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.     

New hypnotic agents: clinical studies in general practice

The type of sleep problem should be determined so that the most appropriate hypnotic can be used, and in this respect duration of action is an important property. The benzodiazepine hypnotics are adequate for this purpose, but problems may arise due to daytime after-effects and the possibility of dependence developing. Non-benzodiazepine hypnotics may be useful alternatives and our group has undertaken double-blind comparative trials with two such compounds, namely zopiclone and zolpidem. Zopiclone was compared to temazepam in a cross-over trial on 36 patients and similar hypnotic effects were recorded. In a parallel group study, zolpidem 10 mg was compared to zolpidem 20 mg and placebo in 88 patients. Both doses of zolpidem were significantly better than placebo on a number of the parameters recorded, side-effects were negligible and there was no evidence of any rebound insomnia during the final control week.     

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: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

Effect of zolpidem on sleep in insomniac patients

Summary The effect of zolpidem 10 mg p.o. on sleep in patients with persistent psychophysiological insomnia was assessed by polysomnographic recordings.An improvement in sleep with no rebound insomnia was observed during treatment for two weeks. Time awake after the onset of sleep was reduced after one week and increased after two weeks, whereas sleep latency remained reduced.Zolpidem markedly increased the duration of Stage 2 sleep without affecting either slow wave sleep or REM sleep. Subjective evaluation of improvement in sleep was well correlated with sleep laboratory findings. Zolpidem did not impair the immediate memory or psychomotor performance of patients on the morning after its administration. Side-effects during the period of drug administration included drowsiness, fatigue, headache, anxiety and irritability. They were mild or moderate and wore off soon after awakening.     

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.     

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.     

Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia

Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.     

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.     

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.     

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies

This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.     

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.     

Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis

OBJECTIVES: To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z-drugs) with either benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other. METHODS: MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z-drugs or any two of the Z-drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. RESULTS AND CONCLUSIONS: Twenty four eligible studies were identified with a total study population of 3,909 (17 studies comparing a Z-drug with a benzodiazepine and 7 comparing a Z-drug). Insufficient or inappropriately reported data meant that meta-analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs.     

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.     

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.     

Ramelteon: a review of its use in insomnia

Ramelteon (Rozeremtrade mark) is the first melatonin receptor agonist to be approved for the treatment of insomnia; it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week 1 was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.     

Rebound insomnia: a critical review

Rebound insomnia, a worsening of sleep compared with pretreatment levels, has been reported upon discontinuation of short half-life benzodiazepine hypnotics. This paper reviews the existing sleep laboratory studies for the presence or absence of rebound insomnia following treatment with triazolam, temazepam, and flurazepam in insomniac patients or poor sleepers and, when possible, in normals. The results indicate that rebound insomnia is a distinct possibility after discontinuation of triazolam in both insomniacs and normal controls. Compared with baseline, disturbed sleep was reported in insomniacs or poor sleepers for the first 1 or 2 nights of withdrawal in seven of nine polygraphically recorded sleep studies following triazolam 0.5 mg and in one of two studies following triazolam 0.25 mg. In one study conducted in normal volunteers, rebound insomnia was observed following triazolam 0.5 mg but not triazolam 0.25 mg. In another study, which used subjective reports of sleep rather than polygraphic recordings, rebound insomnia was significantly attenuated after triazolam 0.5 mg by tapering the dose over 4 nights. The risk of rebound insomnia after temazepam 15 or 30 mg was low. In keeping with its long elimination half-life, flurazepam (30 mg) continued to exert beneficial effects for the first 2-3 withdrawal nights, but the possibility of a mild rebound insomnia cannot be dismissed during the intermediate withdrawal period (nights 4-10) following prolonged, consecutive, nightly administration (more than 30 nights). The benzodiazepine hypnotics are generally preferred over other types (barbiturates or nonbenzodiazepine, nonbarbiturate), but there are advantages and disadvantages related to half-life of the benzodiazepines. The risk of rebound insomnia is greater with the short half-life as compared with the long half-life benzodiazepines.     

Eszopiclone: a review of its use in the treatment of insomnia

Eszopiclone (Lunesta), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency.Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months' duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4-8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months' therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months' treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.     

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.