Zopiclone

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy as an Hypnotic

Summary

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.

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Correspondence to Karen L. Goa.

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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).

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Goa, K.L., Heel, R.C. Zopiclone. Drugs 32, 48–65 (1986). https://doi.org/10.2165/00003495-198632010-00003

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Keywords

  • Triazolam
  • Zopiclone
  • Flunitrazepam
  • Nitrazepam
  • Temazepam