Zopiclone

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Abstract
Zopiclone is a non-benzodiazepine hypnotic which was first reviewed in Drugs in 1986. At that time, zopiclone had shown hypnotic efficacy superior to that of placebo, but had not been extensively compared with benzodiazepine hypnotics in patients with insomnia. A much larger body of clinical data is now available, allowing a more detailed evaluation than was previously possible. Together with results from earlier studies, subsequent clinical trials have shown that zopiclone is generally at least as effective as the benzodiazepines (regardless of duration of action) in the treatment of insomnia, although comparisons between zopiclone and flurazepam have produced inconsistent results. Tolerance to the effects of zopiclone was not seen in short term clinical trials (≤ 4 weeks); data from longer term studies are conflicting and the potential for tolerance during long term zopiclone treatment is therefore unclear. Zopiclone has a relatively low propensity to cause residual clinical effects (such as difficulty in waking or reduced morning concentration). Rebound of insomnia to a level below that at baseline can occur after withdrawal of zopiclone, but, on the basis of data from short term studies, does not appear to be common. Data from prescription-event monitoring suggest that zopiclone does not have a high dependence potential (at least in those who are not regular drug abusers/addicts). Zopiclone is well tolerated in both the elderly and younger patients with insomnia. A bitter aftertaste is usually the most common adverse event, but is relatively infrequent (3.6% in the largest available postmarketing study). Thus, zopiclone is now firmly established as an effective and well tolerated hypnotic agent. Although the available data on rebound insomnia and dependence liability are encouraging, potential differences between zopiclone and the benzodiazepines in these respects may have little clinical relevance in the context of short term intermittent use of hypnotics, as is currently recommended, A low propensity for rebound insomnia and dependence might prove valuable during long term hypnotic therapy (which, although not recommended, is a clinical reality). However, the risk-benefit profile of zopiclone in this context remains unknown. Nevertheless, zopiclone is clearly a suitable alternative to the benzodiazepines for the short term treatment of insomnia. Zopiclone is an agonist at the type A γ-aminobutyric acid (GABA) receptor. It enhances the inhibitory effects of GABA (like the benzodiazepines, which bind to the same recognition site), but appears to have effects on receptor function which are partially distinct from those of the benzodiazepines. The hypnotic effects of zopiclone (such as reduced sleep onset latency, increased total sleep time and a reduction in the number of night-time awakenings) have been demonstrated in numerous studies in healthy volunteers and patients with insomnia. Significant next-day psychomotor impairment was generally absent in patients who received zopiclone 7.5 mg/day in clinical trials. In comparative studies, zopiclone had a psychomotor profile similar to or better than that of the long-acting benzodiazepines nitrazepam and flurazepam. Temazepam, but not zopiclone, significantly impaired performance in the critical flicker fusion test in one clinical trial. Data from pharmacodynamic and clinical studies suggest that, in general, zopiclone does not cause any significant next-day impairment of memory function, although memory impairment is often seen within a few hours of administration. Oral zopiclone is well absorbed and distributes widely, with a volume of distribution of ≈100L. The major metabolites (produced via cytochrome P450) are the N-oxide, which has lower pharmacological activity than zopiclone, and the inactive N-desmethyl derivative; together with a number of minor metabolites, these are removed via the urine and lungs. The elimination half-life of zopiclone is typically ≈5 hours (i.e. similar to that of the short-acting benzodiazepines). Metabolism is reduced in elderly patients and those with hepatic cirrhosis, resulting in increased plasma zopiclone concentrations that may warrant dosage reductions. In patients with renal insufficiency, only severe renal failure has been shown to warrant zopiclone dosage reductions. Pharmacokinetic and/or pharmacodynamic interactions have been described between zopiclone and a number of other drugs, including alcohol and benzodiazepines. Although some studies have documented statistically significant differences in efficacy between zopiclone and comparator benzodiazepines (in favour of either agent), the vast majority of analyses indicate similar hypnotic effects. In controlled clinical trials published since the previous review of zopiclone in Drugs in 1986, the hypnotic efficacy of zopiclone was generally at least as good as that of the long-acting benzodiazepines nitrazepam and flunitrazepam, the intermediate-acting benzodiazepine temazepam, and the short-acting benzodiazepines triazolam and midazolam. A definitive assessment of the relative efficacy of zopiclone and the long-acting benzodiazepine flurazepam is not possible from the available data. Previous findings indicating that zopiclone is generally as effective as the benzodiazepines in the elderly are consistent with the majority of analyses from 3 subsequent clinical trials; however, some statistically significant differences in favour of flunitrazepam or nitrazepam were also noted. EEG analysis of sleep parameters revealed no marked tolerance to the effects of zopiclone during a 17-week study in 6 patients with severe chronic insomnia. In contrast, patients’ self-assessment and EEG analysis in another small study (n = 11) revealed some loss of efficacy (statistical analysis not provided) for sleep onset latency after ≈8 weeks’ treatment with zopiclone. Zopiclone is well tolerated in both elderly and younger patients with insomnia. A bitter metallic aftertaste was generally the most common adverse event in patients receiving zopiclone 3.75 or 7.5 mg/day (3.6% of 20 513 patients in a postmarketing surveillance study, 6.7% of 612 patients in the largest available clinical trial). Clinical trial data suggest that the long-acting benzodiazepines nitrazepam, flurazepam and flunitrazepam are generally more likely than zopiclone to cause residual clinical effects (e.g. difficulty in waking, impaired daytime well-being and reduced morning concentration). No significant differences in this respect were evident between patients receiving zopiclone and those receiving the intermediate-acting benzodiazepine temazepam in 1 study. Results from several investigations indicate that zopiclone is similar or superior to the short-acting benzodiazepine triazolam in terms of next-day impairment. Significant rebound insomnia after withdrawal of zopiclone was seen in 2 clinical studies, whereas several other studies showed no such effect. Zopiclone does not appear to have a high potential to cause dependency in nonabusing patients: there were only 7 reports of possible dependency among 13 177 patients in a prescription-event monitoring study (0.05% total incidence). Where case reports of dependency have emerged, these have involved patients with a history of drug abuse. The recommended zopiclone regimen for patients with acute or chronic insomnia is 7.5mg once daily before going to bed, increasing to 15mg in those affected by severe or persistent insomnia who do not respond to the lower dosage. Elderly patients and those with renal or hepatic impairment should initially be treated with zopiclone 3.75mg but higher dosages can be administered if appropriate. Zopiclone should be avoided in pregnant women and is contraindicated for nursing mothers. Successful substitution of zopiclone for a benzodiazepine has been achieved using a direct switch from one drug to the other or by using a period of overlap followed by the switch to zopiclone alone. Long term regular use of zopiclone is not recommended. The manufacturer states that treatment duration should not exceed 4 weeks but general recommendations are that hypnotic agents should be used only intermittently. Use of zopiclone in patients with chronic insomnia should be accompanied by treatment of any underlying conditions and instruction of appropriate sleep hygiene. 20 cases of intentional overdose with zopiclone alone (≤225mg) were reported among 13 177 patients in a postmarketing study; there were no fatalities. Five case reports (some complicated by alcohol or benzodiazepine use) have documented fatal zopiclone overdosage.

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