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Zopiclone

A Review of its Pharmacological Properties and Therapeutic Efficacy as an Hypnotic

An Erratum to this article was published on 01 September 1993

Abstract

Synopsis

Zopiclone is a cyclopyrrolone which is chemically unrelated to the benzodiazepines and is thought to act on the GABAA receptor complex at a site distinct from, but closely related to, the benzodiazepine binding site. The hypnotic efficacy of zopiclone administered as single oral doses has been demonstrated in patients undergoing next-day surgery and in patients with insomnia, and these studies have established an optimal dose of 7.5mg for elderly patients. Using this dose, clinical studies have shown that zopiclone improved sleep in elderly patients to a similar extent as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg. Studies that also included younger patients have shown that zopiclone 7.5mg is at least as effective as triazolam 0.25 or 0.5mg, and on most sleep parameters is comparable to temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 20mg.

Zopiclone causes minimal impairment to psychomotor performance and mental alertness the morning after night-time administration. The drug is generally well tolerated by patients of all ages; the most frequently reported adverse effects being bitter taste and dry mouth. Treatment withdrawal due to adverse effects is seldom required and reports of rebound insomnia after zopiclone withdrawal are rare. While symptoms of physical dependence have not been observed in clinical studies, there have been isolated reports of physical dependence in patients with a history of substance abuse. Although the latter finding should be kept in mind, it appears that zopiclone has a low dependence liability.

Thus, with its short duration of action and good tolerability profile, zopiclone is a well established alternative to the benzodiazepine hypnotics and may be particularly beneficial in those patients unable or unwilling to tolerate the residual effects associated with many other hypnotic agents.

Pharmacological Properties

Although structurally unrelated to the benzodiazepines, zopiclone also binds to regulatory sites on the GABAA receptor complex in the central nervous system. Zopiclone has marked sedating effects and improves sleep parameters in patients undergoing next-day surgery. Optimum hypnotic activity is achieved with an oral 7.5mg dose. Rebound insomnia after zopiclone withdrawal is rare and is generally less severe than after withdrawal of flurazepam or temazepam, and less frequent than after flurazepam, nitrazepam or triazolam withdrawal. Zopiclone has limited anxiolytic effects but these have not been evaluated in a clinical setting.

Some deterioration of psychomotor function and memory is evident 1 to 2 hours after zopiclone administration; however, only minimal residual impairment is evident after 8 to 10 hours. Combined administration of alcohol (ethanol) 0.2 to 0.8 g/kg and zopiclone 7.5mg has an additive effect on impairment of psychomotor function after 1.5 hours which is negligible after 8 hours. Zopiclone does not appear to have any significant effect on respiration. Symptoms of physical dependence have not been observed in studies of psychiatric patients or former alcoholics given zopiclone in dosages up to 30 mg/day; however, there have been isolated reports of physical dependence in patients with a history of substance abuse.

Peak plasma concentrations following a single oral dose of zopiclone 7. 5mg range from 64 to 86 μg/L and are achieved within 2 hours. Bioavailability is approximately 80% but is increased to 163% in the elderly. Zopiclone undergoes extensive hepatic metabolism; only 4 to 5% is excreted unchanged in the urine and approximately 11% is excreted as a partially active N-oxide metabolite. Plasma zopiclone clearance is about 14 L/h and is not altered by haemodialysis. In elderly patients (aged >65 years), the elimination half-life of zopiclone is approximately 8 hours (the elimination half-life of the partially active metabolite is about 6 hours) compared with 3.5 to 6.5 hours in young healthy volunteers. Despite this small increase in half-life, there is no apparent accumulation during repeated administration.

Clinical Efficacy

The efficacy of zopiclone in young and elderly patients with insomnia has been well established in noncomparative and placebo-controlled investigations. Results of the largest reported study, a postmarketing surveillance study in 20 513 patients with insomnia (mean age 52.3 years) have shown that oral zopiclone 3.75 or 7.5 mg/day produced a good to excellent response in about 80% of patients after 21 days. In other studies, zopiclone produced improvements in sleep parameters in elderly patients with insomnia which were significantly greater than those observed with placebo. Comparative studies have shown that a 7.5mg dose administered on retiring was at least as effective as triazolam 0.125 to 0.5mg, flurazepam 15mg, and nitrazepam 5mg in reducing sleep latency and number of nocturnal awakenings, and in improving sleep duration, sleep quality and morning condition in elderly patients. Other studies, which included younger patients, have reported similar results. Zopiclone 7.5mg was generally at least as effective as triazolam 0.25 or 0.5mg, temazepam 20mg, nitrazepam 5mg, flunitrazepam 2mg, and flurazepam 30mg.

Sleep parameters improved in patients with chronic insomnia who were switched from benzodiazepines to zopiclone. Tolerance to the drug’s hypnotic effects was not observed in the few patients treated with zopiclone for periods of up to 17 weeks.

Tolerability and Overdosage

Zopiclone has been generally well tolerated by patients of all ages treated in clinical trials. In the large postmarketing surveillance study described above, adverse events were reported by 9.1% of patients aged 15 to 64 years, 9.5% of patients aged 65 to 79 years and 9.9% of patients aged more than 80 years; 2.8% of all patients withdrew from therapy. The most frequently reported adverse events in this study were bitter taste (3.6%), dry mouth (1.6%) and difficulty arising in the morning (1.3%). Central nervous system depression is the most frequently reported event following voluntary overdosage.

Dosage and Administration

In elderly patients with chronic insomnia, an initial dosage of 3.75 mg/day is recommended. This can be increased, if necessary, to 7.5 mg/day. This dosage appears to produce optimal hypnotic effects if taken orally 30 to 60 minutes before retiring. A reduced dose (3.75mg) is recommended in patients with hepatic impairment or severe renal insufficiency. Although zopiclone causes minimal ‘hangover’ effects, patients should be forewarned of the possibility of morning impairment of mental alertness or psychomotor skills following night-time zopiclone administration.

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Correspondence to Alison N. Wadworth.

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Various sections of the manuscript reviewed by: H. Allain, Laboratoire de Pharmacologic, Hôpital Pontchaillou, Rennes, France; M. Billiard, Unité des Troubles du Sommeil, Centre Hospitalier et Universitaire de Montpellier, Hôpital Gui de Chauliac, Montpellier, France; D.J. Greenblatt, Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts, USA; O. Kanno, Department of Psychiatry, Teikyo University Hospital, Mizoguchi, Kouzu, Kawasaki-shi, Japan; Y. Mizuki, Department of Neuropsychiatry, Yamaguchi University School of Medicine, Kogushi, Ube, Japan; A.N. Nicholson, Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire, England; H.C. Rettig, Ikazia Hospital, Rotterdam, The Netherlands; B.J. Sahakian, Department of Experimental Psychology, University of Cambridge, Cambridge, England.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259635.

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Wadworth, A.N., McTavish, D. Zopiclone. Drugs & Aging 3, 441–459 (1993). https://doi.org/10.2165/00002512-199303050-00006

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Keywords

  • Triazolam
  • Zopiclone
  • Flunitrazepam
  • Nitrazepam
  • Temazepam