Zopiclone, a third generation of hypnotics.
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Pharmacological studies on zopiclone.
Zopiclone (RP 27 267) is an hypnotic with a chemical structure different from that of the benzodiazepines (BZD) or barbiturates. Studies of zopiclone in classical psychopharmacological tests, in comparison with BZD and barbiturates, have shown that it exhibits the five main types of activity considered as characteristic of the pharmacological profile of BZD and partly of that of barbiturates (anticonvulsant, myorelaxant, antiaggressive, sedative-hypnotic and 'anticonflict'). However, like BZD, zopiclone differs from barbiturates by a high safety margin. Electrophysiological studies performed in cats have shown that zopiclone induces modifications in sleep-wakefulness pattern which are close to those observed with BZD, specially with nitrazepam. Moreover, zopiclone increases the threshold for arousal by reticular formation stimulation, rather more than nitrazepam, but with a shorter duration of action. The short duration of action of zopiclone has been demonstrated in other species using different tests.
Aggression↗
Brain receptors and zopiclone.
Zopiclone (ZPC; RP 27,267), which is chemically unrelated to benzodiazepines (BZD), was found to have a similar pharmacological profile and to possess in man hypnotic activity similar to that of some BZD such as nitrazepam. It was, therefore, interesting to study the interaction of ZPC with rat brain receptors and specially with the so-called 'BZD receptors'. ZPC possesses in three rat brain regions a high affinity for BZD receptors: its Ki values measured against [3H]-flunitrazepam are 24 nM in the cerebral cortex, 31 nM in the cerebellum, and 36 nM in the hippocampus. No other brain receptors such as gamma-aminobutyric acid receptor, dopamine receptor, serotonin and noradrenergic receptors are reached by ZPC. Moreover, ZPC seems to bind only to brain BZD receptors and, contrarily to some BZD such as flunitrazepam, it does not reach the peripheral renal BZD-binding sites. The synthesis of [3H]-ZPC has permitted a more in-depth study of the interaction of ZPC with brain receptors. The high affinity of ZPC has been confirmed by equilibrium-binding studies (KD = 13 +/- 4 nM in rat hippocampus) and the study of the modulating effect of gamma-aminobutyric acid and barbiturates on ZPC binding has revealed some differences between ZPC and BZD. It could, therefore, be postulated that ZPC might bind in rat brain to sites which do not correspond exactly to BZD sites.
Animals↗
Zopiclone: sleep and performance studies in healthy man.
Effects of 2.5, 5.0, 7.5, and 10.0 mg zopiclone on sleep and on performance the next day were studied in 6 healthy adult males aged between 21 and 33 years. The experiment was double-blind and placebo controlled. 5.0 and 10.0 mg zopiclone decreased the amount of awake activity and drowsy (stage 1) sleep over the first 6 h of sleep, but this effect was only present for the whole sleep period with the 10.0-mg dose. The duration and percentage of stage 3 sleep were increased with 7.5 mg. The 7.5- and 10.0-mg doses increased the combined duration of stages 2, 3, and 4 sleep over the first 6 h and over the whole night. The first period of rapid eye movement sleep was delayed with 7.5 mg, and with 10.0 mg the time spent in rapid eye movement sleep was reduced during the first 6 h of sleep, but not over the whole night. The number of substitutions in the digit symbol substitution test was decreased 9 h after ingestion of 7.5 and 10.0 mg, and the number of symbols copied reduced after 10.0 mg. The clinical dose range of zopiclone is likely to be up to 7.5 mg. The latter dose provides a useful hypnotic effect with minimal residual effects the next day, whilst 5.0 mg is appropriate for those involved in skilled tasks where even the most minor changes in performance during the early part of the next day must be avoided.
Adult↗
A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers.
A double-blind study was designed to establish the residual effects of zopiclone on performance in healthy volunteers. 10 healthy male volunteers aged 22-45 years (mean age 27.4 years) were included in this study. 6 of the volunteers were cigar/cigarette smokers and were asked to smoke as little as possible on the study days. The subjects were randomly allocated to a balanced design in which each subject received single oral doses of placebo, 2.5-, 5-, 7.5- and 10-mg tablets of zopiclone under double-blind conditions. A battery of tests were performed 10 and 13 h after overnight ingestion of the drug. The tests comprised: EEG, auditory reaction time, tapping rate, digit symbol substitution test, symbol copying test, mood rating scales, side effects rating scales, and subjective assessments of sleep and performance. Zopiclone is shown to have useful hypnotic properties but residual effects are detectable using EEG and psychological tests both 10 and 13 h after ingestion. The 10-mg dose significantly impairs performance the next day; the 5-mg dose is almost devoid of residual psychomotor effects but is only marginally effective in hastening onset of sleep and does not improve sleep quality. The 7.5-mg dose has definite effects on sleep and limited residual effects the next day. No significant side effects were reported. In this study, using single doses in healthy subjects, the best balance between wanted hypnotic effects and unwanted residual effects the next day was provided by the 7.5-mg dose of zopiclone. It is recommended that further studies with repeated doses in healthy volunteer subjects and in insomniac patients use the 7.5-mg dose as the reference point.
Adult↗
Prediction of clinical efficacy of zopiclone by utilizing two psychophysiological tools in healthy volunteers.
The clinical effects of zopiclone were predicted by using two psychophysiological tests: the averaged photopalpebral reflex and the frontal midline theta activity. Zopiclone at 5 and 10 mg showed a rapid, dose-dependent, moderately lasting prolongation of the latencies of the averaged photopalpebral reflex related to the lowering of the arousal level. Diazepam 5 mg increased markedly the frontal midline theta activity, the appearance of which seems to be related to the relief from anxiety, while zopiclone 10 mg only slightly modified the frontal midline theta activity. The results suggest that zopiclone possesses a potent hypnotic effect, whereas its anxiolytic potential in humans is probably low.
Adolescent↗
Effects of hypnotics on memory.
The influence on memory of 7.5 mg zopiclone, given in single and repeated doses was compared with that of 2 mg flunitrazepam, 5 mg nitrazepam and placebo. Compared with placebo, all three drugs induced some impairment of memory especially after the first day of administration. Effects were more pronounced for the two benzodiazepines and more marked for flunitrazepam. There was one report of an anterograde amnestic episode after flunitrazepam.
Adult↗
Drug-alcohol interactions on psychomotor skills: zopiclone and flunitrazepam.
Interaction between alcohol and zopiclone or flunitrazepam as well as the residual effects of both these hypnotics were studied in 20 normal male volunteers who received each 3 of 6 different drug and drink combinations according to a balanced incomplete block design as follows: placebo, zopiclone (7.5 mg), or flunitrazepam (2 mg) was administered double-blind in identical capsules at 23.00 h, and 0.5 g/kg body weight of alcohol or placebo alcohol was given at 08.30 h the following morning. Psychomotor skills of the volunteers were measured before drinking and 30 min, 1.5 h and 2.5 h after it. As compared with placebo, zopiclone had no residual effects, while flunitrazepam had some effects on standing steadiness, tracking, and flicker recognition. Alcohol alone had a non-significant effect on skills, and the combination zopiclone plus alcohol behaved as alcohol alone. Flunitrazepam plus alcohol impaired significantly standing steadiness, tracking, and reactive skills when compared with all other treatments. Time anticipation and hand and foot proprioception were not affected by any treatment. The results suggest that flunitrazepam, unlike zopiclone, has residual effects and interacts with alcohol in the morning following overnight ingestion of the drug.
Adult↗
Polygraphical sleep recordings in insomniac patients under zopiclone or nitrazepam.
Zopiclone, a new hypnotic with an original chemical structure, was compared in a sleep laboratory study with nitrazepam according to a double-blind, parallel group randomized design. Zopiclone (7.5 mg) and nitrazepam (5 mg) were each given for 14 nights to 5 insomniacs; a placebo washout period of 4 nights and a placebo withdrawal period of 10 nights were included in the design. Both drugs were found to be immediately and lastingly effective. Some slight insomnia rebound was found with nitrazepam, but not with zopiclone. Stage 2 was decreased, slow wave sleep (SWS) increased, and rapid eye movement unchanged by both drugs: however, only nitrazepam increased rapid eye movement latency. The differences between the effects of the drugs were quite limited. However, 3 out of 50 comparisons favoured zopiclone and none nitrazepam.
Adult↗
Effects of zopiclone as compared to flurazepam on sleep in women over 40 years of age.
Zopiclone is a new nonbenzodiazepine hypnotic, the recommended dose of which is 7.5 mg. It was compared to flurazepam 30 mg in a sleep laboratory study. 12 women aged 40-60 years, with subjective sleep disorders for at least 2 months, were treated for 13 nights with each drug in a crossover double-blind design. Each active drug period was preceded by 5 days of placebo washout and followed by 35 days of withdrawal (no treatment). A baseline period of 4 nights (without treatment) was obtained before the study itself. The subjects slept in the sleep laboratory during the baseline period, during the last 3 nights on placebo, during the last 3 nights on active drug, and from the 11th to the 13th night after active drug discontinuation. Polygraphic recordings were obtained during each of these nights. The criteria of Kales and Rechtschaffen were used to score the tracings. Both drugs were shown to be effective when compared to placebo. Comparisons between the two periods with active treatment did not show significant differences for sleep onset latency, total sleep time, sleep efficiency index, stage 0, percent REM, number of REM periods, and REM latency. There was a trend towards an increase with zopiclone of the number of awakenings, percent of stage 3, percent of deep sleep, and an increase with flurazepam of the percent of light sleep. A significant difference was only found for percent of stage 2 (increased with flurazepam).
Azabicyclo Compounds↗
Effects of zopiclone on the sleep of chronic insomniacs.
The purpose of this study was to evaluate the short- and intermediate-term (21 days) effectiveness, as well as the carryover and withdrawal effects of 7.5 mg of zopiclone, a new short-acting hypnotic agent. 6 patients with chronic insomnia, ranging in age from 33 to 57, participated in the study. Both EEG sleep recordings and subjective rating scales were used to evaluate the drug. Zopiclone increased the total sleep time throughout its 3-week administration period although only during the short-term period was this increase statistically above baseline. There was no carryover effect nor rebound insomnia upon drug withdrawal. The drug significantly increased the duration of stage 2 sleep, decreased stages 3 and 4 sleep, and had no effect on the duration of REM sleep. There were no reported side effects.
Adult↗
A comparative study of zopiclone and flunitrazepam in insomniacs seen by general practitioners.
A double-blind crossover trial was conducted in 42 outpatients of either sex in order to obtain information on the properties of 7.5 mg of zopiclone in a general practice setting compared with 2 mg of flunitrazepam. Each patient went through two periods of treatment, each period lasting 10 days. A comparison of the effect of the drugs showed a significant difference with regard to effectiveness and sleep latency favoring flunitrazepam. When patient's preferences were analyzed there was a highly significant difference favoring flunitrazepam both for effectiveness and tolerance. The side effects from both drugs were generally mild.
Adolescent↗
Zopiclone to geriatric patients. A parallel double-blind dose-response clinical trial of zopiclone as a hypnotic to geriatric patients - a study in a geriatric hospital.
Zopiclone was given for 14 nights to 68 geriatric patients (mean age 81 years) with sleep problems. The patients were randomly allocated to four treatment groups: 3.75 mg, 5.0, 7.5, or 10.0 mg of zopiclone. Sleep quantity and quality, side effects, and influence on psychomotor performance (digit symbol substitution and letter cancellation test) were studied before treatment, during active treatment, and after withdrawal of the drug. All patients slept better on zopiclone compared to placebo. There were only slight differences between the different dose levels as regards quantity and quality. No influence on psychomotor performance could be shown. The side effects were mild. Zopiclone showed a good hypnotic efficacy, and 7.5 mg is probably the best dose for elderly patients.
Aged↗
Efficacy and tolerance of zopiclone in insomniac geriatric patients.
Zopiclone is a cyclopyrrolone derivative which exerts, in animal and man, an hypnotic activity comparable to that of flurazepam. In healthy adult insomniacs it was well tolerated upon repeated administration for 28 days. In a double-blind, placebo-controlled, crossover study, three dose levels of zopiclone (5, 7.5, and 10 mg) were compared to 15 mg of flurazepam in 30 geriatric insomniacs. The 7.5- and 10-mg doses demonstrated hypnotic potency comparable to that of flurazepam, and the active treatments were superior to placebo. For most sleep indices, 7.5 mg was the optimal therapeutic dose. Few side effects were reported. These were not clinically significant. Zopiclone is efficacious and well tolerated in the treatment of geriatric patients suffering from insomnia. A dosage range of 7.5-10 mg is recommended.
Aged↗
Comparative study of zopiclone and pentobarbitone as hypnotics.
The safety and efficacy of zopiclone (7.5 mg) and pentobarbitone (100 mg) were compared in 60 adult outpatients suffering from insomnia. The patients were randomly assigned to one of the two treatment groups, and the medication was taken at bedtime for 16 days. Zopiclone and pentobarbitone, compared with placebo, improved sleep onset, duration of sleep, number of night time awakenings, and quality of sleep. Zopiclone was superior to pentobarbitone with regard to sleep quality, judgement of therapy, and condition in the morning. Side effects were reported in each treatment group, but were less frequent in the zopiclone group (p less than 0.005). Zopiclone is a useful drug for the treatment of sleep disturbances, not only because of its efficacy, but also because of its tolerability.
Adult↗
Effectiveness of zopiclone as a preoperative hypnotic.
A controlled, double-blind study was made of the efficacy and safety of a new hypnotic, zopiclone, on the preoperative night's sleep by a Joint Study Unit Group of the anesthesiology departments in 6 national hospitals. The following results were found: (1) zopiclone 7.5 and 10 mg and nitrazepam 10 mg were significantly superior to placebo both on the quality of sleep and the mental state of the patient, while no significant differences were observed among these three active drugs; (2) a significantly higher incidence of side-effects was observed for nitrazepam 10 mg than for zopiclone 7.5 and 10 mg and placebo; (3) zopiclone 7.5 and 10 mg and also nitrazepam 10 mg were significantly more useful than placebo, and (4) the above results show that 7.5 and 10 mg of zopiclone are of great benefit to the preoperative night's sleep and have less side-effects than 10 mg of nitrazepam.
Adult↗
Dose-finding and premedication studies with zopiclone.
The new non-benzodiazepine hypnotic, zopiclone, was investigated as a preanaesthetic medication in a randomized, double-blind, placebo-controlled study in healthy patients scheduled for minor gynaecological surgery. Initially a dose-finding study was conducted in which zopiclone 3.75 mg, 7.5, and 11.25 mg was compared with diazepam 10 mg and placebo; 7.5 mg was established as the optimum dose of zopiclone. In the main study zopiclone 7.5 mg was comparable to diazepam 10 mg at 20, 40, and 60 min after administration and more efficacious at 90 min.
Adult↗
Dependence potential of zopiclone studied in monkeys.
In gross behavioral observation the minimum effective dose of zopiclone was intravenously 0.06-0.25 mg/kg and intragastrically 1-4 mg/kg in rhesus monkeys. Zopiclone suppressed barbital withdrawal signs of rhesus monkeys at a single dose of 16 mg/kg or more. The suppressing effect of zopiclone 32 mg/kg i.g. was comparable to diazepam 8 mg/kg. Crab-eating monkeys treated with zopiclone at doses up to 32 mg/kg twice daily for up to 8 weeks manifested intermediate-grade signs upon withdrawal (i.e., less severe than after treatment with diazepam and similar to nitrazepam). Zopiclone was self-administered by rhesus monkeys relatively frequently by the intravenous route; the infrequent intragastric rate was similar to or slightly higher than with diazepam.
Administration, Oral↗