Synopsis: Zopiclone1 is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex.
Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5mg) improved sleep in chronic insomniacs similarly to nitrazepam 5mg, flurazepam 15 to 30mg, triazolam 0.5mg and temazepam 20mg, but in a single study was slightly less effective than flunitrazepam 2mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of ‘bitter taste’ does not deter patients from continuing therapy.
Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.
Pharmacodynamic Studies: Although chemically unrelated to the benzodiazepines, zopiclone occupies benzodiazepine receptor complex sites and inhibits radioligand binding as strongly as nitrazepam. In animal studies, zopiclone shows anxiolytic, anticonvulsant and myorelaxant properties similar to chlordiazepoxide. Zopiclone improves sleep parameters in healthy volunteers and insomniacs to a degree comparable with usual doses of nitrazepam, flurazepam and temazepam (see Therapeutic Trials below). Dose-ranging studies show zopiclone 7.5mg produces an optimum effect with minimal residual effects the morning after a bedtime dose. After a dose of 7.5mg, the proportion of non-REM (rapid eye movement) sleep increases but without a reduction in REM sleep. Rebound phenomena have not been demonstrated consistently after withdrawal of zopiclone. While preliminary studies in animals suggest the dependence liability of zopiclone may be less than that of diazepam, only much wider clinical use can confirm this. Similarly, it is unclear whether tolerance to zopiclone is likely to develop with longer term use in patients who require continued treatment with an hypnotic.
Pharmacokinetic Studies: Following a single oral dose of 7.5mg zopiclone is rapidly absorbed, with peak plasma concentrations of 60 to 70 µg/L attained in 1 hour. The bioavailability of an oral dose is 80%, suggesting no significant ‘first-pass’ effect. Distribution to body tissues including central nervous system (CNS), breast milk, placenta and salivary glands is rapid and extensive, with a volume of distribution of 100L in healthy subjects. Only 45% of a dose is bound to plasma proteins.
Zopiclone undergoes extensive metabolism. The N-oxide derivative which is less active than the parent compound accounts for 11% of a dose, and inactive N-desmethyl zopiclone about 15%; 4 to 5% is excreted unchanged in the urine. Neither the drug nor its metabolites are detectable in plasma 48 hours after administration. The short elimination half-life of about 5 hours lengthens in cirrhotic and elderly subjects to about 8 hours, but does not increase in patients with renal failure. The elimination half-life of the active metabolite is similar to that of the parent drug. Plasma clearance of zopiclone is about 14 L/h in healthy subjects, and is not increased by haemodialysis.
Therapeutic Trials: A few double-blind trials have compared the hypnotic activity of zopiclone with placebo and several benzodiazepines in patients with chronic insomnia. Zopiclone 7.5mg induced better sleep quality than pentobarbitone 100mg, with fewer side effects, in a single study. After zopiclone, sleep duration and quality increased, and sleep onset time and number of awakenings decreased further than after placebo. In comparison with the benzodiazepines triazolam 0.5mg, temazepam 20mg, flurazepam 15 to 30mg and nitrazepam 5 to 10mg, zopiclone 7.5mg similarly improved sleep in short term studies in chronic insomniacs without serious adverse effects. Sleep structure changes and carryover effect are less after zopiclone than after flurazepam, and some evidence suggests a trend toward patient preference for zopiclone rather than nitrazepam. Conversely, in a single study in patients with chronic insomnia, flunitrazepam 2mg was preferred by patients over zopiclone 7.5mg, even though the drugs produced similar effects on most other evaluation criteria. The dose of flunitrazepam, however, was the highest recommended for use as an hypnotic.
Studies comparing zopiclone with benzodiazepines as hypnotics for hospitalised patients the night before surgery suggest that flunitrazepam 2mg or flurazepam 30mg are more effective than zopiclone 7.5mg, while nitrazepam 5 or 10mg and zopiclone 7.5 or 10mg are comparably effective.
Side Effects: Zopiclone exhibits a side effect profile similar to the shorter acting benzodiazepines. Hence, drowsiness, tiredness in the morning and impairment of psychomotor skills have been reported in some patients, but these are not seriously detrimental to daytime activities. Relatively frequent dose-related ‘bitter taste’ and ‘dry mouth’ have occurred in several studies, but have rarely caused treatment withdrawal. In usual doses, zopiclone does not affect cardiovascular parameters or respiration.
Dosage and Administration: Zopiclone 7.5mg given orally 30 to 60 minutes before retiring provides good hypnotic effect with minimal adverse effects. Doses greater than 7.5mg may benefit selected patients. No reduction of dose is required in elderly patients, or in the presence of renal insufficiency; while the elimination half-life increases in patients with cirrhosis, only those with severe disease will likely need a dose reduction. Although zopiclone causes minimal ‘hangover’ effects, patients should be alerted to the possibility of impaired mental alertness and psychomotor skills.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Anderson A. Controlled efficacy studies of zopiclone in insomniac patients. First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreux, October 6–11, 1985a
Anderson AA. Zopiclone and nitrazepam: a multicentre placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Presented at the First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreaux, October 6–11, 1985b
Bechelli LP, Navas F, Pierangelo SA. Comparison of the reinforcing properties of zopiclone and triazolam in former alcoholics. Pharmacology 27(Suppl. 2): 235–241, 1983
Billiard M, Besset A, De Lustrac C, Brissaud L. Dose-response effects of zopiclone on night sleep and on night-time and daytime functioning. IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983
Blanchard JC, Boireau A, Garret C, Julou L. In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sciences 24: 2417–2420, 1979
Blois R, Gaillard JM. The effects of zopiclone on some polygraphic and subjective aspects of normal human sleep. Presented at the VII World Congress of Psychiatry, Vienna, July 11–16, 1983
Boissl K, Dreyfus JF, Delmotte M. Studies on the dependence-inducing potential- of zopiclone and triazolam. Pharmacology 27(Suppl. 2): 242–247, 1983
Braestrup C, Nielsen M. Anxiety. Lancet 2: 1030–1034, 1982
Braestrup C, Honoré T, Nielsen M, Petersen EN, Jensen LH. Ligands for benzodiazepine receptors with positive and negative efficacy. Biochemical Pharmacology 33: 859–862, 1984
Broadhurst A, Cushnagham BC. Residual effects of zopiclone (Imovane®). Presented at the IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983
Caillé G, DuSouich P, Spenard J, Lacasse Y, Vezina M. Pharmacokinetics and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers. Biopharmaceutics and Drug Disposition 5: 117–125, 1984
Campbell RD, Grace MG, Bourgarin J, Forget JP. A controlled study of zopiclone administration to insomniac subjects over a three-week period. Presented at the VII World Congress of Psychiatry, Austria, July 11–16, 1983
Channer KS, Dent M, Roberts CJ. The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone. British Journal of Clinical Pharmacology 18: 879–886, 1984
Cooper SJ, Moores WR. Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL218,872, zopiclone, tracazolate and phenobarbital. Pharmacology Biochemistry and Behavior 23: 169–172, 1985
Chaudoir PJ, Jarvie NC, Wilcox GJ. The acceptability of a non-benzodiazepine hypnotic (zopiclone) in general practice. Journal of International Medical Research 11: 333–337, 1983
Dehlin O, Rundgren Å, Börjesson L, Ekelund P, Gatzinska R, et al. Zopiclone to geriatric patients. Pharmacology 27(Suppl. 2): 173–178, 1983
de Oggero U. A comparative study of 2 hypnotics: zopiclone and flunitrazepam. VII World Congress of Psychiatry, Vienna, July 11–16, 1983a
de Oggero U. Clinical comparative study of zopiclone and flurazepam. Presented at the IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983b
Dorian P, Sellers EM, Kaplan H, Hamilton C. Evaluation of zopiclone physical dependence liability in normal volunteers. Pharmacology 27(Suppl. 2): 228–234, 1983
Dundee JW, Elwood RJ, Hildebrand PJ, Singleton M. Dose-finding and premedication studies with zopiclone. Pharmacology 27(Suppl. 2): 210–215, 1983
Dundee JW, Wilson CM, Robinson FP, Thompson EM, Elliott P. The effect of ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. British Journal of Clinical Pharmacology, Proceedings of BPS 19: 553–555P, 1984
Duriez R, Barthélémy C, Rives H, Courjaret J, Gregoire J. Traitement des troubles du sommeil par la zopiclone. Thérapie 34: 317–325, 1979
Elie R, Deschenes JP. Efficacy and tolerance in insomniac geriatric patients. Pharmacology 27(Suppl. 2): 179–187, 1983
Elie R, Gagnon MA. Hypnotic properties of zopiclone. Abstract no. 1299. 8th International Congress of Pharmacology, Tokyo, 1981
Elliott P, Chestnutt WN, Elwood RJ, Dundee JW. Effect of atropine and metoclopramide on the plasma concentrations of orally administered zopiclone. British Journal of Anaesthesia (Proceedings of the Anaesthetic Research Society) 55: 1159p–1160p, 1983
Fossen A, Godlibsen OB, Loyning Y, Dreyfus JF. Effects of hypnotics on memory. Pharmacology 27(Suppl. 2): 116–126, 1983
Gaillot J, Heusse D, Houghton G, Aurele J-M, Dreyfus J. Pharmacokinetics and metabolism of zopiclone. Pharmacology 27(Suppl. 2): 76–91, 1983
Gaillot J, Le Roux Y, Houghton GW, Dreyfus JF. Critical factors for pharmacokinetics of zopiclone in the elderly and in liver and renal insufficiency. Personal communication from JF Dreyfus, Rhône-Poulenc.
Giercksky K-E, Wickstrøm E. A dose-response study in situational insomnia with zopiclone, a new tranquilizer. Clinical Therapeutics 3: 21–27, 1980
Goldberg ME, Salama AI, Patel JB, Malick JB. Novel non-benzodiazepine anxiolytics. Neuropharmacology 22: 1499–1504, 1983
Griffiths AN, Jones DM, Marshall RW, Allen EM, Richens A. A comparison of the psychomotor effects of zopiclone with three marketed benzodiazepines and placebo. British Journal of Clinical Pharmacology (Proceedings of BPS 17–19 Dec 1984) 19: 584p–585p, 1985
Haefely W. Benzodiazepine interactions with GABA receptors. Neuroscience Letters 47: 201–206, 1984
Harrison C, Subhan Z, Hindmarch I. Residual effects of zopiclone and benzodiazepine hypnotics on psychomotor performance related to car driving. Drugs under Experimental and Clinical Research 9: 823–829, 1985
Hindmarch I, Subhan Z. Immediate and overnight effects of zopiclone 7.5mg and nitrazepam 5mg with ethanol, on psychomotor performance and memory in healthy volunteers. Presented at the First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreux, October 6–11, 1985
Houghton G, Dennis M, Templeton R, Martin B. A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane®). International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 97–100, 1985
Itil TM, Menon GN, Songar A, Ilkay E, Bozak M, et al. Effects of alcohol during zopiclone treatment (a double-blind controlled study on zopiclone-alcohol interaction). Presented at the VII World Congress of Psychiatry, Vienna, July 11–16, 1983
Jovanovic UJ, Dreyfus JF. Polygraphic sleep recordings in insomniac patients under zopiclone or nitrazepam. Pharmacology 27(Suppl. 2): 136–145, 1983
Julou L, Bardone MC, Blanchard JC, Garret C, Stutzmann JM. Pharmacological studies on zopiclone. Pharmacology 27(Suppl. 2): 46–58, 1983
Julou L, Blanchard JC, Dreyfus JF. Pharmacological and clinical studies of cyclopyrrolones: zopiclone and suriclone. Pharmacology Biochemistry and Behavior 23: 653–659, 1985
Karobath M, Supavilai P. Distinction of benzodiazepine agonists from antagonists by photo affinity labelling of benzodiazepine receptors in vitro. Neuroscience Letters 31: 65–69, 1982
Kawamoto H, Ohmori S, Kitada M, Ueno K, Kitagawa H. Effect of successive administration of zopiclone, a new class of minor tranquillizer, on mouse liver microsomal mono-oxygenase system. Xenobiotica 14: 355–357, 1984
Kazamatsuri H. A clinical study on dependence liability of zopiclone. IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983
Lader M, Denney SC. A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers. Pharmacology 27(Suppl. 2): 98–108, 1983
Lader M, Frcka G. A study of subjective effects during and following administration of zopiclone, temazepam and placebo. First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreux, October 6–11, 1985
Liu HJ, Sato K, Shih HC, Shibuya T, Kawamoto H, et al. Pharmacologic studies of the central action of zopiclone: effects on locomotor activity and brain monoamines in rats. International Journal of Clinical Pharmacology Therapy and Toxicology 23: 121–128, 1985
Maillard F, Autret E, Autret A. Effects of zopiclone as compared to triazolam on adult insomniacs. 7th European Sleep Congress, Munich, Sept 5, 1984
Mamelak M, Scima A, Price V. Effects of zopiclone on the sleep of chronic insomniacs. Pharmacology 27(Suppl. 2): 136–145, 1983a
Mamelak M, Buck L, Csima A, Price V, Smiley A. The effects of flurazepam and zopiclone on the performance of chronic insomniacs. A study of ethanol-drug interaction. Presented at the IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983b
Marc-Aurele J, Caillé G, Bourgouin J. Comparison of zopiclone pharmacokinetics in patients with impaired renal function and normal subjects. Effect of hemodialysis. IV International Congress of Sleep Research (A.P.S.S.). Bologna, July 18–22, 1983
Matheson I, Sande HA, Gaillot J, Vegdahl K. Zopiclone excretion in breast milk. British Journal of Clinical Pharmacology 20: 290P–291P, 1985
Mello de Paula AJ. Comparative study of zopiclone and pentobarbitone as hypnotics. Pharmacology 27(Suppl. 2): 188–195, 1983
Mizuki Y, Hashimoto M, Tanaka T, Inanaga K, Tanaka M. A new physiological tool for assessing anxiolytic effects in humans: frontal midline theta activity. Psychopharmacology 80: 311–314, 1983
Möhler H, Okada T. Benzodiazepine receptor. Demonstration in the central nervous system. Science 198: 849–851, 1977
Möhler H, Richards JG. Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature 294: 763–765, 1981
Momose T. Effectiveness of zopiclone as a preoperative hypnotic. Pharmacology 27(Suppl. 2): 196–204, 1983
Moon CA. Effects of zopiclone on sleep and performance in volunteer shiftworkers. First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreux, October 6–11, 1985
Nicholson AN, Stone BM. Zopiclone: sleep and performance studies in healthy men. Pharmacology 27(Suppl. 2): 92–97, 1983
Nicholson AN, Stone BM. The effect of a Cyclopyrrolone (zopiclone) on the sleep of young adult and middle-aged subjects. British Journal of Clinical Pharmacology (Proceedings of BPS 11–13 April 1984): 284p–285p, 1984
Parker G, Roberts C. Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease. British Journal of Clinical Pharmacology 16: 259–265, 1983
Patel JB, Martin C, Malick JB. Differential antagonism of the anti-conflict effects of typical and atypical anxiolytics. European Journal of Pharmacology 86: 295–298, 1983
Polc P, Laurent J-P, Scherschlicht R, Haefely W. Electrophysiological studies on the specific benzodiazepine antagonist RO 15-1788. Naunyn-Schmiedeberg’s Archives of Pharmacology 316: 317–325, 1981
Ponciano E, Freitas F, Camara J, Faria M, Barreto M, et al. A comparison of the efficacy, tolerance and residual effects of zopiclone, flurazepam and placebo in insomniac out-patients. Presented at the First International Conference on Recent Advances in Drug Treatment in Psychiatry, Montreaux, October 6–11, 1985
Pull CB, Dreyfus JF, Brun JP. Comparison of nitrazepam and zopiclone in psychiatric patients. Pharmacology 27(Suppl. 2): 205–209, 1983
Quadens OP, Hoffman G, Buytaert G. Effects of zopiclone as compared to flurazepam in women over 40 years of age. Pharmacology 27(Suppl. 2): 146–155, 1983
Ranlov PJ, Nielsen SP. The effect of zopiclone and diazepam on ventilatory responses in normal human subjects. IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983
Reker V, Müller-Deile J. Examination of residual effects of zopiclone and of flunitrazepam by means of the characteristics of eye-movements and coordinated eye-head movements. 7th European Sleep Congress, Munich, September 5, 1984
Samuelsson SM, Rundgren A, Hansen PP, Kahanpaa A, Pedersen K, et al. A multicenter comparative study of zopiclone and nitrazepam in the treatment of chronic insomnia in hospitalized geriatric patients. Presented at the IV International Congress of Sleep Research (A.P.S.S.), Bologna, July 18–22, 1983
Sanger DJ, Joly D, Zivkovic B. Behavioral effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. Journal of Pharmacology and Experimental Therapeutics 232: 831–837, 1985
Sato K, Hong YL, Yang MS, Shibuya T, Kawamoto H, et al. Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 204–210, 1985
Seppälä T, Nuotto E, Dreyfus JF. Drug-alcohol interactions on psychomotor skills. Pharmacology 27(Suppl. 2): 127–135, 1983
Skerritt JH, MacDonald RL. Benzodiazepine receptor ligand actions on GABA responses. Benzodiazepines, CL 218872, zopiclone. European Journal of Pharmacology 101: 127–134, 1984
Squires RE, Braestrup C. Benzodiazepine receptors in rat brain. Nature 266: 732–734, 1977
Stanley C, Mitchell P, Kaye CM. Simple and sensitive method for monitoring zopiclone in plasma by high-performance liquid chromatography with fluorescence detection. Analyst 110: 83–84, 1985
Subhan Z, Hindmarch I. Effects of zopiclone and benzodiazepine hypnotics on search in short-term memory. Neuropsychobiology 12: 244–248, 1984
Tamminen T, Ahokallio A, Aropuu R, Syrja R, Taskinen E, et al. Zopiclone and nitrazepam in the treatment of chronic insomnia. Presented at the VII World Congress of Psychiatry, Vienna, July 11–16, 1983
Tanaka M, Mizuki Y, Isozaki H, Inanaga K. Effects of zopiclone on the arousal level of healthy volunteers assessed by the averaged photopalpebral reflex. European Journal of Clinical Pharmacology 24: 469–474, 1983
Trifiletti RR, Snyder SH. Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepines. Molecular Pharmacology 26: 458–469, 1984
Trifiletti RR, Snowman AM, Snyder SS. Anxiolytic Cyclopyrrolone drugs allosterically modulate the binding of [35S] t-Butylbicyclophosphorothionate to the benzodiazepine/γ-aminobutyric acid-A receptor/chloride anionophore complex. Molecular Pharmacology 26: 470–476, 1984
Ueki S. Behavioral pharmacology of zopiclone. Presented at the VII World Congress of Psychiatry, Vienna, July 11–16, 1983
Volkerts ER, O’Hanlon JF. Zopiclone residual effects on real car driving performance versus those of two benzodiazepine hypnotics (flunitrazepam and nitrazepam). Presented at the 14th Collegium Internationale Neuro-Psychopharmacologicum Congress, Florence, June 22, 1984
Wheatley D. Zopiclone: a non-benzodiazepine hypnotic controlled comparison to temazepam in insomnia. British Journal of Psychiatry 146: 312–314, 1985
Wickstrøm E, Giercksky K-E. Comparative study of zopiclone, a novel hypnotic, and three benzodiazepines. European Journal of Clinical Pharmacology 17: 93–99, 1980
Wickstrøm E, Barbo SE, Dreyfus JF, Jerkø D, Kleiven R, et al. A comparative study of zopiclone and flunitrazepam in insomniacs seen by general practitioners. Pharmacology 27(Suppl. 2): 165–172, 1983
Williams M. Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex. Progress in Neuro-Psychopharmacology and Biological Psychiatry 8: 209–247, 1984
Yanagita T. Dependence potential of zopiclone studied in monkeys. Pharmacology 27(Suppl. 2): 216–227, 1983
Various sections of the manuscript reviewed by: F. Ayd Jr, Ayd Medical Communications, Baltimore, Maryland, USA; D.D. Breimer, Department of Pharmacology, Leiden University, Leiden, The Netherlands; D.J. Greenblatt, Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts, USA; I. Hindmarch, Human Psychopharmacology Research Unit, University of Leeds, Leeds, England; L. Hollister, Veterans Administration Medical Center, Palo Alto, California, USA; M. Mamelak, Department of Psychiatry, Sunnybrook Hospital, University of Toronto Clinic, Toronto, Ontario, Canada; A.N. Nicholson, RAF Institute of Aviation Medicine, Farnborough, Hants, England; M. Tanaka, Department of Pharmacology, Kurume University, Kurume, Japan; D. Wheatley, Psychopharmacology Research Group, Twickenham, England; E. Wickstrøm, Universitetet i Oslo, Ullevaal Hospital, Oslo, Norway.
‘Imovane’, ‘Imovance’, ‘Amovane’ (Rhône-Poulenc); ‘Zimovane’ (May & Baker); ‘Amovane’, ‘Imovane’ (Chugai); ‘Amovane’, ‘Imovane’ (Rhône-Poulenc Yakuhin).
About this article
Cite this article
Goa, K.L., Heel, R.C. Zopiclone. Drugs 32, 48–65 (1986). https://doi.org/10.2165/00003495-198632010-00003