Two distinct double-blind randomized multicentre studies were undertaken at the same time using the same design. Patients treated for insomnia with zopiclone 7.5 mg or zolpidem 10 mg for at least three months were allocated to two groups: gradual withdrawal or control. In each study the two groups were compared but there was no comparison between zopiclone and zolpidem. The main criteria was the number of patients in each group with “withdrawal syndrome” defined as: the occurrence of an adverse event, or premature discontinuation of treatment or a total score increase of at least 3 points on the Tyrer questionnaire. In both studies the incidence of “withdrawal syndrome” as defined above was significantly higher in the “withdrawal” groups than in the “control” groups 38% vs 20% for zopiclone p = 0.008 and 38% vs 24% for zolpidem P = 0.049. In most cases, the notified symptoms were sleep complaints.

Withdrawal from hypnotics can produce a variety of problems, especially sleep difficulties, some of which may arise from the multiple actions of most hypnotics, thus producing a range of rebound effects. This study examined whether switching patients to a hypnotic with a narrower range of action and of a different class would reduce these problems. One hundred and thirty-four patients participated; they were randomly allocated to one of three methods of switching from “previous hypnotic” to zopiclone (a cyclopyrrolone). The methods were gap (an interval between taking the two drugs); abuttal (taking zopiclone immediately on stopping previous drug); and overlap (gradually reducing previous drug after starting zopiclone). The main findings were that zopiclone was associated with better sleep and increased alertness; the abuttal method was the best method of switching; and no serious side effects from zopiclone were reported. It was concluded that zopiclone has a useful role in benzodiazepine withdrawal, and that immediate substitution is the best method.

From 20,000 households regularly surveyed by a national survey institute (Sofres), two groups were selected and questioned (using a 23-item questionnaire) about sleep vigilance and quality of life. The first group was composed of insomniacs using zopiclone for the last 12 months and no other CNS treatments (167 subjects). The second group was composed of 381 “good sleepers” selected as having no or occasionally one sleep disturbance in the last 12 months. No difference was found between the two groups in average total sleep time. Sleep disturbances were statistically equal in the two groups except for difficulties in initiating sleep which is more present for zopiclone users (13% vs 3%). Vigilance was mostly comparable in both groups.Five aspects of quality of life explored by the questionnaires (the professional, relational and sentimental, domestic, leisure and safety aspects) appeared to be comparable in the two groups.

During the early treatment of a major depressive episode with amitryptiline, insomnia was treated in 81 patients in a double-blind comparative trial comparing zopiclone and flunitrazepam. The study showed no major differences in the efficacy profile and showed better tolerability for zopiclone than for flunitrazepam.

The effect of treatment (28 days) with zopiclone, triazolam, flunitrazepam and placebo on sleep quality and daytime well-being was proven in a randomised, double-blind, parallel group, multicentre study in private practice. Results of an exploratory statistic of treatment efficacy in a subgroup of 1,291 patients suffering from insomnia are presented. Patients met the following criteria: insomnia lasting at least four weeks and the presence of at least two of the following: 1) sleep latency ≥ 45 minutes, 2) total sleep time ≤ 6 hours, and 3) nocturnal awakening ≥3 times. Treatment efficacy was assessed according to the following factors: either a shortening of sleep latency by at least 15 minutes, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a refreshed feeling in the morning as well as no impairment in daytime well-being due to tiredness or anxiety. The total response rate was markedly higher with zopiclone (42.3%; p = 0.0003) than with placebo (29.0%). Triazolam (36.6%; p = 0.0905) and flunitrazepam (33.1%; p = 0.3401) were also more effective than the placebo, but they both tended to have a lower response rate than with zopiclone (p = 0.1199 and 0.0151, respectively). Total response was found to be essentially a reflection of the response of the socially important parameter of daytime well-being. These results suggest that zopiclone is more effective in the treatment of insomnia than either triazolam or flunitrazepam. Since the response of daytime well-being to therapy was generally poor, this parameter embodies the next main therapeutic challenge in the treatment of patients with insomnia.

All of the components of quality of life can be altered in insomniacs because of sleep disorders themselves but theoretically also in consequence to side effects from hypnotic agents. The presented international study, carried out with a multicentre, randomised and double-blind design, investigated zopiclone effects on quality of life in insomniac patients as compared to placebo. A total of 458 patients completed the study, 231 receiving zopiclone 7.5 mg and 227 receiving placebo, with mean treatment durations of 48 and 44 days. Sleep parameters and quality of life, measured with extensive and validated scales, were assessed at baseline and at 14, 28 and 56 days after admission. Zopiclone showed hypnotic efficacy and significantly greater improvement of quality of life as compared to placebo, both at 14 days and at endpoint.

Before and after its introduction in 1987, zopiclone was the object of investigation in 16 psychometric studies employing both healthy volunteers and insomniac patients. Their common purpose was to determine whether nocturnal doses (usually the standard 7.5 mg) possess residual sedative effects that interfere with skilled safety-relevant performance, such as car driving, over the following day. Most studies have found no residual effects. Those that did, have shown them to be modest in magnitude and not to persist for longer than about 12 hours from the time of dosage. Without altering the general conclusion that zopiclone possesses few if any residual effects of clinical relevance, it must be said that the studies reviewed failed to meet current methodological standards and may have left some important questions unanswered.

Increases in psychosocial stress and disruption of the biological clock due to irregular sleep-wake schedules as well as an increase in the elderly population have resulted in an increase in sleep disorders, most notably insomnia. In order to manage insomnia, correction of a poor sleep environment is of primary importance. We now have many good GABA A receptor agonists such as benzodiazepines and cyclopyrrolones (zopiclone) for use as hypnotics, but to achieve improvements in nocturnal sleep and restoration of daytime functions, short- or ultra-short acting hypnotics are recommended. Zopiclone has been reported to show weaker effects on sleep architecture than other benzodiazepines and does not exacerbate mild or moderate sleep apnea syndrome. Some patients are therapeutic-dose dependent on hypnotics or anxiolytics without showing detectable side effects. It may be possible for some insomniacs, particularly forelderly people, to use the minimum necessary dose of hypnotics to achieve good sleep and live a happy life from the standpoint of good quality of life.

The effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale — Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective “residual” effect.

The mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displaces the binding of [3H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [35S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different α-subunits (BZ1 and BZ2 phenotype). Studies with protein-modifying agents (eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.