Review of Zopiclone [Somnosan, Zimovane, Imovane, Rhovane, Ximovan]

Since 1987 when zopiclone (Somnosan, Zimovane, Imovane, Rhovane, Ximovan) was introduced into clinical practice, extensive evaluations have shown that some rebound changes can be detected in healthy individuals. In patients with insomnia more than 20 studies have assessed rebound. Rebound can be found in such patients, but is usuallymore frequent and present in greater intensity in comparison groups given triazolam.

Studies in the elderly have been carefully reviewed by Soldatos and his colleagues. Some deterioration in the soundness of sleep has been detected but the amount of rebound insomnia following zopiclone discontinuation is relatively weak. Although one would certainly expect rebound in a hypnotic with a half-life of around 5 h, the frequency and severity of such rebound seems definitely less than those observed with comparative benzodiazepines such as triazolam and temazepam.

Longer-term studies have been designed to detect withdrawal as well as rebound phenomena. A large scale study in France recorded any reactions to stopping zopiclone after it had been taken for up to 12 months. Over a thousand patients took part, most of whom stopped abruptly. In only 1.3% of the overall population was there substantial evidence of any withdrawal. The symptoms comprised anxiety, irritability, malaise and perceptual changes, which are characteristic of a sedativetype withdrawal reaction. Two parallel studies evaluated the withdrawal following long-term zopiclone and long-term zolpidem. Thirty eight percent of those who withdrew from zopiclone had apparent symptoms, but these were also found in 27% of those who continued. Most of the withdrawal symptoms related to sleep complaints. Excluding these, no treatment-emergent increase in withdrawal symptoms was found.

An evaluation has beenmade of the utility of zopiclone substitution in facilitating the withdrawal of flunitrazepam. Twenty-four volunteers with insomnia and a history of long-termbenzodiazepine hypnotic usewere assessedwith both subjective and objective measures during a 5-week substitution with zopiclone and subsequent withdrawal or continuation on flunitrazepam. Withdrawal from flunitrazepam was accompanied aworsening of sleep quality, both subjectively and objectively. No such deterioration was seen in the zopiclone - substituted groups.

Lemoine and Ohayon completed a much larger scale study. Over 1000 patients being treated with a hypnotic were allocated to one of three treatments: gradual substitutionwith zopiclone ; immediate substitutionwith zopiclone ; remained on their benzodiazepine. The gradual and abrupt substitution group had improved sleep during this initial phase; the abrupt substitution group did best. During withdrawal, the last group (benzodiazepine-using) fared worst and more resumed their medication. The PSG withdrawal effects of zopiclone (7.5 mg), zolpidem (10 mg) and triazolam (0.25 mg) as compared with placebo were studied in 38 healthy subjects over 4 weeks. Slight, non-signi?cant rebound effects on sleep continuity were detected after withdrawal of zopiclone and zolpidem. Total sleep time and sleep efficiency were lower the first night after cessation of triazolam.

A very detailed review of zopiclone noted its proven efficacy and good tolerability.With respect to withdrawal, clinical trials showed no evidence for significant rebound insomnia. The risk of withdrawal reactions was very low, although dependency and abuse have been reported.

Post-marketing surveillance and pharmacovigilance data contain few convincing cases of withdrawal from zopiclone. Most consist of rebound insomnia, but there are a few instances of withdrawal convulsions following high-dose dependence. A reviewof 25 zopiclone discontinuation studies found rebound effects andwithdrawal symptoms to be minimal.