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.     

Comparative efficacy of zolpidem and temazepam in transient insomnia

This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and placebo in healthy adults. Two factors expected to promote insomnia, the 'first night effect' and a 2-hour phase advance, were combined in a single night laboratory-based double-blinded protocol. This was a multi-center study, with data collected in 13 sleep laboratories. Subjects with normal sleep histories and without prior sleep laboratory experience were randomly assigned to treatment groups. Medications were administered 15 min before lights out, with polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were administered at study entry and after arising. 630 subjects completed the study and provided data analyzed using repeated measures ANOVAs. Neither agent significantly reduced objective sleep latency relative to placebo. Zolpidem reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both agents improved sleep efficiency and most subjective sleep measures relative to placebo, with zolpidem superior for five of six subjective outcome measures compared to temazepam. SCT, morning sleepiness and morning concentration were not altered by any treatment. Zolpidem significantly reduced morning DSST performance; temazepam did not. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.     

Temazepam's efficacy in patients with sleep onset insomnia.

The hypnotic efficacy of temazepam capsules (30 mg) was studied in twelve patients who had objective polysomnographic evidence of sleep onset insomnia. Patients slept in the laboratory, retiring at their usual bedtime after taking placebo or temazepam 30 min earlier, and were monitored for 8 h using standard polysomnographic techniques. Acute (nights 5-7) and chronic (nights 11-13) temazepam improved the sleep of these patients by reducing sleep latency and increasing sleep time compared to the placebo baseline (nights 2-4). No detrimental effects on daytime function the following morning were observed using questionnaires and objective tests of performance. No consistent evidence of disturbed sleep after discontinuation of treatment was obtained over three recovery nights.     

The effects of midazolam and temazepam on sleep and performance when administered in the middle of the night

A multicenter, double-blind, sleep laboratory and performance study was conducted to evaluate the hypnotic efficacy and residual effects of midazolam (15 mg) and temazepam (30 mg) compared to placebo when administered in the middle of the night. Eighteen volunteers with objectively verified sleep maintenance insomnia received placebo for 3 nights during week 1 (adaptation and screening). During weeks 2, 3, and 4 they received 2 consecutive nights of midazolam, temazepam, and placebo (one treatment per week) in a balanced crossover design. Treatment was administered in the middle of the night (3.5 hours after bedtime). Neither drug reduced the latency to return to sleep after the middle of the night awakening. Both drugs significantly increased total sleep time, reduced wake during sleep, and number of awakenings over 4.5 hours in bed after treatment. In the morning (5 to 6.5 hours postdrug) significant performance decrements and reduced daytime sleep latency (7 hours postdrug) were found with temazepam but not midazolam.     

Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam

Experimental sleep disturbances (model insomnia) were produced by the administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg. The effect of temazepam (TEM), 15 mg or 30 mg, on the model was investigated. All-night polysomnography was performed on 8 normal young male subjects under each of the following 9 conditions: baseline, MPD 10 mg, CAF 150 mg, TEM 15 mg, TEM 30 mg, MPD + TEM 15 mg, MPD + TEM 30 mg, CAF + TEM 15 mg, CAF + TEM 30 mg. A reduction in total sleep time and total amount of stage REM (S-REM) sleep and an increase in the sleep latency and wake time (S-W) were observed in both the MPD and CAF nights. The sleep latency was significantly longer in the CAF night than in the MPD night. Administration of TEM 15 mg or TEM 30 mg alone caused very few modifications in the sleep parameters. These drugs in combination with MPD or CAF resulted in almost complete recovery of the sleep disturbance induced by MPD or CAF. The results indicate that CAF and MPD produced similar models of insomnia except for a greater sleep latency for CAF than for MPD. Both models were useful in the evaluation of hypnotic drugs such as temazepam.     

Acute effects of hydroxyzine on nocturnal sleep and sleep tendency the following day: A C-EEG study

The acute hypnotic effects of hydroxyzine 25 mg and 50 mg nocte, were examined in six male and six female volunteers. Continuous electrophysiological measures (C-EEG) were taken to assess both nocturnal sleep and sleep tendency the following day. Both doses produced significant reductions in sleep onset latency and decreases in waking during sleep; reciprocal increases in sleep duration were also seen. Female subjects demonstrated a greater hypnotic response, including a dose-dependent decrease in sleep onset latency. Increases in sleep duration following both doses were significant for the female group alone. C-EEG measures of increased drowsiness the following day failed to achieve significance; although the largest effects on daytime sleepiness, including dose-dependent increases, were again seen with the female subject group and corresponded with subjective ratings. These results demonstrate the hypnotic efficacy of hydroxyzine whilst failing to detect significant C-EEG hangover effects. However, variability in response to antihistamines, registered here as differences between the sexes, requires further consideration.     

Dose effects of temazepam tablets on sleep

The dose effects of temazepam tablets (15 and 30 mg) were studied at two sleep centres in 48 volunteers who had objective polysomnographic evidence of sleep onset insomnia. Volunteers slept in the laboratory, retiring at their usual bedtime after taking placebo or temazepam 30 min earlier, and were monitored for 8 h using standard polysomnographic techniques. Acute (nights 5-7) and short term (nights 11-13) temazepam, both 15 and 30 mg, improved the sleep of these volunteers by reducing sleep latency and increasing sleep time compared to the placebo baseline (nights 2-4). Dose differences were found primarily on the measurement of sleep staging, with 30 mg having a greater or more consistent effect than 15 mg. No residual effects were observed on the basis of questionnaires and objective tests of performance and no consistent evidence of disturbed sleep after discontinuing treatment was seen.     

Evaluation of temazepam as a hypnotic

Temazepam is a 1,4-benzodiazepine, newly marketed in the United States for the symptomatic treatment of the complaint of insomnia. The manufacturer recommends a dose of 30 mg before bedtime for most adults and 15 mg for geriatric or debilitated patients. A dose of 30 mg usually produces peak plasma concentrations within 3 hours after oral ingestion and has a mean half-life of 10 to 15 hours. Thus, temazepam is absorbed more slowly and metabolized more quickly than flurazepam, the only other benzodiazepine marketed in the United States specifically for insomnia. Eight sleep laboratory and 21 clinical studies on temazepam indicate that temazepam reduces awakening during the night and increases sleep duration. However, there was no consistent evidence that temazepam reduces sleep latency--probably because temazepam, taken at bedtime, does not reach sufficiently high blood levels in time to affect sleep onset. One sleep laboratory study on 8 insomniac patients given 35 consecutive nightly doses of 30 mg found no evidence of tolerance or rebound insomnia. Studies on tolerance, metabolism and carry-over effects have shown that temazepam has no long-acting metabolites and does not affect waking function following use at bedtime. In patients for whom hypnotic medication is appropriate, temazepam should be an effective drug for reducing most symptoms of insomnia.     

Zolpidem is not superior to temazepam with respect to rebound insomnia: a controlled study.

This randomised controlled trial was conducted to compare zolpidem to an equivalent dose of temazepam with respect to subjective rebound insomnia after cessation of 4 weeks of treatment in chronic insomnia (zolpidem 10 mg, n=79; temazepam 20 mg, n=84). Both agents improved total sleep time (TST) as well as sleep onset latency (SOL) significantly during the 4 treatment weeks. Prevalence rates for rebound insomnia, defined as a worsening of TST or SOL of more than 40% compared to baseline, were 27% for TST and 53% for SOL in the Zolpidem condition and 26% and 58%, respectively, in the temazepam condition. No significant differences were found between both agents with respect to rebound insomnia, nor with respect to their efficacy or safety. We conclude that in clinical practice zolpidem has no advantages over temazepam with respect to rebound insomnia.     

Dose effects of temazepam in transient insomnia

A transient insomnia model, the "first night" effect in the sleep laboratory, was used to assess the dose range for the hypnotic and sleep stage effects of temazepam. 201 healthy, normal subjects (97 men and 104 women), 21 to 49 years old, with no sleep complaints were studied. Each was randomly assigned to receive either placebo, 7.5, 15, or 30 mg temazepam hard gelatin capsules (Restoril) administered double-blind 30 min before bedtime on their first night in the sleep laboratory. Over the 8-h polysomnogram total sleep time and sleep efficiency increased significantly in a linear fashion with increasing doses of temazepam. Sleep tendency was significantly reduced by increasing doses again in a linear manner. Wake time during the sleep period was reduced significantly only by the higher dose. The percentage of stage 1 sleep was reduced and the percentage of stage 2 sleep was increased, each linearly with increasing doses. These data are the first to demonstrate the hypnotic effects of a 7.5 mg dose of temazepam and also support previous studies of 15 and 30 mg temazepam administered to chronic insomniacs. They also illustrate the utility of the "first night" effect as a model of transient insomnia.     

The effects of a single night's dosing with triazolam on sleep the following night

This study was undertaken to determine whether a single night's use of triazolam by normal healthy sleepers leads to withdrawal insomnia on the subsequent night, and whether there is a dose response relationship to this phenomenon. Thirty normal sleepers of both sexes were randomly assigned to three parallel treatment groups. All subjects were studied for five consecutive nights by means of pre- and post-sleep questionnaires and all night polysomnography. Multiple sleep latency tests were conducted on the days following the second, third, and fourth nights in the laboratory. All subjects received placebo capsules on the first, second, fourth, and fifth nights in the laboratory and either placebo, 0.25 mg triazolam or 0.5 mg triazolam according to their assigned group on the third night. Both doses of the drug increased subjective estimates of sleep duration, but no objective increase was found. Neither dose altered daytime measures of sleepiness. No changes were found in any of the sleep parameters on withdrawal of the 0.25 mg dose of triazolam. However, discontinuation of the 0.5 mg dose did lead to significant objective and subjective withdrawal effects. It was concluded that higher doses of triazolam could lead to withdrawal effects in normal sleepers even when this drug was used for only a single night.     

Effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance and sleep architecture in a model of transient insomnia

OBJECTIVE: To compare the effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance during the last third of the night (last 160 min) and on sleep architecture throughout the night. RESEARCH DESIGN AND METHODS: This was a retrospective analysis of a previously reported double-blind, randomized, uncontrolled, parallel-group, multicenter study. Healthy subjects with previous but no current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic measures of sleep were evaluated for 1 night. The primary, prospectively-defined analysis of this study showed that 7.5-mg and 15-mg doses of temazepam had equivalent effects on latency to persistent sleep, total sleep time, and the number of sleep interruptions recorded over an 8-h period. Both doses were well tolerated. The post hoc analysis reported here compared these 2 doses for their effects on sleep maintenance and architecture. Sleep efficiency during the last third of the night was designated as the primary endpoint. The methodology for this analysis was fully defined and documented prior to re-analysis of the database for these parameters. RESULTS: Sixty-five subjects received temazepam 7.5 mg and 66 received temazepam 15 mg. No statistically significant differences between doses were detected for sleep efficiency or number of sleep interruptions during the last third of the night. Sleep architecture (measured over 8 h) did not differ significantly between groups. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for maintaining sleep during the last third of the night. Continuity of sleep throughout the night, as reflected by sleep architecture, was also similar regardless of dose. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should begin with the 7.5 mg dose.     

Double-blind evaluation of the safety and hypnotic efficacy of temazepam in insomniac outpatients.

1 Efficacy of temazepam 30 mg at night as an hypnotic was compared with placebo in 55 out-patients with insomnia. The study was double blind, with two comparable groups of patients established by random allocation. Placebo and medication were taken for 4 consecutive nights and sleep questionnaires were completed the next day. 2 Patients reported that temazepam was more effective than placebo in reducing the difficulty of falling asleep and improving sleep maintenance. They also indicated that they awoke less and were less disturbed by early morning awakenings reported as a group that the average duration of sleep was increased by 1 hour. 3 The patients receiving temazepam reported being more alert in the morning and for the entire day than with placebo.     

Dose level effects of triazolam on sleep and response to a smoke detector alarm

Thirty-six young adult, male subjects with sleep-onset insomnia were equally divided into placebo, 0.25 mg, and 0.5 mg triazolam groups to examine the effects of the hypnotic, with particular attention to dose level on efficacy, sleep stages, and awakening to a smoke detector alarm. On nights 1 and 4 of a five-consecutive-night protocol, a standard home smoke detector alarm was sounded during stage 2, 5 min after sleep onset, in slow wave sleep (SWS), and at the time of the early morning awakening. The alarm registered 78 dB SPL at the pillow. EEG arousal latency and reaction time to a button press were studied. Failure to awaken to three 1-min alarm presentations was scored as no response. Both dose levels produced similar reductions in sleep latency, decreases in SWS, increases in stage 2, and increases in sleep efficiency. Both dose levels showed similar sedative effects to the smoke alarm. Fifty percent of triazolam subjects failed to awaken on night 1 during SWS, and EEG arousal and response latencies were significantly slowed. Some drug tolerance or sensitization to the alarm was seen by night 4. By morning, all subjects were easily awakened on both nights. The 0.25 mg dose is clearly an effective dose level for both sleep efficacy and sedative effects to outside noise, which in some instances could pose potantial problems.     

A sub-chronic study of the subjective quality of sleep and psychological measures of performance on the morning following night time medication with temazepam.

A sub-chronic study of 7-chloro-2,3-dihydro-3-hydroxy-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (temazepam, Euhypnos) at three dose levels was carried out in 30 healthy volunteers. A matching placebo was given before and after the 4 nights of active compound. The subjective response was measured by means of a sleep evaluation questionnaire, and the objective measurements used were the critical flicker fusion threshold and choice reaction time. A clear dose-response relationship was seen in the subjective and objective measurements with the three doses used. A rebound phenomenon was seen only at the high dose levels in two subjective measures, viz. getting to sleep and behaviour following waking.     

Pharmacodynamics of milnacipran in young and elderly volunteers

AIMS: To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. METHODS: Randomized double-blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days' dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). RESULTS: Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0. 05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. CONCLUSIONS: The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.     

Nighttime versus daytime hypnotic self-administration

RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study assessed whether insomniacs' self-administration of hypnotics extended to the daytime. METHODS: Forty-four healthy men and women, 21-55 years old, with ( n=22) and without ( n=22) insomnia volunteered. They were randomized to one of two triazolam dose groups (0.125 or 0.25 mg) and their preference for placebo versus triazolam was assessed at night (2300 hours) and day (0900 hours) over 7 consecutive days in each phase. In both night and day phases of the study, subjects received triazolam or placebo in color-coded capsules on two sampling days or nights and then were forced to choose their preferred capsule on 5 subsequent days or nights. The order of day and night study phases and the placebo and triazolam sampling days was counterbalanced. In the night phase subjects went to bed from 2330 to 0730 hours and in the day phase they were tested for level of sleepiness-alertness at 1000, 1200, 1400, and 1600 hours by the multiple sleep latency test (MSLT) and mood and performance at 1100 and 1500 hours. RESULTS: More triazolam was chosen at night than during the day. No dose differences in preferences at night versus day or between insomniacs and normals were found. Insomniacs did not differ in their triazolam preferences between night and day, while the normals chose triazolam less frequently during the day. Among insomniacs, 40% chose triazolam on >3 of the 5 days. On both screening and placebo sampling days, those with a high (>60%) daytime triazolam preference had greater average daily sleep latencies on the MSLT than those with a low (<50%) daytime triazolam preference (i.e. with a placebo preference). In the triazolam preference group, triazolam reduced daily MSLT latencies to the level of the placebo preference group. CONCLUSIONS: This study shows that the minority of insomniacs who self-administer hypnotics during the day are physiologically aroused and the drug reduces their arousal suggesting that their daytime self-administration, like their night-time self-administration, is more consistent with therapy-seeking than drug-seeking behavior, at least for the short-term.     

Temazepam 7.5 mg: effects on sleep in elderly insomniacs

Temazepam, 7.5 mg was evaluated in the sleep laboratory in 8 elderly insomniacs, using a 14-night protocol (4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights). With short-term use temazepam was found to be effective, producing a significant improvement in total wake time from baseline (100 vs. 145 min). With continued drug administration, total wake time remained below baseline but not significantly so (125 vs. 145 min). During drug administration, there were no major CNS and behavioral adverse effects reported such as daytime sedation, memory impairment or hyperexcitability (daytime anxiety). Following drug withdrawal, there was no significant increase in wakefulness, i.e., no rebound insomnia (150 vs. 145 min).In summary, temazepam, 7.5 mg is effective in elderly subjects with short-term use and has a minimum of adverse effects. Use of hypnotic drugs is an adjunctive therapy which should be for a short-term period with subsequent short-term intermittent use as needed. Because of its low propensity for producing rebound insomnia, temazepam can be effectively used in this manner.     

A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality

Rationale: The effects of caffeine, especially caffeinated coffee, on human performance have been extensively studied. However, few studies have been naturalistic representations of how tea/coffee is normally consumed in terms of dose and time of consumption. Objectives: This study investigated the effects of day-long consumption of tea, coffee and water on cognitive and psychomotor performance, and sleep quality at night. Methods: Thirty healthy volunteers received equal volume drinks equivalent to either 1 or 2 cups of tea (containing 37.5 mg or 75 mg caffeine), or coffee (75 mg or 150 mg caffeine), or water, in a randomised five-way crossover design. Drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours). A psychometric battery consisting of critical flicker fusion (CFF), choice reaction time (CRT) and subjective sedation (LARS) tests, was administered pre-dose and at frequent time points post-dose. The Leeds Sleep Evaluation Questionnaire (LSEQ) was completed each morning and a wrist actigraph was worn for the duration of the study. Results: Caffeinated beverages maintained CFF threshold over the whole day (P<0.05), independent of caffeine dose or beverage type. During the acute phase of beverage ingestion, caffeine significantly sustained performance compared to water after the first beverage for CFF and subjective sedation (P<0.05), and after the second beverage for the Recognition component of the CRT task (P<0.05). Additionally, there were significant differences between tea and coffee at 75 mg caffeine after the first drink. Compared to coffee, tea produced a significant increase in CFF threshold between 30 and 90 min post-consumption (P<0.01). However, following the second beverage caffeinated coffee at 75 mg significantly improved reaction time (P<0.05), compared to tea at the same dose, for the Recognition component of the CRT task. Caffeinated beverages had a dose dependent negative effect on sleep onset (P<0.001), sleep time (P<0.001) and sleep quality (P<0.001). Conclusions: These results indicate that ingestion of caffeinated beverages may maintain aspects of cognitive and psychomotor performance throughout the day and evening when caffeinated beverages are administered repeatedly. This study also demonstrates that day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep. Other differences between tea and coffee were more subtle, and require further investigation. Received: 16 February 1999 / Final version: 20 December 1999     

A comparison of chlormezanone and temazepam in sleep disturbance

Fifty-five patients complaining of insomnia entered a single-blind general practice study and were treated with either 400 mg chlormezanone or 20 mg temazepam at night for 2 weeks. There was a significant increase from baseline for both treatments in average duration of sleep, quality of sleep and frequency of waking refreshed. There was no significant difference between the treatments, with overall effectiveness rated similarly. It is concluded that chlormezanone is at least as useful as temazepam in treating insomnia.