Performance and mood following partial sleep deprivation: A randomized,double-blind crossover study of zopiclone,triazolam, flunitrazepam,ethanol and placebo

The effects of zopiclone 7.5 and 15 mg, triazolam 0.25 and 0.5 mg, flunitrazepam 1 and 2 mg, ethanol and placebo on performance, mood and sleep onset latency after partial sleep deprivation, were compared in a randomized, double-blind, crossover, single-dose study. Sixteen healthy volunteers of both sexes, aged 21–31 years, were included in the study. The overall assessment of the total psychological measurement indicated that zopiclone 7.5 mg, triazolam 0.25 mg and ethanol (C_max = 0.40 parts per thousand) did not affect the daytime performance of an unacceptable degree even when given late at light. The findings for flunitrazepam 1 mg were not so uniform, but also seemed acceptable. Zopiclone 15 mg, triazolam 0.5 mg and flunitrazepam 2 mg were rated as not acceptable alternatives. No significant differences were shown concerning mood. The overall assessment for sleep onset latency and subjective alertness indicated that zopiclone 7.5 mg and triazolam 0.25 mg had a more appropriate profile than the other drugs and doses tested.     

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.     

Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.     

Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic

Zopiclone is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex. Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5 mg) improved sleep in chronic insomniacs similarly to nitrazepam 5 mg, flurazepam 15 to 30 mg, triazolam 0.5 mg and temazepam 20 mg, but in a single study was slightly less effective than flunitrazepam 2 mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of 'bitter taste' does not deter patients from continuing therapy. Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.     

Comparison of the short-acting benzodiazepines midazolam and triazolam with placebo

The hypnotic effect of midazolam (Dormicum, 15 mg) and triazolam (0.5 mg) were compared with each other and with a placebo. Their effects on the quality of dreams and of morning awaking were also evaluated. 30 out-patients were included in a double-blind cross-over study for a period of 11 consecutive nights in which the order of the drugs was randomized according to the Latin squares method. The active substances and the placebo were each administered in 3-night blocks separated from each other by an intercalary placebo night. On waking each morning the patients answered a questionnaire concerning the previous night. Some of the responses were recorded on a visual analogue scale. Midazolam and triazolam significantly decreased the latency of onset of sleep and the number of nocturnal and premature morning awakenings. The patients' overall impression of their night was better under the active drugs than under placebo. However, there were no differences between placebo and the benzodiazepines as far as side effects or the quality of dreams and of morning awakening were concerned. The two drugs had an identical effect on sleep latency, but under midazolam the patients woke more frequently during the night and slightly earlier in the morning, suggesting that the duration of action is shorter. The intercalary placebo nights were better after 3 nights of placebo than after 3 nights of benzodiazepine. This rebound effect was more marked after triazolam than after midazolam. In conclusion the two benzodiazepines were both effective and well tolerated but midazolam is slightly shorter acting and has slightly less rebound effect than triazolam.     

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.     

Double-blind,placebo-controlled comparison of zolpidem,triazolam, and temazepam in elderly patients with insomnia

Sleep disturbances and need for hypnotics are disproportionately greater in the elderly compared to younger adults. The present study provides a placebo-controlled subjective hypnotic efficacy of zolpidem, triazolam, and temazepam in elderly insomniacs. After a single-blind placebo screening week (DSM-III-R criteria), 335 elderly insomniacs (ages 60 to 85) were randomized to 28 days of double-blind treatment with zolpidem 5 mg, triazolam 0.125 mg, temazepam 15 mg, or placebo, followed by a 4-day single-blind, placebo withdrawal period. The primary efficacy parameters were self-reported sleep latency (SSL) and self-reported total sleep duration (SSD); they were measured by responses on daily Morning Questionnaires. SSL values were compared by Cox proportional hazards regression technique. SSD values were compared by ANOVA. Compared to placebo, zolpidem and temazepam produced significantly shorter SSL over the 4 treatment weeks, but triazolam did not. In the zolpidem group, SSL was significantly shorter than in the placebo group at all four treatment weeks; in the temazepam group, SSL was significantly shorter than in the placebo group at weeks 1, 3, and 4. SSD was increased above baseline levels in all groups. No tolerance to the subjective effects or rebound above baseline levels occurred in any of the treatment groups. Overall, the drugs were well tolerated. No difference was found among the placebo and treatment groups in overall adverse event incidence rates. However, compared with zolpidem and placebo, temazepam produced significantly higher incidences of drowsiness and fatigue, and triazolam produced a significantly higher incidence of nervousness than zolpidem. Drug Dev. Res. 40:230–238, 1997. © 1997 Wiley-Liss, Inc.     

A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs

The effects of oral, bedtime triazolam 0.5 mg and flurazepam 30 mg, on the laboratory sleep of 12 insomniacs were compared in a double blind, crossover study. A 22 consecutive night schedule was used: Nts. 1–2 placebo; 3–6 first drug; 7–8 placebo; 9–14 no drugs; 15–16 placebo; 17–20 second drug; 21–22 placebo. In 6 Ss first drug was triazolam and second drug was flurazepam. In the other 6 Ss the drug order was reversed. Effects on sleep were assessed objectively by conventional EEG/EOG/EMG sleep recordings and subjectively by questionnaires administered each morning. Side or toxic effects were assessed by physical exams, clinical lab tests, and twice daily questionnaires. During their administration the two drugs were practically indistinguishable in their effects. Both significantly reduced objective and subjective measures of insomnia, such as total wake time and sleep latency. On discontinuation the drugs differentially affected sleep, e.g., on the first post flurazepam night total sleep time was significantly more than baseline whereas on first post triazolam night, total sleep time was significantly less than baseline. There were no remarkable side or toxic effects with either drug.     

Caffeine Moderately Antagonizes the Effects of Triazolam and Zopiclone on the Psychomotor Performance of Healthy Subjectsf

Abstract: 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.     

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.     

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

Summary 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.     

A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia

Zopiclone, a cyclopyrrolone with hypnotic properties was compared with temazepam and placebo in the treatment of insomnia. After a week's washout period, suitable subjects were allocated at random to zopiclone 7.5 mg or temazepam 20 mg or placebo for 2 weeks. Measurements of psychomotor function using the Leed's psychomotor tester and letter cancellation were carried out on day 0, 7 and 14. Sleep latency, duration of sleep and number of times waking during the night were recorded on a sleep diary filled by the subjects nightly. Forty-four subjects completed the trial, 15 taking zopiclone, 16 taking temazepam and 10 taking placebo. Both zopiclone and temazepam had significant hypnotic properties when compared to placebo. Zopiclone increased total sleep time in both weeks of the trial while temazepam increased sleep time in the first week only. There was no significant deterioration in psychomotor performance at the end of both weeks for zopiclone. Critical flicker fusion was significantly increased in subjects on temazepam. There were no abnormalities for both zopiclone and temazepam subjects in the blood picture, renal profile, liver function, urine and ECG before and after the study. Zopiclone is an effective hypnotic comparable to temazepam.     

Treatment regimen and hypnotic self-administration

RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study determined whether prior experience with different treatment regimens (i.e., instructions and capsule availability) would alter the previously observed high hypnotic self-administration rates. METHODS: Sixty-four healthy men and women with (n = 32) and without (n = 32) insomnia, 21-55 years, self administered placebo or triazolam (0.25 mg) after different prior treatment regimens. They received one of three different treatment regimens enforced for 11 nights: a capsule each night, a capsule as needed, or a capsule every third night. On 14 subsequent nights they choose to self-administer a capsule or not, placebo during 1 week and triazolam (0.25 mg) the other (counterbalanced in order). RESULTS: Insomniacs self-administered more capsules than normals and triazolam was self-administered more than placebo. For both groups, treatment regimen had a minimal effect on capsule self-administration. During the treatment phase, triazolam improved self-ratings of sleep relative to placebo. During the choice phase, nightly variations in self-rated sleep predicted self-administration of a capsule on the following night, regardless of whether the capsule was active drug or placebo. CONCLUSIONS: The data of this study are consistent with the view that hypnotic self-administration by insomniacs is therapy-seeking behavior and not drug abuse.     

Halazepam and diazepam in neurotic anxiety: A double-blind study

Halazepam (160 mg/day) was compared to diazepam (20 mg/day) and to a placebo in a double-blind study with anxious neurotic outpatients from general family practice and a symptomatic volunteer clinic. One hundred twenty-five patients completed at least 4 weeks of treatment. Halazepam produced the most amount of side effects followed by diazepam, while placebo produced the least amount of side effects. Sedation was the most frequently reported side effect.No significant drug x population interaction effects were found and only very few population effects occurred indicating SVC patients to improve more than GP patients. Treatment differences indicate diazepam to be slightly more effective than halazepam, and both drugs to be superior to placebo according to several outcome criteria. At the 6-week period, diazepam, in fact, was significantly more effective than halazepam according to physician and patient questionnaire ratings. Global ratings of improvement, however, indicated both drugs to be equally effective and to produce significantly more improvement than placebo.Initial levels of anxiety and depression were found to have a differential effect on treatment outcome. Anxious patients with little secondary depression improved more than patients with more marked secondary depression regardless of treatment agent prescribed. High anxious halazepam-treated patients were found to improve significantly more than low anxious halazepam-treated patients, while initial level of anxiety showed little effect on the diazepam response. It would thus seem that in the present study diazepam (20 mg/day) was slightly more efficacious in reducing anxious symptomatology than halazepam (160 mg/day) and particularly in the only mildly anxious patient. Perhaps a daily dosage of 120 mg/day of halazepam might have been more appropriate for most anxious patients.     

Relative abuse liability of GHB in humans: A comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB.

Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.     

Effect of oestrogen on the sleep, mood, and anxiety of menopausal women.

A double-blind controlled study of the effect of piperazine oestrone sulphate on sleep, depression, anxiety, and hot flushes was performed in 34 perimenopausal women. Half of the patients were given six weeks' placebo followed by eight weeks' oestrogen, and half remained on placebo throughout. Sleep was recorded electrophysiologically every week, and mood and anxiety were rated daily by means of visual analogue scales. Hot flushes were counted daily. Observer rating scales of anxiety and depression were complete at intervals. During the first month of active treatment the amount of intervening wakefulness in the first six hours of sleep decreased significantly more in the oestrone group than in those on placebo. Between the baseline period and the second treatment month the oestrone group showed a significantly greater decrease in the total amount of intervening wakefulness and in the frequency of awakenings. Their total amount of rapid eye movement sleep increased. Mood and anxiety improved and the number of hot flushes decreased to a similar degree in both groups. Although oestrogen did reduce the number of episodes of wakefulness in perimenopausal women complaining of insomnia, its effects on their psychological symptoms were little different to those of placebo.     

Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic leg movements in sleep.

Fifteen subjects (9 men and 6 women) exhibiting objective evidence of excessive daytime somnolence and periodic leg movements in sleep underwent 4-7 days of treatment with triazolam (0.25 or 0.50 mg) and placebo in a double-blind crossover design. One night of polysomnography followed by daytime multiple sleep latency testing were conducted on the first and last days of each treatment block. By the last day of treatment, the mean multiple sleep latency test score after triazolam (9.0 minutes) was significantly greater than that after placebo (5.7 minutes). Thus, triazolam treatment led to a decrease in daytime somnolence. Triazolam also improved sleep architecture and continuity; it increased total sleep time, decreased the number of awakenings and arousals, and decreased stage 1 and increased stage 2 percentages. Although the frequency of periodic electromyographic bursts remained unchanged, the frequency of associated arousals decreased after treatment. Short-term treatment with triazolam is thus effective in diminishing daytime sleepiness and in improving sleep architecture, continuity and duration in patients with periodic leg movements in sleep. These effects do not seem to be mediated through a decrease in periodic leg movement activity.     

Long-term comparison of alprazolam, lorazepam and placebo in patients with an anxiety disorder

In a double-blind, placebo-controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam. Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam. The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg. Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale, with a trend toward more improvement in the alprazolam group in the later weeks of the study. Target Symptoms, Physician's and Patient's Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo. The major side effects were sedation and drowsiness; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo. An overall rating of side effect severity was not significantly different among the three groups.     

Difference in action between oral triazolam and zopiclone

Summary The effects of oral triazolam 0.25 mg and zopiclone 7.5 mg in 7 supine volunteers were compared by means of quantitative measurements of the EEG, saccadic eye movements, visual analogue scale (VAS) for alertness, critical flicker fusion frequency (CFF) and the Maddox wing.Zopiclone reached its maximum effect earlier (62 min) than triazolam (91 min; CFF). On linear regression analysis the average rate constant (regression coefficient) of onset of action of zopiclone was significantly greater than that of triazolam (0.29 vs. 0.17).Triazolam and zopiclone had similar effects, but zopiclone seemed to have a faster onset of action, probably indicating swifter absorption in supine subjects.Quantitative EEG evaluation gave parallel results to the other parameters used, but triazolam and zopiclone showed a dissimilar mechanism of action, as characterized by changes in the alpha frequency.