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PubMed1989

Effects of zopiclone and temazepam on sleep, behaviour and mood during the day.

Over a 3 week period the hypnotic effect of zopiclone 7.5 mg, temazepam 20 mg and placebo was investigated in a double-blind, cross-over study in 60 out-patients. The hypnotic effect, subdivided in the parameters sleep quality, latency of sleep onset and status after awaking, was scored daily by the patient after arising. The results showed that zopiclone 7.5 mg and temazepam 20 mg were almost equally effective. In sleep quality and latency of sleep onset, there appeared to be a non-significant trend favouring zopiclone. Both hypnotics differ significantly from placebo. Mood and behaviour during the day, as well as somatic symptoms and side-effects, were also scored daily and showed no significant differences between the treatments. The third week, which was a placebo week for all patients, showed a gradual improvement in sleep quality. It supports the case for not prescribing hypnotics for more than 2 weeks.

Adolescent↗
PubMed1980

Comparative study of zopiclone, a novel hypnotic, and three benzodiazepines.

The hypnotic effect and tolerance of zopiclone 7.5 mg, nitrazepam 5 mg, flurazepam 30 mg, flunitrazepam 2 mg and placebo were compared in a one-night double blind study in 414 hospitalised patients who were to undergo an operation on the following day. Zopiclone was slightly superior to nitrazepam but was inferior both to flurazepam and flunitrazepam. All the active drugs differed clearly from placebo. The results from a subset of patients, excluding those who felt anxious either before treatment on the evening prior to the operation or on the following morning, were analysed separately. All the active products differed significantly from placebo; zopiclone was slightly less effective than the three benzodiazepines. All the benzodiazepines decreased the percentage of patients feeling anxious about the operation by about 25%, zopiclone by about 10% and placebo did not change it at all.

Adult↗
PubMed1987

Comparison of the clinical hypnotic effects of zopiclone and triazolam.

In a double blind crossover therapeutic trial the hypnotic effect of Zopiclone 7.5 mg and Triazolam 0.5 mg given orally at bedtime for 7 consecutive days have been compared. 5 of the items in Spiegel's questionnaire and 12 of the 18 items in Norris' visual analogue scale were significantly more improved by Zopiclone than by Triazolam. Both drugs caused few side-effects.

Adult↗
PubMed1983

Effect of zopiclone on the arousal level of healthy volunteers assessed by the averaged photopalpebral reflex.

The averaged photopalpebral reflex (PPR) represents the mean of summed reflex contractions of the orbicularis oculi muscle in response to periodic photic stimuli. The latency of PPR can be used to assess a drug effect on human arousal level, since it is prolonged if there is a reduction in the arousal level of the subject. In the present study of the clinical effects of zopiclone, healthy male volunteers aged 18-22 years were given zopiclone 5 mg and 10 mg, nitrazepam 5 mg and 10 mg, or placebo, in a double-blind, cross-over design. Changes in the latencies of PPR were examined from 0.5 to 4 h after medication. Both zopiclone and nitrazepam prolonged the latency in a dose-dependent manner, but the prolongation induced by zopiclone appeared more rapidly, was slightly more marked and lasted for a shorter period than that induced by nitrazepam. Zopiclone produced slightly fewer subjective changes, such as vagueness of thought and weakness, than did nitrazepam. From these results, it is suggested that zopiclone possesses a potent hypnotic action which appears more rapidly and is slightly more potent and shorter lasting than that of nitrazepam. In addition, zopiclone may also exhibit fewer side effects, such as vagueness of thought and weakness than nitrazepam, and it may cause less "hang over".

Adolescent↗
PubMed1993

Effect of zopiclone on sleep quality, morning stiffness, widespread tenderness and pain and general discomfort in primary fibromyalgia patients. A double-blind randomized trial.

Thirty-three patients fulfilling the diagnostic criteria for primary fibromyalgia completed an eight-week double-blind treatment trial with the drug zopiclone. Of outcome measures studied a score expressing subjective sleep quality showed improvement in more than ninety percent of zopiclone patients at 4 weeks and nearly eighty percent at 8 weeks, but similar improvement was also reported by more than sixty percent of the patients on placebo. Patient self-assessment of a treatment effect also showed an advantage for zopiclone, with most patients in the placebo group considering their state as unchanged at 8 weeks. According to examiner assessment, however, half the patients in both groups showed improvement at 8 weeks. For other assessment variables, e.g. dolorimeter assessment of widespread tenderness, visual analogue scales and pain drawings for pain and other subjective feelings of discomfort, the effects of zopiclone treatment were at the same level as those of placebo.

Adolescent↗
PubMed1996

Polysomnographic effects of hypnotic drugs. A review.

This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.

Adult↗
PubMed1997

Zopiclone: is there any dependence and abuse potential?

Both published and unpublished data concerning the rebound, withdrawal, dependence and abuse potential of zopiclone have been reviewed. As expected for an hypnotic drug of about 5 h elimination half-life, rebound has occasionally been detected but is substantially less frequent than with equivalent benzodiazepines. Tolerance to zopiclone does not occur regularly and cross-tolerance to the benzodiazepines may help in a regimen to withdraw from the latter drugs. Dependence on long-term use, as shown by either a characteristic withdrawal syndrome or by psychological craving, is rare considering the world-wide extent of usage. Abuse (addictive non-medical use) is documented but is also rare, in comparison with the widely abused benzodiazepines. It is concluded that zopiclone has substantial advantages over the benzodiazepines in terms of dependence and abuse potential.

Azabicyclo Compounds↗
PubMed1999

[Dependency of non-benzodiazepine hypnotics. Two case reports].

With the introduction of the non-benzodiazepine hypnotics zopiclone and zolpidem it was expected to have hypnotics without side effects and risks characteristically seen with benzodiazepines. We report two cases with high-dose usage and dependency of non-benzodiazepine hypnotics. Both patients were prescribed the drugs to treat sleep disturbances occurring during a depressive episode. While one patient had a polysubstance abuse there was no evidence for an abuse history in the other patient. To reduce withdrawal symptoms long-acting benzodiazepines were given to both patients. Thus, it seems that not only patients with a history of substance abuse but also patients with a psychiatric disorder are at risk for abuse of non-benzodiazepine hypnotics. Considering the increasing number of case reports with abuse and dependence of zopiclone and zolpidem it seems necessary to reevaluate the dependency risk of the currently available non-benzodiazepine hypnotics.

Adult↗
PubMed2005

Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring.

RATIONALE: Most studies that investigated the next-day residual effects of hypnotic drugs on daytime driving performances were performed on healthy subjects and after a single drug administration. OBJECTIVES: In the present study, we further examine whether the results of these studies could be generalised to insomniac patients and after repeated drug administration. METHOD: Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8+/-2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia. Driving tests were performed 9-11 h post-dose. RESULTS: Results showed that treatment effects were evidenced for subjective sleep, for driving abilities, and for electroencephalogram (EEG) recorded before (resting EEG) and during the driving simulation test (driving EEG). Compared to placebo, zopiclone increased the number of collisions and lormetazepam increased deviation from speed limit and deviation from absolute speed, whereas zolpidem did not differentiate from placebo on these analyses. EEG recordings showed that in contrast to zolpidem, lormetazepam and zopiclone induced typical benzodiazepine-like alterations, suggesting that next-day poor driving performance could relate to a prolonged central nervous system effect of these two hypnotics. CONCLUSION: The present results corroborate studies on healthy volunteers showing that residual effects of hypnotics increase with their half-lives. The results further suggest that drugs preserving physiological EEG rhythms before and during the driving simulation test 9-11 h post-dose, such as zolpidem, do not influence next-day driving abilities.

Adult↗
PubMed1998

The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics.

Twenty-four volunteers (19 women and five men) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a randomized, double blind, controlled clinical trial. The study was designed to assess the effects of substituting zopiclone (ZOP)- as an hypnotic- among chronic users of flunitrazepam (FLU), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objectively measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aimed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow- ups.

Adult↗
PubMed2000

Effects of zopiclone on the rest/activity rhythm after a westward flight across five time zones.

The effects of zopiclone on the rest/activity rhythm were investigated after a westward flight with a 5-h phase delay (Grenoble-Martinique). The rest/activity rhythm was recorded continuously with an actigraph monitor during a 6-day baseline episode in Grenoble and a 6-day sojourn in Martinique. Rectal temperature was recorded before the flight on day 2 and after the flight on days 2 and 5. Subjective jet-lag score was assessed before the flight on days 1 and 2 and in Martinique on days 1, 2, 5 and 6. Zopiclone (7.5 mg) or placebo were administered double blind 30 min prior to bedtime during the first 4 post-flight days (D1-D4). Under zopiclone treatment, sleep was less fragmented on the first post-flight night and the curtailment of sleep duration observed on D2 and D3 under placebo was prevented. During day-time, subjects tended to be more active than with placebo. By contrast, subjective jet-lag scores did not differ between both groups. Zopiclone seemed to accelerate the readjustment of the rest/activity rhythm and the normalisation of the phase relationship between sleep and the temperature rhythm. Zopiclone probably exerts its "resetting" effects on jet-lag desynchronosis by facilitating sleep induction rather than via a chronobiotic action.

Analysis of Variance↗
PubMed2003

Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo.

OBJECTIVE: In elderly patients, both falls and impaired memory are considerable medical problems. Hypnotics, which are frequently administered to this patient group for the treatment of insomnia, should ideally not impair equilibrium or memory functions. This double-blind, randomised, four-way, cross-over study investigated the effects of frequently prescribed hypnotics from different classes on postural oscillation and memory under real life conditions. Zolpidem 5 mg, zopiclone 3.75 mg, lormetazepam 1 mg (i.e. usual starting doses in elderly) or placebo were administered at night to 48 healthy elderly volunteers aged 65 years or more. The study included four treatment periods separated by wash-out periods of at least 1 week. METHODS: Psychomotor tests up to 9 h or 10 h after drug intake included, for attention and body sway, clinical stabilometric platform (CSP) tests, simple reaction time (SRT), and the critical tracking test (CTT); for memory, the learning memory tasks (LMT) and the Sternberg memory scanning test (mean reaction time [MRT] and percentage of correct answers) were used. For subjective sleep evaluation the Leeds sleep evaluation questionnaire (LSEQ) and for sedation a visual analogue scale (VAS) were used. For safety evaluations, adverse events (AEs) were recorded. RESULTS: The results demonstrate that compared with placebo, the active drugs increased body sway (area eyes open and closed in the CSP); however, this effect disappeared after 5 h with zolpidem, while it disappeared only after 8 h with lormetazepam and zopiclone. All three drugs did not affect attention assessed by the SRT and CTT. Concerning memory, Sternberg MRT at 9 h was not significantly different up to 5 digits for all groups in comparison with placebo, while for 6 digits it was significantly increased with lormetazepam and zopiclone. In the LMT, an impairment of performance was observed with lormetazepam relative to both zolpidem and placebo. CONCLUSION: The safest compared drug with regard to body sway was zolpidem, because of its short-lasting effect. In addition, zolpidem did not show any significant effect on memory functions, in the present dose comparison.

Aged↗
PubMed2006

The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone.

OBJECTIVE: Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone. METHODS: In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes. RESULTS: The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (C(max)) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve (AUC(0)-infinity) values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 microM) and itraconazole (8 microM) decreased the elimination rate of zopiclone enantiomers by about 65-95%, while montelukast (16 microM), gemfibrozil (200 microM) and sulfaphenazole (10 microM) had no appreciable effect. CONCLUSIONS: Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.

Adult↗
PubMed1996

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone.

OBJECTIVE: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. METHODS: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. RESULTS: Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng.ml-1. The t 1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0-inifinity) of zopiclone was increased from 415 to 719 ng.ml-1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. CONCLUSIONS: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.

Adult↗
PubMed1998

Rebound insomnia after hypnotic withdrawal in insomniac outpatients.

The effect of abrupt medication withdrawal (no-pill discontinuation) was investigated in 1507 insomniacs using the patients' self-ratings on visual analogue scales. Drug discontinuation followed a 28-day treatment period with either 7.5 mg zopiclone, 0.25 mg triazolam, 1.0 mg flunitrazepam, or placebo in a randomized, double-blind, parallel group, multicenter study in private practice. Deterioration below individual pretreatment values (no-pill baseline) in at least one of three subjective parameters of sleep quality (sleep latency, total sleep time, nocturnal awakenings) and three parameters of daytime well-being (morning freshness, daytime tiredness, anxiety) were defined as rebound. The number of patients with rebound (rebound rate) was analyzed for every day of a 2-week posttreatment period. The overall rebound rate was higher in the placebo group (p < or = 0.001) than in each group treated with active drugs. Rebound rates affecting sleep quality were higher for placebo than for zopiclone (p < or = 0.001) and for flunitrazepam (p < or = 0.05). Rebound rates were smaller for zopiclone (p < or = 0.001) and flunitrazepam (p < or = 0.01) than for triazolam. Rebound in at least one item per day appeared in 21.5% (sleep quality) and 25.5% (daytime well-being) of the patients. Rebound decreased with increasing numbers of items of sleep quality or daytime well-being. Patients who did not respond to treatment showed higher rebound rates than those who were treatment responders (p < or = 0.001). Concerning treatment nonresponders, highest rebound was seen in the placebo group, whereas rebound was lowest in placebo responders. These results show that pill discontinuation itself may worsen sleep and daytime well-being in the sense of a rebound phenomenon. Furthermore, the number of patients with rebound remained at a high and varying level during the whole posttreatment period. This result indicates that a deterioration of sleep after drug withdrawal is not apparent during a few days but may last for longer periods in some patients and is modified by marked night-to-night variations.

Adolescent↗
PubMed2001

A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects.

Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29,30,41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses.

Adult↗