zopiclone, a nonbenzodiazepine hypnotic. References Blanehard, J. c., A. Boireau, L. Julou: Brain receptors and zopiclone. Pharmacology 27 (Suppl. 2) (1983) 59 - 69 Beehelli, L. P., R. Navas, S. A. Pierangelo: Comparison of the reinforcing properties of zopiclone and triazolam in former a1cohoIics. Pharmacology 27 (Suppl. 2) (1983) 235 - 241 Boissi, K., J. F. Dreyfus, M. Delmotte: Studies on the dependence-inducing potential of zopiclone and triazolam. Pharmacology 27 (SuppI.2)(1983)242 - 247 Cappell, H D., E. M. Seilers, U. Busto: Benzodiazepines as drugs of abuse and dependence. In: Cappell et a1. (eds.): Research Advances in Alcohol and Drug Problems, Vol. 9. Plenum Press, New York(\ 986)53 - 126 Dorian, P., E. M. Seilers, H Kaplan, C. Hamilton: Evaluation of zopiclone physical dependence liability in normal volunteers. Pharmacology 27 (Suppl. 2)(1983)228 - 234 Editorial: Zopiclone: another carriage on the tranquilliser train. Lancet335(1990)507 - 508 Fraser, H. F., A. Wikler, C. F. Essig, H. Isbell: Degree of physical dependence induced by secobarbital or phenobarbital. J. Am. Med. Assoc. 166 (\ 958) 126-9 Goa, K. L., R. C. Heel: Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs32(1986)48 - 65 Gaillot, J., D. Heusse, G. W. Hougton, J. Mare Aurele, J. F. Dreyfus: Pharmacokinetics and metabolism of zopiclone. Pharmacology 27 (Suppl. 2) (1983) 76 - 91 Griffiths, A. N., D. M. Jones, A. Riehens: Zopiclone produces efTects on human performances similar to flurazepam, lormetazepam, and triazolam. Br. J. Clin. Pharmacol. 21 (1986) 647- 653 Hollister, L. E.. F. P. Motzenbeeker, R. 0. Degan: Withdrawal reactions from chlordiazepoxide ("Librium"). Psychopharmacologia 2(1961)63 - 68 Houghton, G., M. Dennis, R. Templeton, B. Martin: A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane).Int.J. Clin. Pharmacol. Ther. Toxiol. 23 (\ 985)97 - 100 Isbell, H., S. Altsehul, D. H. Kornetsky, A. J. Eisenman, H G. Flanary, H. G. Fraser: Chronic barbiturate intoxication: an experimental study. Arch. Neurol. Psychiat. 64(1950) 1- 28 Jolou, L., M. C. Bardone, J. C. Blanehard, C. Garret, J. M. Stutzmann: Pharmacological studies on zopiclone. Pharmacology 27 (Suppl. 2)( 1983)46 - 58 Lader, M., G. Freka: Subjective efTects during and on discontinuation of zopiclone in normal subjects. Pharmacopsychiatry 20 (\ 987) 67-71 Marks, J.: The benzodiazepines. Use, overuse, misuse, abuse? 2nd ed., MTP Press Limited, Lancaster 1985 Morgan, K.. I. Oswald: Anxiety caused by a short-Iife hypnotic. Br. Med.J.284(1982)942 Petursson. H, M. H. Lader: Dependence on tranquilIizers. Maudsley Monographs 28. Oxford University Press, Oxford 1984 Rowland, M., T. N. Tozer: Clinical Pharmacokinetics. Concept and Applications. 2nd edition. Lea & Febiger, Philadelphia-London 1989 Triftletti, R. R., S. H. Snyder: Anx.iolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked a1losterically to benzodiazepine receptor. Mol. Pharmacol. 26 (\ 984)458 - 469 Van der Kleijn, E.: EfTects of zopiclone and temazepam on sleep, behaviour and mood during the day. Eur. J. Clin. Pharmacol. 36 (1989)247 - 251
K. Aranko, M Henn'ksson, C. Hublin, A. M Seppäläinen Wood5,J. H., J. L. Katz. G. Winger: Abuse liability of benzodiazepines. Pharmacol. Rev. 39 (1987) 215 - 413 Yanagita, T.: Dependence potential of zopiclone studied in monkeys. Pharmacology 27 (Suppl. 2)(1983) 216 - 227
Kari Aranko, M.D.
Department of Clinical Pharmacology University ofHelsinki Paasikivenkatu 4 SF-00250 Helsinki Finland
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140
Case Report
Misuse of Zopiclone and Convulsions during Withdrawal K. Aranko 1, M Henriksson 2, C. Hublin 3, A. M. Seppä/äinen 3 Departments of Clinical Pharmacology I, Psychiatry2 and Neurology 3, U niversity of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
It has been documented that benzodiazepines have the potential to cause dependence and withdrawal reactions, including convulsions. However, the available data concerning zopiclone, a nonbenzodiazepine hypnotic, are insufficient. The present study describes the case of a 36year-old man who repeatedly rnisused zopiclone, in daily doses of 60 - 90 mg. Furthermore, the patient sufTered from convulsion on two occasions following abrupt withdrawal of zopiclone. The concominant use of alcohol, trimiprarnine, and promazine may have contributed to the development of convulsions. It is concluded that zopiclone may cause problems associated with misuse and withdrawal reactions similar to those ofbezodiazepines.
Introduction
The dependence-inducing potential of benzodiazepines and withdrawal reactions, including convulsions, are well recognized (Hollister et al., 1961; Petursson and Lader, 1984; Cappell et al., 1986; Woocß et al., 1987). Zopiclone, a nonbenzodiazepine hypnotic, is one of their successors; its efficacy is well-established and it causes few side-effects (Goa and Hee/, 1986). Zopiclone, a cyclopyrrolone derivative, difTers in chemical structure from benzodiazepines, but resembles them very closely in pharmacological profile (lu/ou et al., 1983; Griffiths et al., 1986). It binds to sites on the benzodiazepine receptor complex linked to the GABAA"receptor and chloride-ion channel ("central type benzodiazepine receptors") (B/anchard et al., 1983), however, there are some dissimilarities between zopiclone and benzodiazepines as regards receptor-binding properties (Trift/etti and Snyder, 1984). In spite of experience with benzodiazepines, data on the 10ngterm efTects, dependence potential, and withdrawal reactions of zopiclone are incomplete (Editorial,
Pharmacopsychiat. 24 (1991) 138 - 140 lC> GeorgThieme Verlag Stuttgart·New York
Der Mißbraucb von Zopiclon und KrampfanfliUe während des Arzneimittelentzugs - Ein Fallbericbt
Es ist bekannt, daß der Mißbrauch von Benzodiazepinen Abhängigkeit und Entzugssymptome, einschließlich Konvulsionen, verursachen kann. Über Zopiclon, ein Non-Benzodiazepin-Hypnotikum, gibt es allerdings nur unzureichend Daten. Wir beschreiben einen Fall von einem 36jährigen Mann, der wiederholt Zopiclon mißbrauchte, wobei die tägliche Dosis 60 - 90 mg war. Der Patient hatte zweimal einen Krampfanfall, nachdem er plötzlich eine hohe Dosis Zopiclon abgesetzt hatte. Ein mäßiger Alkoholgebrauch sowie die Behandlung mit Trimipramin und Promazin zu der gleichen Zeit haben möglicherweise zur Auslösung von Konvulsionen beigetragen. Zusammenfassend läßt sich feststellen, daß Zopiclon Probleme wie Mißbrauch und Entzugssymptome ähnlich wie die Benzodiazepine verursachen kann.
1990). To the authors' knowledge, this is the first report of misuse and convulsions after abrupt withdrawal of zopiclone.
Case report The patient, a 36-year-old man with a masters degree in technology, had no history of cerebral or other somatic disease. He had been prone to perfectionism and preoccupation with the schedules of daily Iife. In Januar 1987 he was admitted to the psychiatric outpatient department of Helsinki University Central Hospital (HUCH) and diagnosed as sufTering from major depression and compulsive personality disorder. His physical examination, EEG, and routine laboratory screening aIl showed normal findings. A comprehensive psychiatric interview revealed no evidence of memory disturbances. Clomipramine (ad, 150 mg daily) and supportive psychotherapy were initiated. In autumm 1987 the patient's depression recurred and clomipramine was reintroduced together with 5 mg of nitrazepam to relieve the subjective distress caused by difficulties in falling asleep and early awakenings. The patient insisted on sleeping 10 hours per night to maintain his working capacity, and started to misuse ni-
Received: 28. 9. 1990 Revised version: 28.2. 1991 Accepted: 1.3. 1991
Downloaded by: Universite Laval. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Misuse ojZopiclone and Convulsions during Withdrawal
In autumm 1988 the next major depressive episode was again characterized by very distressing sleep difficulties. After trimipramine (ad, 150 mg for nights) and promazine (100 mg for nights) had failed to alleviate the patient's difficulties in falling asleep, 7.5 mg of zopiclone was added (zopiclone has been on the market in Finland since 1987). In August 1989, following an accumulation of psychosocial stress in his life, the patient experienced increased anxiety, and he began to suffer from being awake for several short periods every nigh1. He started to use an additional 15 - 30 mg ofzopiclone in the early morning hours so that he could meet his requirement of 10 hours ofuninterrupted sleep. According to the patient's diary written over the next two months, he gradually increased the dose of zopiclone to 60 - 90 mg per nigh1. He began to suffer from memory difficulties, but he was able to keep up with his normal daily activities. At the beginning of November he began to run out of zopiclone tablets, and before he discontinued taking them he had 7.5 mg on two nights. On the first day of total abstinence, he experienced a grand-mal-type convulsion observed by his sister (a nurse). One week later, at an appointment with his psychiatrist, he had marked difficulties in recalling the events of the past month. He also reported that while taking high doses of zopiclone he daily found hirnself in situations and places without remembering why and what to do there. The patient refused further examinations, and agreed to restrict the dose of zopiclone to 7.5 mg. In December, 1989, however, his diary documented daily use of 60 - 90 mg of zopiclone which was confirmed by the drug delivery data records in his prescriptions. The pattern of consumption of beer was unchanged (30 - 40 g of alcohol daily). In spite of the resulting daytime sleepiness, he had also increased the daily doses of trimipramine and promazine to 200 - 300 mg and 200 - 300 mg (600 mg once) respectively. Zopiclone tablets were now being taken throughout the whole night, usually two tablets immediateiy upon awakening. The nightly dose of zopiclone fluctuated, usually between a high dose (30 - 80 mg) one night and a low dose (15 mg) the nex1. In January 1990, after almost two months of high-dose zopiclone administration, he agreed to be hospitalized. A day before admission to the inpatient department of psychiatry (HUCH), he reduced the dose of zopiclone to 7.5 mg, and those of trimipramine and promazine to the prescribed doses (i. e., 150 mg and 100 mg respectively). Soon after his arrival at the hospital, on 19 January 1990, he was found in bed at noon with a grand-mal-type convulsion lasting about four minutes. Diazepam rectiole (10mg) was given within five minutes. Later in the afternoon the patient was anxious, dysphoric, and suffering from memory difficulties. Carbamazepine (100 mg 1. i. d.) was added to the medieation and zopiclone gradually withdrawn over a one-week period, starting from 15 mg per nigh1. Except for impairments in longterm memory storage and/or retrieval processes, the results of a detailed neurological examination (performed 21 January 1990) were normal. A neuropsychological examination performed two weeks after hospital admission and repeated testing two months later showed no obvious memory deficits, with slight improvement occurring over time (Wechsler Memory Scale land 11, MQ ~ 129 and 135 respectively). Extensive laboratory screening revealed no plausible cause for the patient's convulsion, nor did erythrocyte indices or liver tests indicate signs of alcohol toxicity. Five days after the convulsion, an EEG examination displayed a slight abnormality. Alpha activity was somewhat disorganized and slow transients were noted in the posterior areas; both abnormalities were possibly duc to overuse of drugs. No paroxysmal abnormalities were notcd. In March 1990, the patient's EEG was again normal; alpha activity was regular and resembled his EEG examination in January 1987. In addition, a brain er scan revealed no pathologie changes. Soon after discharge from the hospital in April 1990, the patient's fear of insomnia returned and he increased the doses of chlorprothixen and promazine to 200 mg and 300 mg per night respectively. In addition, he resumed his daily consumption ofbeer (30-
40 g of a1cohol). For the first two days after readmission to the hospital, he was only given 100 mg of promazine daily; no withdrawal symptoms were seen.
Discussion
Although there were several confoundings factors, the patient's compulsive use of high doses of zopiclone and concurrent reversible memory deficits, and the subsequent convulsions on abrupt withdrawal, were reasonably weil documented. It is evident that the regular misuse of zopiclone in doses ten times higher than those recommended was due to the patient's psychopathology; thc resulting neuropsychological consequences are the pharmacological efTects to be expected given the doses ingested. The patient's history and extensive examinations detected no reasons for a lowered convulsion threshold aside from zopiclone withdrawal. However, the concomitant use of antidepressants and neuroleptics, both of which are known to precipitate convulsions (Marks, 1985), the lack of drug concentration data, and the regular use of alcohol confound the conclusions. Alcohol is a known predisposing factor for both convulsions and benzodiazepine dependence (Petursson and Lader, 1984; Woods et al., 1987). Interestingly, the patient had previously misused nitrazepam in a similar pattern and, indeed, nitrazepam and zopiclone have been shown to have an equal dependence potential in rhesus monkeys (Yanagita, 1983). Furthermore, the withdrawal symptoms of nitrazepam and zopiclone were reported to be comparable. In contrast to diazepam withdrawal, however, no convulsions were manifested upon abrupt discontinuation of zopiclone (Yanagita. 1983). The results of two double-blind studies (Bechelli et al., 1983; Boiss! et al., 1983) suggest that the dependence-inducing potential of zopiclone may be slightly lower than that of triazolam. However, both drugs may produce efTects similar to those induced by alcohol in 60 to 70% of former alcoholics (Bechelli et al., 1983). Furthermore, when zopiclonc was tested with hcalthy volunteers, withdrawal symptoms manifested in a form of rebound insomnia or increased anxiety were documented after discontinuation of treatment lasting only up to three weeks at the recommended doses (Dorian et al., 1983; Lader and Frcka, 1987). The same symptoms were reported for insomniacs (van der Kleijn, 1989). The present patient had used high doses of zopiclone for months, and convulsions had occurred during two consecutive withdrawal periods. The short elimination half-life (t l / 2 ß = 5 - 6.5 hours) of zopiclone (Gaillot et al., 1983; Houghton et al., 1985) may partly explain the pattern of misuse, characterized by one "wash-out" day between high doses. In fact, this fluctuating pattern of intake may have contributed to the present patient's continuation of misuse: one is reminded here of the daily withdrawal syndromes described among users of triazolam, another hypnotic with a short halflife (Morgan and Oswald, 1982). This concept also correlates with the emergence of convulsions after more than six t l / 2ß have elapsed from the high dose and three t 1/ 2ß from the last small dose; i. e., after 98 % and 88 '% of the doses have been eliminated respectively (Rowland und Tozer, 1989). It is also worth recalling that abnormal anxiolytic or hypnotic doses of barbiturates (Isbell at al., 1950; Fraser et al., 1958) and benzodiazepines (Hollister et al. , 1961; Cappell et al., 1986) are
Downloaded by: Universite Laval. Copyrighted material.
trazepam (ad, 50 mg nightly). He also reported daily consumption of beer equivalent to 30 - 40 g of absolute alcohol. It took one week to taper down nitrazepam; no withdrawal symptoms occurred and attention was paid to the potential dangers of hypnotic misuse.
139
Pharmacopsychiat. 24 (1991)
usually needed for a prolonged period to induce convulsions upon withdrawal.
In conclusion, the authors would like to emphasize the problems, analogous to those associated with benzodiazepines, encountered by the patient during and upon withdrawal from high doses of zopiclone, a nonbenzodiazepine hypnotic. References Blanehard, J. c., A. Boireau, L. Julou: Brain receptors and zopiclone. Pharmacology 27 (Suppl. 2) (1983) 59 - 69 Beehelli, L. P., R. Navas, S. A. Pierangelo: Comparison of the reinforcing properties of zopiclone and triazolam in former a1cohoIics. Pharmacology 27 (Suppl. 2) (1983) 235 - 241 Boissi, K., J. F. Dreyfus, M. Delmotte: Studies on the dependence-inducing potential of zopiclone and triazolam. Pharmacology 27 (SuppI.2)(1983)242 - 247 Cappell, H D., E. M. Seilers, U. Busto: Benzodiazepines as drugs of abuse and dependence. In: Cappell et a1. (eds.): Research Advances in Alcohol and Drug Problems, Vol. 9. Plenum Press, New York(\ 986)53 - 126 Dorian, P., E. M. Seilers, H Kaplan, C. Hamilton: Evaluation of zopiclone physical dependence liability in normal volunteers. Pharmacology 27 (Suppl. 2)(1983)228 - 234 Editorial: Zopiclone: another carriage on the tranquilliser train. Lancet335(1990)507 - 508 Fraser, H. F., A. Wikler, C. F. Essig, H. Isbell: Degree of physical dependence induced by secobarbital or phenobarbital. J. Am. Med. Assoc. 166 (\ 958) 126-9 Goa, K. L., R. C. Heel: Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs32(1986)48 - 65 Gaillot, J., D. Heusse, G. W. Hougton, J. Mare Aurele, J. F. Dreyfus: Pharmacokinetics and metabolism of zopiclone. Pharmacology 27 (Suppl. 2) (1983) 76 - 91 Griffiths, A. N., D. M. Jones, A. Riehens: Zopiclone produces efTects on human performances similar to flurazepam, lormetazepam, and triazolam. Br. J. Clin. Pharmacol. 21 (1986) 647- 653 Hollister, L. E.. F. P. Motzenbeeker, R. 0. Degan: Withdrawal reactions from chlordiazepoxide ("Librium"). Psychopharmacologia 2(1961)63 - 68 Houghton, G., M. Dennis, R. Templeton, B. Martin: A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane).Int.J. Clin. Pharmacol. Ther. Toxiol. 23 (\ 985)97 - 100 Isbell, H., S. Altsehul, D. H. Kornetsky, A. J. Eisenman, H G. Flanary, H. G. Fraser: Chronic barbiturate intoxication: an experimental study. Arch. Neurol. Psychiat. 64(1950) 1- 28 Jolou, L., M. C. Bardone, J. C. Blanehard, C. Garret, J. M. Stutzmann: Pharmacological studies on zopiclone. Pharmacology 27 (Suppl. 2)( 1983)46 - 58 Lader, M., G. Freka: Subjective efTects during and on discontinuation of zopiclone in normal subjects. Pharmacopsychiatry 20 (\ 987) 67-71 Marks, J.: The benzodiazepines. Use, overuse, misuse, abuse? 2nd ed., MTP Press Limited, Lancaster 1985 Morgan, K.. I. Oswald: Anxiety caused by a short-Iife hypnotic. Br. Med.J.284(1982)942 Petursson. H, M. H. Lader: Dependence on tranquilIizers. Maudsley Monographs 28. Oxford University Press, Oxford 1984 Rowland, M., T. N. Tozer: Clinical Pharmacokinetics. Concept and Applications. 2nd edition. Lea & Febiger, Philadelphia-London 1989 Triftletti, R. R., S. H. Snyder: Anx.iolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked a1losterically to benzodiazepine receptor. Mol. Pharmacol. 26 (\ 984)458 - 469 Van der Kleijn, E.: EfTects of zopiclone and temazepam on sleep, behaviour and mood during the day. Eur. J. Clin. Pharmacol. 36 (1989)247 - 251
K. Aranko, M Henn'ksson, C. Hublin, A. M Seppäläinen Wood5,J. H., J. L. Katz. G. Winger: Abuse liability of benzodiazepines. Pharmacol. Rev. 39 (1987) 215 - 413 Yanagita, T.: Dependence potential of zopiclone studied in monkeys. Pharmacology 27 (Suppl. 2)(1983) 216 - 227
Kari Aranko, M.D.
Department of Clinical Pharmacology University ofHelsinki Paasikivenkatu 4 SF-00250 Helsinki Finland
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