Double-blind,placebo-controlled study comparing effects of zopiclone and temazepam on cognitive functioning of insomniacs

The purpose of this study was to compare the cognitive effect of two medications frequently prescribed to patients suffering from insomnia. Using a double-blind design, we evaluated three parallel groups of 20 insomniac patients treated over a period of 3 weeks with zopiclone, temazepam and placebo, respectively. Our hypothesis was that the impact of zopiclone 7.5 mg/day on cognitive functioning would be minimal 12 h after administration and that temazepam 30 mg/day would affect explicit memory, as is the case with other benzodiazepines. Patients were assessed at baseline following a 1-week, single-blind placebo-intake period, and again at the end of each of the 3 weeks of the comparative phase. Then, in order to estimate the severity and duration of potential rebound insomnia, patients were again assessed following another 1-week, single-blind placebo-washout period at the end of the 3 weeks of treatment. The overall duration of the study for each patient was thus 5 weeks. The instruments of measure used were the Hamilton scale for anxiety, daily self-rating questionnaire for assessment of sleep onset, duration and quality, and two large batteries of psychometric tests. The first of these batteries assessed memory and included span tests for short-term memory, cued recall tasks for long-term explicit memory, and a word-completion task for implicit memory; the second measured attention and concentration through the assessment of alertness, sustained attention and divided attention. The sleep and anxiety results obtained confirm the findings of previous research. Zopiclone and temazepam possess a clinically significant hypnotic activity, with no rebound insomnia or anxiety, during the week of drug withdrawal. The results indicate that the two hypnotic drugs studied have little impact on cognitive functioning. We can therefore conclude that at the doses administered over the 3 weeks, the two hypnotic drugs in question are relatively safe and efficacious in the treatment of insomnia and enable patients to enjoy a good quality of life. Copyright © 1999 John Wiley & Sons, Ltd.     

Effect of temazepam and temazepam-ethanol on sleep

Summary The effects of temazepam 20 mg and temazepam 20 mg plus whisky 100 ml on sleep and performance were investigated in 5 healthy volunteers in comparison with placebo. In the sleep laboratory, after temazepam there was a trend for reduction of sleep latency, stage wake and stage 1 sleep, and for an increase in REM sleep. The addition of alcohol to the regimen reduced the sleep latency still further, and diminished REM sleep. In subjective assessments, temazepam received the highest score for quality of sleep and the temazepam/alcohol combination that for ease of falling asleep. None of the observed changes reached statistical significance. No morning hangover, as measured by effects on wakefulness, performance or affective state, was seen after the combined treatment. Its effect on blood pressure was negligible. It is concluded that the combined administration of temazepam and alcohol in the doses used here does not result in excessive additive, but in moderate pharmacological effects.     

Objective and subjective assessment of hangover during subacute administration of temazepam and nitrazepam to healthy subjects

Summary Fourteen, healthy students volunteered for a double-blind, cross-over trial of temazepam 20 mg (soft gelatine capsule), nitrazepam 10 mg (uncoated tablet) and placebo in matched formulations, single doses of each being given for 10 nights with a three-week wash-out period between each treatment. Residual drug effects were measured objectively (psychomotor skills) and subjectively (visual analogue scales) in the morning and afternoon of Days 0 (before the first tablet), 1 and 10. The subjects also recorded various events during each treatment period. Serum benzodiazepine concentrations were bioassayed in blood samples taken after the last assessment. Both benzodiazepines shortened sleep latency during the first few nights, and nitrazepam prolonged the duration of sleep. The residual effect of drowsiness was noted during the nitrazepam period, whilst temazepam proved less sedating. The morning after effect was a subjective observation and not an objective measurement. The learning effect interfered with the complex objective assessments, and simple measurement of exophoria with the Maddox wing test provided the clearest objective evidence of drug effects. On Day 10 residual concentrations of nitrazepam were detectable in the serum whereas the level of temazepam was found to be low or negligible. It is concluded, that temazepam 20 mg in a soft gelatine capsule is a suitable hypnotic for subjects whose daily work requires constant alertness.     

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.     

Evaluation of the effect of Fosazpeam (a new benzodiazepine), nitrazepam and placebo on sleep patterns in normal subjects

Summary The nocturnal sleep of eight healthy young volunteers was studied after placebo, Fosazepam 100 mg and Nitrazepam 10 mg. Overall results were very similar after the two drugs. During drug periods there was less of sleep Stages I, III+IV and REM, compensated by an increase in Stage II. The decrease in SWS (III+IV) persisted during the withdrawal periods. There was also an increase in Stage I during Fosazepam withdrawal, whereas the percentage of other sleep stages returned to normal. Sleep quality was reported to be slightly better and morning drowsiness, as well as hangover effects, were said to be less pronounced after Fosazepam than after Nitrazepam.     

佐匹克隆与艾司唑仑治疗老年睡眠障碍的临床疗效比较

目的 比较佐匹克隆与艾司唑仑治疗老年睡眠障碍的临床疗效。方法 选取陕西省人民医院收治的200例老年睡眠障碍患者,随机分为两组,艾司唑仑组（96例）给予艾司唑仑治疗,佐匹克隆组（104例）采用佐匹克隆治疗,通过对患者治疗2周的疗效,治疗前、治疗2周的SRSS评分、HAMA评分及不良反应情况进行记录,评价佐匹克隆与艾司唑仑治疗老年睡眠障碍的疗效。结果 治疗2周,佐匹克隆组与艾司唑仑组治疗睡眠障碍的有效率分别为95.2%和90.6%,两组有效率相比,差异没有统计学意义。与治疗前相比,治疗2周,两组SRSS评分均明显降低（P<0.05）,但两组间SRSS评分相比,差异没有统计学意义。与治疗前相比,治疗2周两组HAMA评分均有所降低（P<0.05）,但佐匹克隆组HAMA评分与艾司唑仑组相比,差异没有统计学意义。治疗2周期间,佐匹克隆组不良反应发生率明显低于艾司唑仑组（P<0.05）。结论 艾司唑仑和佐匹克隆对老年睡眠障碍均具有较好的治疗作用,但佐匹克隆不良反应少,且症状轻微,是短期治疗老年睡眠障碍的首选药物。     

佐匹克隆对慢性睡眠剥夺老年大鼠神经递质及脑电的影响

目的：探讨佐匹克隆对慢性睡眠剥夺老年大鼠神经递质及脑电的影响。方法：制备大鼠慢性睡眠剥夺模型,将80只大鼠随机分为空白组、模型组、西药组和对照组,分析各组的全身变化、神经递质含量以及脑电活动情况。结果：空白组精神状态良好。模型组各项均减弱,对照组及西药组精神状态、活动及体质量增长低于空白组。与模型组比,对照组体质量增加量、总睡眠时间、5-HT、IL-1、IL-6和TNF-α含量升高明显,觉醒比例降低明显（P<0.05）。结论：佐匹克隆可改善老年失眠模型大鼠的全身症状和睡眠状态,其机制可能与调控神经递质水平和脑电活动有关。     

Caffeine-induced sleep disruption: effects on waking the following day and its reversal with an hypnotic

The effects of 4 mg/kg and 8 mg/kg caffeine nocte as a model of insomnia, and its potential for reversal with an hypnotic (temazepam 20 mg) were investigated in two double-blind placebo controlled crossover studies, each with six healthy volunteers. Following an adaption night and day, two nights per treatment were assessed with multiple sleep latency tests (MSLTs), performance measures and subjective questionnaires undertaken the following day. In comparison to placebo significant (P < 0.05) increases in sleep onset latency of 30 and 40 min were seen for low and high doses respectively. Significant reductions in sleep duration were limited to the higher dose (total sleep time 80 min, sleep efficiency 17 per cent), as were reductions in slow wave sleep and non-REM sleep which contrasted with increased waking. However, contrast analysis revealed significant dose-related effects for these measures, whilst the lower dose produced more stable effects across nights, suggesting it as more suitable for a model of insomnia in healthy sleepers. Significant decrements in critical flicker fusion (CFF) performance and reduced MSLT latencies reflected increased daytime sleepiness following both doses; although significant subjective changes to sleep and sleep tendency next day were limited to the higher dose. Co-administration of temazepam elixir successfully reversed increased sleep latency seen with the lower caffeine dose and improved subjective sleep, but significant effects on other sleep measures were more limited despite improved mean trends. Similarly, improvements in CFF performance and MSLT latencies failed to achieve significance, suggesting a possible limitation of the hypnotic in overcoming the effects of sleep disturbance and consequences for waking function next day.     

Withdrawal from long‐term use of zopiclone,zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia

Long‐term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short‐term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life. We studied perceived sleep and quality of life in 92 older (age 55‐91 years) outpatients with primary insomnia before and after withdrawal from long‐term use of zopiclone, zolpidem or temazepam (BZDA). BZDA was withdrawn during 1 month, during which the participants received psychosocial support and blindly melatonin or placebo. A questionnaire was used to study perceived sleep and quality of life before withdrawal, and 1 month and 6 months later. 89 participants completed the 6‐month follow‐up. As melatonin did not improve withdrawal, all participants were pooled and then separated based solely on the withdrawal results at 6 months (34 Withdrawers. 55 Nonwithdrawers) for this secondary analysis. At 6 months, the Withdrawers had significantly (P < 0.05) shorter sleep‐onset latency and less difficulty in initiating sleep than at baseline and when compared to Nonwithdrawers. Compared to baseline, both Withdrawers and Nonwithdrawers had at 6 months significantly (P < 0.05) less fatigue during the morning and daytime. Stress was alleviated more in Withdrawers than in Nonwithdrawers (P < 0.05). Satisfaction with life and expected health 1 year later improved (P < 0.05) in Withdrawers. In conclusion, sleep disturbances, daytime fatigue and impaired quality of life may resolve within 6 months of BZDA withdrawal. These results encourage withdrawal from chronic use of benzodiazepine‐type hypnotics, particularly in older subjects.     

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.     

Effects of dietary caffeine on mood when rested and sleep restricted

Prolonged use of caffeine can lead to physical dependence evidenced by characteristic withdrawal symptoms during abstinence. Debate exists as to whether mood enhancement by caffeine represents a net effect or merely the restoration of abstinence-induced mood decrements. One aim of this study was to determine the net effects on mood of dietary caffeine compared with prolonged abstinence. In addition, the study aimed to determine whether caffeine restores mood degraded by a non-caffeine source, namely, sleep restriction. A double-blind placebo-controlled cross-over design was employed in which 48 male and female volunteers alternated weekly between ingesting placebo and caffeine (1.75 mg/kg) three times daily for 4 consecutive weeks, while being either rested or sleep restricted. Mood was assessed using a computerized version of the profile of mood states (POMS), giving scores for overall mood and six mood dimensions. Gender had small effects on mood, whereas all mood dimensions were markedly adversely affected by sleep restriction. Caffeine had no significant net enhancing effects on mood when participants were rested, and produced no net restorative effects when mood was degraded by sleep restriction. On the contrary, caffeine-induced decrements in mood were observed during both conditions of rest and sleep restriction.     

Effects of dietary caffeine on EEG, performance and mood when rested and sleep restricted

Rationale: Until recently, little account had been taken of the confounding effects of caffeine withdrawal and withdrawal reversal when examining the net effects of dietary caffeine. Objectives: By including a manipulation involving sleep restriction, the present study aimed to extend recent findings from research in which caffeine withdrawal and withdrawal reversal were controlled. The main aims of the study were to examine the net effects of caffeine, as well as its potential restorative effects following sleep restriction, on EEG, performance and mood. Method: A randomised cross‐over design was used in which 15 participants alternated weekly between ingesting placebo and caffeine (1.75 mg/kg) three times daily for four consecutive weeks following either usual sleep or sleep restriction. EEG activity was measured at 32 sites during eyes closed, eyes open and performance of a vigilance task. Results: Modest effects of caffeine were found in the delta and beta bandwidths, but no main effects of caffeine were observed in the theta or alpha bandwidths. Overall, the effects of caffeine on EEG activity were relatively few, weak and inconsistent, and no evidence was found of net restorative effects of caffeine for any outcome variables. Conclusions: The findings do not support the use of caffeine as a means for enhancing human function or as an antidote to the negative effects of sleep loss. Copyright © 2008 John Wiley & Sons, Ltd.     

Effects of transderman nicotine on mood and sleep in nonsmoking major depresssed patients

The role of nicotine as an indirect cholinergic agent in sleep has been studied in normal subjects. There are no studies of its effects on sleep in depressed patients. Nicotine transdermal patches (17.5 mg), were studied in eight depressed patients (DSM-III-R) and eight normal volunteers. Subjects wore placebo and nicotine patches for 24 h. Depressed patients showed increased REM sleep without changes in other sleep variables. They also showed a short term improvement of mood. Normal volunteers had sleep fragmentation, and reduction of REM sleep time. No major side effects were reported in either group.     

A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population

Aims The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long-term users of temazepam and lorazepam in a clinical population. Methods The sensitivity to benzodiazepine effects in chronic users (1–20 years) of lorazepam (n=14) or temazepam (n=13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales. Results Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1–2.5 mg of lorazepam. In addition, there was a two- to four fold reduction in the slopes of concentration-effect plots for measures of saccadic eye movements and body sway (all; P≤0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half-life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam. Conclusions Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.     

The pharmacodynamic influence of three benzodiazepines on rapid eye movements,K-complexes and sleep spindles in healthy volunteers

‘Equipotent’ doses of lormetazepam, triazolam and flunitrazepam were studied for their effect on K-complexes, sleep spindles and rapid eye movements (REM). Receptor affinity was used as the criterion for equipotency. This showed that triazolam, lormetazepam and flunitrazepam display a ratio to each other of 1:2:4. However, it was found that lormetazepam caused only slight changes in the three neurophysiological parameters despite being given at twice the dose considered to be equipotent. In contrast, triazolam and flunitrazepam produced a great reduction in the number of K-complexes, a marked increase in sleep spindles and a substantial reduction of REM activity; both substances suppressed the first REM period, and flunitrazepam even suppressed the second in some cases. The influence of all three benzodiazepines on the dissociation of K-complexes and sleep spindles is, however, equal; epochs with either K-complexes or sleep spindles are favoured compared to epochs with both K-complexes and sleep spindles. The general reduction in the number of K-complexes and increase in sleep spindles can be interpreted as a sleep-protective effect. However, the parameter for dose-finding should be REM suppression, since this has the most profound adverse effect on the cyclical structure of sleep—now considered to be the most reliable indicator of a balanced sleep pattern.     

Effects of estazolam and triazolam on transient insomnia associated with phase-shifted sleep

Forty-eight healthy volunteers with a normal sleep/wake history participated in a two-centre, double-blind, parallel group study comparing the effects of estazolam 2.0 mg, triazolam 0.25 mg, and placebo on sleep, performance and alertness following 180 degree reversal in sleep/wake schedule. Sleep-phase reversal produced decreased sleep time, primarily during the last 2 hours of the sleep period. Estazolam prevented this transient insomnia by maintaining sleep in the latter part of the sleep period. Triazolam did not significantly change total sleep time, which was intermediate between that of the estazolam and placebo groups. Neither active compound produced significant effects on subsequent performance or alertness.     

Influence of zopiclone, a new generation hypnotic, on the intermediate stage and paradoxical sleep in the rat

This study examined the influence of zopiclone, a third generation hypnotic, on the transition from slow wave sleep to paradoxical sleep (PS) which is increased at the expense of PS by barbiturates and benzodiazepines. The compound decreased sleep latency and increased the latency of the intermediate stage (IS) and PS at 2.5, 5 and 7.5 mg/kg IP. The amount of the IS was decreased because of the decrease in phase number up to 6 h at all doses. PS amount was decreased during 2 h at 2.5 mg/kg and during 4 h at 5 and 7.5 mg/kg also because of the decrease in phase number. The IS never substituted for PS. The IS spindle characteristics were not modified and the theta rhythm frequency slightly decreased at 5 mg/kg (IS) and 7.5 mg/kg (PS). Received: 11 June 1996 /Final version: 2 October 1996     

The effects of quazepam,triazolam, flunitrazepam and placebo,alone and in combination with ethanol,on day-time sleep,memory, mood and performance

Day-time sleep and residual effects of quazepam 15 mg, triazolam 0·25 mg, flunitrazepam 1 mg, and placebo, alone and in combination with ethanol, were studied using a randomized, double-blind, crossover, single-dose design. Eight healthy volunteers, four male and four female, aged 19–24 years, received each medication in the morning after a ‘normal’ sleep at home the preceding night. Quazepam and triazolam decreased the sleep onset when compared to placebo. The combination with ethanol did not change these findings. Quazepam and placebo showed less residual effects than triazolam and flunitrazepam at 4 hours after drug intake: in combination with ethanol at 4 and 6 hours. No significant differences in mood were found between the different ‘treatments’, except with regard to alertness for quazepam and placebo compared to flunitrazepam, alone and in combination with ethanol, all at 4 hours. The combination drug/ethanol showed an increase in C_max of the former and a delay in T_max when compared to drug alone. The study indicated few clinically useful correlations between clinical effect and plasma concentration.     

Evaluation of the efficacy of metaclazepam and its effects on sleep,psychomotor performance and cognitive function in anxious patients

The effects of single and multiple doses of metaclazepam were investigated in 60 anxious patients. A 15 mg nocturnal dose of metaclazepam was compared to two daily doses (5 mg in the morning and 10 mg at bedtime) in terms of efficacy and effects on various aspects of sleep, cognitive function and psychomotor performance. Anxiolytic efficacy was assessed by means of questionnaires, including the Self Rating Anxiety Scale of Zung, State Trait Anxiety Inventory of Spielberger, and a modified version of the Hamilton Anxiety Rating Scale. Hypnotic activity was evaluated using a clinical rating of insomnia questionnaire. The psychometric battery consisted of tests of Critical Flicker Fusion, Choice Reaction Time and Digit Span. In terms of clinical efficacy, metaclazepam administered in either dosage regimen demonstrated a good anxiolytic activity profile. Both dosage regimens were effective in improving the quality and quantity of sleep, however the number of intermittent awakenings were significantly higher with the daily divided dose. In addition, the nocturnal administration of metaclazepam did not appear to be associated with any undesirable side effects or decrements in psychomotor performance the following morning. In conclusion, it appears that a 15 mg bedtime dose of metaclazepam is efficacious in relieving anxiety without impairing psychomotor performance the following morning. © 1998 John Wiley & Sons, Ltd.