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PubMed1994

Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone.

Electroencephalographic slow-wave activity (SWA; power density in the 0.75 to 4.5 Hz band) and spindle frequency activity (SFA; 11.25 to 15.0 Hz) exhibit a typical time course and a distinct mutual relationship during sleep. Because benzodiazepines (BDZ) suppress SWA and enhance SFA, we investigated the effect of two BDZ-receptor agonists on the dynamics of these EEG parameters. A single dose of midazolam (15 mg), zopiclone (7.5 mg), or placebo was administered before bedtime to healthy young men. Although the two drugs reduced SWA and enhanced SFA, their time course across and within sleep cycles as well as their mutual relationship were little affected. The results constitute further evidence that hypnotics acting as BDZ-receptor agonists do not substantially interfere with the homeostatic aspect of sleep regulation.

Adult↗
PubMed1994

Development of a radioimmunoassay for the determination of N-desmethylzopiclone in urine.

The development of a specific and sensitive radioimmunoassay for the detection of N-desmethylzopiclone in urine samples is described. The assay will be used to pre-screen for N-desmethylzopiclone as an indication of zopiclone intake in a forensic and emergency context. N-Hemisuccinyldesmethylzopiclone has been prepared as a hapten. The immunization of rabbits with the hapten-bovine serum albumin conjugate resulted in the production of highly specific antibodies, showing no significant cross-reactivities with existing drugs. The four-parameter logistic model was used to process the calibration data into a fitting curve (r2 = 0.9979). Intra- and inter-assay relative standard deviations were < 9.1 and < 19.1%, respectively. The minimum detectable dose of the immunoassay was calculated to be 0.1 ng ml-1 (Pooled-variance t-distribution, p = 0.01, degrees of freedom = 14).

Animals↗
PubMed2005

On the origin of the DNA sequence selectivity of the azinomycins.

Simplified synthetic azinomycins preferentially induce in vitro DNA interstrand cross-links at the same 5'-d(GCC)-3' site as the natural products revealing that non-covalent interactions are relatively unimportant in defining sequence specificity.

Azabicyclo Compounds↗
PubMed2003

Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data.

AIMS: The non-benzodiazepine hypnotics zolpidem and zopiclone, which are indicated for short-term treatment of insomnia, were considered originally by physicians as almost devoid of abuse and dependence potential. Several recent publications, however, have suggested that both agents carry a significant risk of abuse. To substantiate and re-evaluate this situation, the world literature was reviewed for cases of dependence of both agents; these cases were analysed in order to identify certain underlying patterns, if evident. METHODS: A systematic review based on a Medline literature search was conducted including the years 1966-2002 to assemble all available clinical case reports that were analysed for typical features of abuse and dependence according to prespecified criteria. Only case reports were of interest, and clinical studies were excluded. No limitations as to language or publication year were applied. The terms 'zolpidem', 'zopiclone' and 'abuse', 'dependence', 'addiction', 'withdrawal' and 'intoxication' were used to identify relevant publications. Potentially relevant citations were retrieved and assessed for inclusion independently by two authors. RESULTS: A total of 36 cases for zolpidem were identified, most of them reported in recent years, and 22 cases for zopiclone. Both sexes were involved to a similar extent; and cases were reported in all age groups. In extreme cases, dose increases reached a factor of 30-120 above the recommended doses. The majority of patients had a history of former drug or alcohol abuse and/or other psychiatric conditions. CONCLUSION: On the basis of world-wide prescription numbers, which are approximately twofold higher for zolpidem (1,338,774,000 tablets from June 2001 to June 2002 in Europe, Japan and United States) than for zopiclone (664,897,000 tablets during the same period in Europe and Japan), the relative incidence of reported dependence similar for both drugs and remarkably lower than that of benzodiazepines used for the treatment of disturbed sleep. The findings offer the conclusion that zolpidem and zopiclone are relatively safe drugs. However, as both drugs are psychotropic drugs, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse of these agents.

Adult↗
PubMed1997

Concentrations and effects of zopiclone are greatly reduced by rifampicin.

AIMS: The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied. METHODS: In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. RESULTS: The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5-22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P<0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P<0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P<0.005). A significant (P<0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. CONCLUSIONS: The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.

Adult↗
PubMed2001

[A case of primary zopiclone dependence].

MEDICAL HISTORY: A 59-year-old female patient reported an increasing intake of up to 20 pills of zopiclone per day (150 mg) during the past 3 years. The dose increase was associated with euphoria and subjectively improved fitness. The patient suffered from anxiety and inner restlessness when trying to discontinue the medication, as well as from fatigue and forgetfulness when on medication. The medical history was free of psychiatric disorders and abuse of psychoactive substances. CLINICAL FINDINGS: Apart from mild attention and concentration deficits with a mildly depressed mood the psychiatric findings were normal. COURSE AND TREATMENT: Consistent with the preliminary diagnosis of a primary non-benzodiazepine dependence (zopiclone), after withdrawal of zopiclone the patient suffered from inner restlessness and psychomotor agitation, vague abdominal pain, and hypertension. The symptoms subsided after administration and subsequent gradual discontinuation of diazepam. CONCLUSION: Zopiclone dependence has repeatedly been reported in patients with pre-existing substance-related addictions, and in patients with other psychiatric disorders. Primary zopiclone dependence may be regarded as rare. Despite the low dependence potential of non-benzodiazepine hypnotics, the indication of prescription should be thoroughly considered.

Anti-Anxiety Agents↗
PubMed1991

Misuse of zopiclone and convulsions during withdrawal.

It has been documented that benzodiazepines have the potential to cause dependence and withdrawal reactions, including convulsions. However, the available data concerning zopiclone, a nonbenzodiazepine hypnotic, are insufficient. The present study describes the case of a 36-year-old man who repeatedly misused zopiclone, in daily doses of 60-90 mg. Furthermore, the patient suffered from convulsion on two occasions following abrupt withdrawal of zopiclone. The concomitant use of alcohol, trimipramine, and promazine may have contributed to the development of convulsions. It is concluded that zopiclone may cause problems associated with misuse and withdrawal reactions similar to those of benzodiazepines.

Adult↗
PubMed1987

Subjective effects during administration and on discontinuation of zopiclone and temazepam in normal subjects.

The purpose of the study was to ascertain whether the new hypnotic, zopiclone, was likely to produce rebound problems after short-term use, in comparison with placebo and a standard hypnotic, temazepam, and whether tapering the dosage lessened any such effects. Ten normal v olunteer subjects were administered 5 treatment sequences, each lasting 4 weeks, using a balanced design, with at least 2 weeks between sequences. The treatment sequences were: (table: see text) Each drug was given at night before retiring to bed. Daily ratings comprised a Sleep Questionnaire, Mood Rating Scales, the Spielberger State Anxiety Inventory and Bodily Symptom Scales. Both drugs improved quality of sleep but their discontinuation was followed by some worsening which was postponed but not avoided by halving the dosage for a week. Speed of, and feeling on, awakening showed discontinuation effects with temazepam but not with zopiclone. Zopiclone was associated with feelings of being troubled, tense, antagonistic and bored whereas temazepam produced drowsiness, clumsiness, dreaminess and sadness. Some increase in these ratings was noted after stopping temazepam and these were less after having the dosage. Zopiclone was associated with minimal such effects. For bodily symptoms, zopiclone produced some headache, a metallic taste, and some blurring of vision; temazepam induced nausea, memory impairment and pins and needles. Withdrawal effects on bodily symptom ratings were inconsistent and not affected by tapering off the dose. In conclusion, the administration of zopiclone tends to be associated with some dysphoric effects, temazepam with sedation. Rebound effects are minimal with zopiclone and reducing the dosage gradually does not seem necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Pregnancy outcome following first-trimester exposure to zopiclone: a prospective controlled cohort study.

BACKGROUND & AIM: Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic. To date, no published data exist regarding human pregnancy experience with zopiclone. The purpose of this study was to compare pregnancy outcome following first-trimester exposure to zopiclone with that of a matched control group of women, who were counseled for nonteratogenic exposure. METHODS: The Motherisk Program, the Toronto Teratogen Information Service, prospectively collected and followed up 40 women exposed to zopiclone during pregnancy. Pregnancy outcome was compared with that of a matched control group of women, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in the rate of major malformations (0 of 31 [0%] for zopiclone vs. 1 of 37 [2.7%] for nonteratogenic controls; p = 1). CONCLUSIONS: Our study, which is the first cohort on zopiclone use during embryogenesis, albeit small, suggests that zopiclone does not appear to be a major human teratogen. Larger studies are needed to establish its safety during pregnancy.

Abnormalities, Drug-Induced↗
PubMed1998

Zopiclone as night medication in rheumatoid arthritis.

Sleep disturbances and related daytime complaints are frequent in rheumatoid arthritis (RA). The aim of the current study was therefore to evaluate the effect of a newer hypnotic on sleep structure and clinical parameters in RA. Forty outpatients were randomized to a two week treatment regimen with either 7.5 mg zopiclone or placebo at bedtime. Clinical examinations were performed before and after treatment and the degree of pain, fatigue, sleepiness, morning stiffness, and activities of daily living were assessed. Two sleep questionnaires were also completed weekly. Polysomnography was performed before the study and after 14 days of treatment. Recordings were evaluated using conventional sleep scoring as well as frequency analysis of the electroencephalography (EEG). Patients in the zopiclone group had subjective improvement of sleep, but otherwise no differences in pain score or the other clinical parameters were found. Conventional sleep assessments showed only minor changes during treatment, but frequency analysis demonstrated a shift from the lower towards the higher EEG frequencies in the active treatment group. Although the modulation of the EEG can represent a non-specific pharmacologic epiphenomenon, it might also reflect a disturbance of sleep microstructure. In conclusion, treatment with zopiclone may be of value for subjective sleep complaints in selected patients with RA, but it is doubtful whether hypnotics improve daytime symptoms in this patient group.

Adult↗
PubMed2003

Comparison of the fatal toxicity index of zopiclone with benzodiazepines.

BACKGROUND: Zopiclone is a hypnosedative structurally unrelated to the benzodiazepines but operating at the same receptor complex. Although zopiclone has been used in clinical practice for many years, relatively little is known of its relative toxicity in comparison with other hypnosedatives. METHOD: Deaths, where hypnosedatives were implicated, in New Zealand (NZ) in 2001 were identified from a chemical injury database. Prescription and aggregate defined daily dose (DDD) data forNZ in 2001 were obtained from a national prescribing database. Rates of death per prescription and DDD, and relative rates between individual hypnosedatives and benzodiazepines, and their respective 95% CI were calculated. RESULTS: Of the 200 poisoning deaths in NZ for 2001, 39 involved hypnosedatives, and zopiclone was involved in 12. Hypnosedatives were the sole agents in only one death and were the primary agents in eight deaths. Zopiclone was the sixth most commonly involved agent in poisoning deaths in NZ in 2001. The relative rate of death per prescription (95% CI) and DDD (95% CI) of zopiclone compared with benzodiazepines were 1.04 (0.49-2.05) and 0.59 (0.28-1.16), respectively. The relative rates of death per DDD (95% CI) for alprazolam and chlormethiazole compared with the other sedatives/anxiolytics were 6.2 (1.6-17.0) and 20.9 (2.5-79.8) respectively. CONCLUSIONS: The fatal toxicity for zopiclone was not significantly different from that for benzodiazepines as a group when adjusted for usage, whereas alprazolam and chlormethiazole had greater toxicity. Hypnosedatives are contributory factors rather than primary substances in poisoning deaths.

Adolescent↗
PubMed2000

Characterization of zopiclone crystal forms found among generic raw materials.

This paper deals with the occurrence of polymorphs and pseudopolymorphs and their effect on the solid-state properties of zopiclone, a poorly water soluble nondiazepine sedative and hypnotic drug. X-ray powder diffraction (XRPD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), particle size analysis, dissolution studies, and solubility determinations were used to characterize the zopiclone raw materials. An anhydrated form, a dihydrated form, and a mixture of these two crystal forms were found and characterized among the zopiclone powders.

Azabicyclo Compounds↗
PubMed2005

Zopiclone withdrawal: an unusual cause of delirium in the elderly.

We report a case of an elderly lady who was admitted for congestive heart failure. She developed delirium during the course of her hospital stay. Multiple investigations were performed but were unremarkable. Finally, a diagnosis of abrupt zopiclone withdrawal causing delirium was made. Zopiclone was resumed at a lower dose and delirium resolved completely.

Aged↗
PubMedDate not supplied

Dependence on legal psychotropic drugs among alcoholics.

AIMS: Dependence on legal psychotropic drugs (PTD) has been reported to have increased in alcoholics, but previous studies report conflicting results concerning the rate of increase and clinical characteristics. The aim of the present study was first, to assess the dependence rate of PTD among alcoholics in open and institutionalized care, and to compare these populations with the general population, and second, to assess rates and doses of high- and low-dose PTD-dependence among alcoholics. METHODS: In 1997, alcoholics in open and institutionalized care were asked to anonymously fill in a questionnaire on their drug use and dependence. Healthy controls were included. The number of attending subjects was 130 open-care alcoholics at the Department of Alcohol and Drug Diseases in Malmö, Sweden; 23 alcoholics in institutionalized care at Karlsvik Rehabilitation Centre in Höör, Sweden; and 120 healthy controls at Vårdcentralen Kirseberg, a primary health care centre located in a Malmö area. The approximate attendance rate was 75, 70 and 95%, respectively. The questionnaire was based on DSM-IV criteria for dependence. RESULTS: The total rate of PTD-dependent alcoholics was higher in the institutionalized group (35%) than in the open-care setting (14%): difference in proportions (p(1)-p(2) 21%; 95% CI: 1%, 41%). Alcoholics were more often PTD-dependent (17%) than were healthy controls (2%), (p(1)-p(2) 15%; 95% CI: 9%, 21%). Benzodiazepines (BZD) were the most common PTD. Only four out of a total of 23 BZD-dependent alcoholics developed high-dose BZD-dependence. Those subjects were also misusing other drugs, including cannabis. CONCLUSIONS: We conclude that alcoholism is associated with legal PTD-dependence and illegal drug misuse. High-dose BZD-dependence is infrequent among BZD-dependent alcoholics.

Adult↗
PubMed1986

Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. A clinical study.

Patients receiving midazolam, temazepam or zopiclone by mouth as premedication for minor gynaecological surgery were pretreated with either ranitidine or an inert tablet. Pretreatment with ranitidine was associated with a greater degree of drowsiness at 20 and 40 min after midazolam, and a shorter mean time to peak hypnotic effect than in the non-pretreated group. Ranitidine did not affect the degree of drowsiness in the patients receiving temazepam or zopiclone.

Adolescent↗