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PubMed2006

Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial.

OBJECTIVE: To evaluate eszopiclone 3 mg for treatment of insomnia in perimenopausal and early postmenopausal women, as well as the impact of insomnia treatment on mood, menopause-related symptoms, and quality of life. METHODS: This was a double-blind, placebo-controlled study with 410 women (aged 40-60; perimenopausal or early postmenopausal) who reported insomnia defined as sleep latency of at least 45 minutes and total sleep time less than or equal to 6 hours per night for at least 3 nights per week over the previous month. Patients were randomly assigned to eszopiclone 3 mg or placebo nightly for 4 weeks. Sleep data were collected once a day. Physician global assessments of menopause, menopause-specific questionnaire, Greene Climacteric Scale, the Montgomery Asberg Depression Rating Scale, and the Sheehan Disability Scale were collected at baseline and end of treatment. RESULTS: Patients receiving eszopiclone reported improvements in sleep induction, sleep maintenance, sleep duration, sleep quality, and next-day functioning relative to placebo (P<.05). Patients receiving eszopiclone reported fewer total awakenings and awakenings due to hot flushes (P<.05). Eszopiclone use led to greater improvement in Montgomery Asberg Depression Rating Scale scores (P<.05) and physician global assessments of menopause scores (P<.001); total Greene Climacteric Scale score and the vasomotor and psychological sub-scores (P<.05); vasomotor and physical domains of the menopause-specific questionnaire (P<.05); and family life/home domain of the Sheehan Disability Scale (P<.05). CONCLUSION: In this study, eszopiclone provided significant improvements in sleep and positively impacted mood, quality of life, and menopause-related symptoms in perimenopausal and early postmenopausal women with insomnia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00366093 LEVEL OF EVIDENCE: I.

Affect↗
PubMed1990

Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone.

Lormetazepam, midazolam and zopiclone were compared as night medication in patients scheduled for elective surgery the next morning. Sixty patients divided at random into three groups, received double-blind lormetazepam 1 mg, midazolam 15 mg or zopiclone 7.5 mg, by mouth at 2200 hours. The quality of sleep was assessed at 0700 hours from responses to a questionnaire, and psychomotor function by comparing paper and pencil (p-deletion) and Maddox Wing tests with reference values from the day before. The three hypnotics were equally effective as sleep medication for time until onset of sleep, duration of sleep and condition upon awakening, whereas zopiclone provided significantly fewer (p less than 0.05) spontaneous awakenings. The p-deletion test did not differ in any of the three groups from the reference values. The ocular imbalance test in all three groups was significantly different (p less than 0.01) from control. The lormetazepam group scored significantly better (p less than 0.05) than the zopiclone group. No side effects were seen.

Adolescent↗
PubMed1983

Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease.

Eight healthy individuals and seven cirrhotic patients received 7.5 mg zopiclone orally. Two further cirrhotics received 3.75 mg. Plasma concentrations of zopiclone and psychometric tests including reaction time and critical flicker fusion threshold and electroencephalographic tracings were performed at regular intervals after drug administration. Peak plasma levels of zopiclone were similar in the two groups but the time to peak was delayed in the cirrhotics. Plasma zopiclone half-life was 8.53 +/- 0.83 h in the cirrhotics and 3.50 +/- 0.33 h in the healthy individuals. In the group of cirrhotics there was a negative correlation between zopiclone half-life and serum albumin concentration (r = -0.87). Zopiclone caused sedation in both groups. Reaction time was prolonged and critical flicker fusion threshold reduced in both groups. Recovery was delayed in the cirrhotics compared to the healthy subjects but was complete by 8 h. The size of the changes was somewhat greater in the cirrhotics but baseline observations differed between the groups. The mean dominant frequency was lower in the cirrhotics and fell slightly in that group after zopiclone administration. The response to zopiclone is delayed and exaggerated in cirrhosis. Precautions are therefore required when using this drug in patients with chronic liver disease.

Adult↗
PubMed1984

The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.

Nine healthy volunteers swallowed 7.5 mg zopiclone in the standing and lying positions on different occasions. Plasma concentrations of zopiclone and psychometric tests, including simple and complex reaction time, and critical flicker fusion threshold, were performed at regular intervals after drug administration. The results show that when the drug was swallowed in the supine position, there was a significant delay in the onset of the impairment of psychomotor function, with prolongation in time to peak impairment by 30-40 min (P less than 0.02). The overall impairment in psychomotor performance was found to be significantly less after administration of the drug in the supine position (P less than 0.005). Pharmacokinetic analysis revealed a prolongation in lag time of greater than 20 min before absorption began (P less than 0.002) after supine drug administration, with a significantly lower rate constant of absorption (P less than 0.02). Area under the plasma concentration-time curve extrapolated to infinity and rate constant of elimination were not significantly different between the two modes of administration. We conclude that to obtain a rapid and complete effect from the hypnotic zopiclone, the tablet should be swallowed in the standing position.

Adult↗
PubMed1986

Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.

The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo. The performance tests selected (stroop task, five choice serial reaction time, memory span, logical reasoning, mood and saccadic eye movement analysis) were thought to reflect aspects of normal daily activity. The tests demonstrated a clear reduction of performance for all active treatments. No drug emerged as the most potent sedative overall, as each of the tests was affected to a different degree by each drug. Drug effects were not qualitatively different between active treatments so that zopiclone was indistinguishable from the three benzodiazepines with which it was compared.

Adult↗
PubMed1990

The excretion of zopiclone into breast milk.

1. The excretion of zopiclone into breast milk was studied in 12 lactating women in the early postpartum period following the oral administration of a single zopiclone tablet (7.5 mg). 2. The milk/plasma AUC ratio of zopiclone was 0.51 +/- 0.09 (mean +/- s.d.). Individual mean milk/plasma concentration ratios of zopiclone showed significant interindividual variation (range 0.41-0.70). 3. A comparison of pharmacokinetic parameters in the postpartum women with those reported previously in non-pregnant women, showed significantly higher Cmax values in the lactating mothers; tmax occurred later in milk than in maternal plasma. 4. Assuming a daily milk intake of 0.15 l kg-1 and 100% absorption the average infant dose of zopiclone in milk would be 1.4% of the weight adjusted dose ingested by the mother.

Azabicyclo Compounds↗
PubMed1990

Actions of zopiclone and carbamazepine, alone and in combination, on human skilled performance in laboratory and clinical tests.

1. Possible interactions of zopiclone and carbamazepine on human skilled performance were studied in a randomized, double-blind, crossover trial with 12 healthy young subjects. 2. Psychomotor performance (coordination, reactions, attention, cognition) and subjective effects (VAS) were measured and venous blood sampled before and 1.5, 3, 4.5 and 6 h after single oral doses of placebo, 7.5 mg of zopiclone and 600 mg of carbamazepine, which were given alone or combined. Clinical test for drunkenness (CTD) was done 2 and 5 h after drug intake. 3. Both zopiclone and carbamazepine, when administered alone, impaired performance on laboratory tests, the decrements being recorded 1.5 to 6 h after intake. In line with the plasma concentrations, the zopiclone effects peaked earlier (at 1.5 h) and lasted for a shorter time than those of carbamazepine. Zopiclone had a more pronounced effect on perceptual and cognitive functions (digit substitution) and it affected extraocular muscle tone (Maddox wing), whereas carbamazepine had stronger effects on attention. Additive pharmacodynamic actions were found in most tests after the combined treatment with zopiclone and carbamazepine. 4. CTD proved to be less sensitive than the laboratory tests in revealing drug-induced decrement of performance after administration of one agent alone. However, it revealed the combined decremental effects of zopiclone and carbamazepine. 5. When the drugs were given together, the absorption of drugs was retarded. Carbamazepine-10,11-epoxide levels were lower after intake of the drug combination than those measured after intake of carbamazepine alone. 6. The results suggest that the clinical tests developed to detect alcohol effects do not necessarily reveal drug-induced impairment of performance.

Adult↗
PubMed1994

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

Administration, Oral↗
PubMed1993

Effects of zopiclone on slow wave sleep and spontaneous K-complexes for normal healthy young adults.

Benzodiazepine (BZD) hypnotics have been known to decrease, to some degree, human slow wave sleep (SWS) although they elevate the arousal threshold during sleep. Zopiclone (ZPC), a cyclopyrrolone hypnotic, has attracted the interest of sleep researchers because an increase in human SWS has been reported. Since the increase has not been fully confirmed by all of the studies, the authors investigated the effects of ZPC 10 mg on SWS and the K-complexes for 7 healthy young adults because there is evidence indicating that delta waves consisting of SWS and the spontaneous K-complexes are identical. SWS and st. 4 sleep did not decrease on any of the ZPC nights but st. 3 sleep showed a tendency to reduce on the 1st ZPC night. The frequency of the K-complexes decreased significantly on the 2nd ZPC night and tended to reduce on the 1st ZPC night. Moreover, a significant positive correlation was noted between the decrease rates of SWS and the K-complexes on both the ZPC nights. The authors, therefore, could not obtain any findings suggesting an increase in SWS with ZPC.

Administration, Oral↗
PubMed1998

Treatment of insomnia by concomitant therapy with Zopiclone and Aniracetam in patients with cerebral infarction, cerebroatrophy, Alzheimer's disease and Parkinson's disease.

For insomniac patients, sleeping drugs are used: in addition, concomitant therapy with other drugs has been tried in an effort to prevent a decrease in the effects due to long-term continuous use. This report presents the results of a study on the sleeping effects in nine aged patients with insomnia associated with cerebrovascular and noncerebrovascular disorders who received concomitant therapy with Zopiclone and Aniracetam. The treatment in 7/9 cases (78%) was found to be effective, showing more than 50% prolongation of sleeping time, and in two cases (22%) was found to be ineffective. We discuss the mechanism of action referring to the literature.

Aged↗
PubMed1987

Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers.

This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.

Adult↗
PubMed1986

Insomnia in general practice: the role of temazepam and a comparison with zopiclone.

The aetiology of insomnia can be conveniently divided into six groups: physical (pain, cough, etc.), physiological (shift-workers etc.), psychological (life events), psychiatric (depression, anxiety, etc.), iatrogenic (stimulant drugs, etc.) and idiopathic (no obvious cause). The four main types of insomnia are: prolonged latency, frequent short awakenings, one or two long awakenings and early morning awakening. Patients' habits that may interfere with sleep are related to: alcohol, smoking, tea and coffee drinking, and bedtime drinks. In a double-blind comparison between temazepam and nitrazepam, both drugs were shown to be effective hypnotics, nitrazepam being better for early morning wakening, although at the expense of more hangover effects. Zopiclone, a new cyclopyrrolone hypnotic, was also compared to temazepam in a double-blind cross-over trial and similar hypnotic effects were recorded with both drugs.

Anti-Anxiety Agents↗
PubMed1992

Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects.

To determine whether caffeine antagonizes the decremental effects of triazolam and zopiclone on human performance, oral single doses of 0.250 mg triazolam, 7.5 mg zopiclone, or respective placebos, with and without 300 mg caffeine, were given to parallel groups of student volunteers in two double-blind studies. Objective tests and subjective visual analogue ratings were done at baseline and 30 min. and 90 min. after the intake. In Study I, triazolam produced drowsiness at 30 min. but did not differ from the placebo in other tests. Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured. Caffeine and triazolam were interpreted as being antagonists. In Study II, zopiclone impaired digit substitution and flicker fusion, produced exophoria and lowered systolic blood pressure. Caffeine differed from zopiclone in several test functions, but it also differed from caffeine + zopiclone whereas zopiclone differed from caffeine + zopiclone only in two tests (Maddox wing, systolic blood pressure). Thus, zopiclone counteracted the effects of caffeine more easily than caffeine counteracted the decremental effects of zopiclone. We conclude that triazolam may not differ importantly from diazepam as regards their antagonism towards caffeine, whereas further research on the antagonism between zopiclone and caffeine needs to be done.

Anti-Anxiety Agents↗
PubMed1996

Pharmacokinetic-pharmacodynamic modelling of zopiclone effects on human central nervous system.

The present data shows the pharmacokinetics and concentration-effect relationship of a single 7.5 mg oral dose of zopiclone in ten healthy volunteers. Plasma concentrations and effects of zopiclone on central nervous system as quantified by changes in saccadic peak velocity and digit symbol substitution test were measured for 17 hr after ingestion of zopiclone. Pharmacokinetics was described with a linear one-compartment open model. Maximum effects preceded peak plasma zopiclone concentrations causing a clockwise hysteresis, i.e. proteresis, in concentration versus effect loops. Therefore, pharmacodynamics was described both with a tolerance model and a model with distributional pseudo-tolerance where the concentration in the blood sampling site is assumed to equilibrate slower with arterial blood than the site of action of zopiclone. Both models related the changes in pharmacodynamics linearly to changes in zopiclone concentrations. The median (range) values for clearance, volume of distribution and elimination half-life were 21 (15-53) L/hr, 132 (58-161) L and 3.4 (1.7-5.7) hr, respectively. Both pharmacodynamic models were able to describe the relationship between zopiclone concentrations and changes in psychomotor performance equally well. However, because the pharmacodynamics of zopiclone were studied in a non-steady-state situation, the mechanism for proteresis, i.e. true tolerance versus distributional pseudotolerance cannot be identified.

Adult↗