A Clinical Trial of Four Hypnotic Drugs

A clinical trial of four hypnotic drugs was carried out: Ro 4-5360, 10 mg. (Mogadon), methyprylon, 200 mg. (Noludar), Ro 4-5360, 5 mg. (Mogadon), secobarbital sodium, 100 mg. (Seconal), and a placebo. The study was on the usual double-blind basis, and all observations were made by a full-time nurse. Capsules were given at 10 p.m. for five successive nights, with two nights free from medication or observation. There were five such periods. The nurse carried out her observations right through the night, determining whether the patients were awake or asleep. Each of these drugs was statistically significantly different from the placebo, in terms of length of sleep. Differences between the individual drugs were not significant. The length of action of the various drugs appeared to be similar, with a somewhat longer period of activity for the Mogadon in both dosages. The major side effect was some drowsiness: this was more marked with Mogadon 10 mg. With the hypnotics, the patients had, on the average, about one hour more sleep than on the placebo.     

A Clinical Evaluation of Four Hypnotic Agents,Using a Latin-Square Design

A double-blind study with a Latin-square design was undertaken on 25 elderly patients, using a placebo and four hypnotic drugs: ethchlorvynol 500 mg., glutethimide 500 mg., chloral hydrate 500 mg., and secobarbital sodium 100 mg. The trial lasted for five weeks. The drugs were all effective compared with the placebo, differences in sleeping time being statistically significant. Differences between these four drugs were not statistically significant. Sleep was induced soonest by secobarbital and ethchlorvynol. Ethchlorvynol and glutethimide had a relatively somewhat longer period of activity than the others. Glutethimide produced most side effects, especially morning drowsiness. Ethchlorvynol and chloral hydrate produced relatively few cases of drowsiness.     

A comparative study of three hypnotics: methyprylon,glutethimide and chloral hydrate

A controlled study designed to evaluate the hypnotic potentiality of methyprylon (300 mg.), glutethimide (500 mg.) and chloral hydrate (1000 mg.) was carried out on 50 in-patients experiencing long-standing insomina. The patients ranged in age from 21 to 60 years, the sexes were equally represented and the clinical diagnoses were psychoneurosis, reactive depression, or anxiety reaction. An interesting feature of the experimental design allowed for the exclusion of placebo reactors before the initiation of the main trials. No difference in effectiveness of maintaining sleep could be established among the three hypnotic agents, indicating that at the usual levels of statistical significance, all three agents were equally effective as hypnotics. However, a significant trend (P = .05) was found for methyprylon (Noludar) to be the most effective and chloral hydrate to be the least effective of the three drugs in maintaining sleep. Methyprylon was found statistically (P = .05) to be the fastest sleep-inducing agent, whereas glutethimide (Doriden) proved to be the slowest of the three hypnotics with respect to sleep induction time.     

Persistent Behaviour and Electroencephalographic Changes after Single Doses of Nitrazepam and Amylobarbitone Sodium

In a double-blind cross-over trial the effects of nitrazepam (5 and 10 mg.), amylobarbitone sodium (100 and 200 mg.), and placebo were compared in normal healthy young people. Though they reported a good night''s sleep and adjudged themselves to be alert after all four drug treatments, behavioural tests showed their performance to be significantly impaired 13 hours after treatment with nitrazepam or amylobarbitone, and E.E.G. records showed more drowsiness and light sleep 18 hours after treatment with nitrazepam than with amylobarbitone or placebo. E.E.G. fast activity was more plentiful after drugs in either dosage than with placebo.     

Evaluation comparée des effets subjectifs de la dextroamphétamine,du méthylphénidate et du placebo

The subjective effects of dextroamphetamine, methylphenidate and placebo were evaluated in 16 medical students during the period just prior to their final oral examinations. The subjects served as their own controls. The order of administration of the three medications for each student was randomized, and a double-blind technique was used throughout. A questionnaire method was employed for the collection of results, which proved to be a useful and effective means. It demonstrated that dextroamphetamine, methylphenidate and placebo were statistically different from one another with regard to their effect on efficiency of studying, fatigue, duration of sleep and appetite. There were also significant differences in the number of side effects caused by the three medications. The stimulants, however, did not increase the number of study hours, nor was their use recommended by the students when preparing for important examinations.     

Morning Melatonin Has Limited Benefit as a Soporific For Daytime Sleep After Night Work

Exogenous melatonin administration in humans is known to exert both chronobiotic (phase shifting) and soporific effects. In a previous study in our lab, young, healthy, subjects worked five consecutive simulated night shifts (23:00 to 07:00 h) and slept during the day (08:30 to 15:30 h). Large phase delays of various magnitudes were produced by the study interventions, which included bright light exposure during the night shifts, as assessed by the dim light melatonin onset (DLMO) before (baseline) and after (final) the five night shifts. Subjects also ingested either 1.8 mg sustained‐release melatonin or placebo before daytime sleep. Although melatonin at this time should delay the circadian clock, this previous study found that it did not increase the magnitude of phase delays. To determine whether melatonin had a soporific effect, we controlled the various magnitudes of phase delay produced by the other study interventions. Melatonin (n=18) and placebo (n=18) groups were formed by matching a melatonin participant with a placebo participant that had a similar baseline and final DLMO (±1 h). Sleep log measurements of total sleep time (TST) and actigraphic measurements of sleep latency, TST, and three movement indices for the two groups were examined. Although melatonin was associated with small improvements in sleep quality and quantity, the differences were not statistically significant by analysis of variance. However, binomial analysis indicated that melatonin participants were more likely to sleep better than their placebo counterparts on some days with some measures. It was concluded that, the soporific effect of melatonin is small when administered prior to 7 h daytime sleep periods following night shift work.     

Morning melatonin has limited benefit as a soporific for daytime sleep after night work

Exogenous melatonin administration in humans is known to exert both chronobiotic (phase shifting) and soporific effects. In a previous study in our lab, young, healthy, subjects worked five consecutive simulated night shifts (23:00 to 07:00 h) and slept during the day (08:30 to 15:30 h). Large phase delays of various magnitudes were produced by the study interventions, which included bright light exposure during the night shifts, as assessed by the dim light melatonin onset (DLMO) before (baseline) and after (final) the five night shifts. Subjects also ingested either 1.8 mg sustained-release melatonin or placebo before daytime sleep. Although melatonin at this time should delay the circadian clock, this previous study found that it did not increase the magnitude of phase delays. To determine whether melatonin had a soporific effect, we controlled the various magnitudes of phase delay produced by the other study interventions. Melatonin (n=18) and placebo (n=18) groups were formed by matching a melatonin participant with a placebo participant that had a similar baseline and final DLMO (±1 h). Sleep log measurements of total sleep time (TST) and actigraphic measurements of sleep latency, TST, and three movement indices for the two groups were examined. Although melatonin was associated with small improvements in sleep quality and quantity, the differences were not statistically significant by analysis of variance. However, binomial analysis indicated that melatonin participants were more likely to sleep better than their placebo counterparts on some days with some measures. It was concluded that, the soporific effect of melatonin is small when administered prior to 7 h daytime sleep periods following night shift work.     

Growth hormone-releasing hormone and corticotropin-releasing hormone enhance non-rapid-eye-movement sleep after sleep deprivation

The neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) regulate sleep and nocturnal hormone secretion in a reciprocal fashion, at least in males. GHRH promotes sleep and GH and inhibits hypothalamo-pituitary-adrenocortical (HPA) hormones. CRH exerts opposite effects. In women, a sexual dimorphism was found because GHRH impairs sleep and stimulates HPA hormones. Sleep deprivation (SD) is the most powerful stimulus for inducing sleep. Studies in rodents show a key role of GHRH in sleep promotion after SD. The effects of GHRH and CRH on sleep-endocrine activity during the recovery night after SD are unknown. We compared sleep EEG, GH, and cortisol secretion between nights before and after 40 h of SD in 48 normal women and men aged 19-67 yr. During the recovery night, GHRH, CRH, or placebo were injected repetitively. After placebo during the recovery night, non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) increased and wakefulness decreased compared with the baseline night. After GHRH, the increase of NREMS and the decrease of wakefulness were more distinct than after placebo. Also, after CRH, NREMS increased higher than after placebo, and a positive correlation was found between age and the baseline-related increase of slow-wave sleep. REMS increased after placebo and after GHRH, but not after CRH. EEG spectral analysis showed increases in the lower frequencies and decreases in the higher frequencies during NREMS after each of the treatments. Cortisol and GH did not differ between baseline and recovery nights after placebo. After GHRH, GH increased and cortisol decreased. Cortisol increased after CRH. No sex differences were found in these changes. Our data suggest that GHRH and CRH augment NREMS promotion after SD. Marked differences appear to exist in peptidergic sleep regulation between spontaneous and recovery sleep.     

Two Anti-anxiety Drugs: A Psychoneuroendocrine Study

Eight males were studied during 27 weeks, including two periods of five weeks during which they received clinical doses of sodium amylobarbitone and benzoctamine. Substitution of placebo for either drug caused raised anxiety and impairment of mental concentration. The drugs reduced restlessness during sleep and reduced paradoxical sleep. By the fifth week of sodium amylobarbitone, although sleep was still less restless in the early night it was more restless than normal in the late night.Blood samples were taken half-hourly during sleep by indwelling venous catheter. Plasma growth hormone concentration was little affected during drug administration but rose temporarily after withdrawal. There was a reduction of plasma corticosteroid concentration during sleep throughout administration of the drugs and a rebound above normal during the first withdrawal week.     

Effects of Low Doses of Melatonin on Late Afternoon Napping and Mood

The effects of low doses of melatonin (0.1, 0.5 and 1 mg) given at 16:00 h on induction and quality of sleep in the late afternoon (17:00-21:00 h), as well as on subjective fatigue and mood ratings before and after sleep were studied. Ten healthy male volunteers (age 26-30 years) were given on a double-blind crossover basis, tablets containing melatonin, or placebo, with one day washout between treatments. Mood and fatigue were assessed before and after bedtime. Sleep quality was objectively monitored using wrist-worn actigraphs and subjectively by using sleep logs. Data were analysed by means of analysis of variance for repeated measures with a factor of group (placebo and the three melatonin doses). The analysis revealed dose-dependent increase by melatonin in subjective evaluation of fatigue and sleepiness, and decrease in alertness, efficiency, vigor and concentration before the nap. Melatonin did not significantly affect actigraph-measured nap sleep latency and efficiency but reduced wake time after sleep onset and delayed sleep offset time compared to placebo, Melatonin did not significantly affect sleep latency and sleep efficiency in the night following the treatment. These data indicate acute effects of low doses of melatonin given at 16:00h on sleepiness and fatigue but not on sleep efficiency or latency in healthy young individuals.     

Effects of Low Doses of Melatonin on Late Afternoon Napping and Mood

The effects of low doses of melatonin (0.1, 0.5 and 1 mg) given at 16:00 h on induction and quality of sleep in the late afternoon (17:00-21:00 h), as well as on subjective fatigue and mood ratings before and after sleep were studied. Ten healthy male volunteers (age 26-30 years) were given on a double-blind crossover basis, tablets containing melatonin, or placebo, with one day washout between treatments. Mood and fatigue were assessed before and after bedtime. Sleep quality was objectively monitored using wrist-worn actigraphs and subjectively by using sleep logs. Data were analysed by means of analysis of variance for repeated measures with a factor of group (placebo and the three melatonin doses). The analysis revealed dose-dependent increase by melatonin in subjective evaluation of fatigue and sleepiness, and decrease in alertness, efficiency, vigor and concentration before the nap. Melatonin did not significantly affect actigraph-measured nap sleep latency and efficiency but reduced wake time after sleep onset and delayed sleep offset time compared to placebo, Melatonin did not significantly affect sleep latency and sleep efficiency in the night following the treatment. These data indicate acute effects of low doses of melatonin given at 16:00h on sleepiness and fatigue but not on sleep efficiency or latency in healthy young individuals.     

Interferon-alpha acutely impairs sleep in healthy humans

We investigated the effects of two low doses of interferon-alpha (IFN-alpha) on nocturnal sleep in 18 healthy men by means of polysomnographic sleep recordings. At 1900h, human recombinant IFN-alpha (1000 or 10000 U/kg body weight) or placebo was administered subcutaneously. Between 2300h and 0700h subjects were allowed to sleep. In general effects were stronger at the dose of 10000 than 1000 U/kg body weight of IFN-alpha. Although, after IFN-alpha subjects experienced increased fatigue, the cytokine impaired the quality of nocturnal sleep. The higher dose of IFN-alpha suppressed slow wave sleep (17.8 +/- 2.0% vs 25.2 +/- 2.6% following placebo, P<0.003) but increased time spent in shallow sleep (P<0.05) during the first half of sleep time. Rapid eye movement (REM) sleep latency was postponed (P<0.02) and time spent in REM sleep was significantly decreased after IFN-alpha (P<0.04). The impairing influence of IFN-alpha on sleep in humans is in contrast with findings of sleep promoting effects of this cytokine in animals. Our data suggest that endogenous IFN-alpha may be a factor responsible for alterations of sleep, e.g. in the course of viral infections.     

Proof-of-concept human laboratory study for protracted abstinence in alcohol dependence: effects of gabapentin

There is a need for safe medications that can effectively support recovery by treating symptoms of protracted abstinence that may precipitate relapse in alcoholics, e.g. craving and disturbances in sleep and mood. This proof-of-concept study reports on the effectiveness of gabapentin 1200 mg for attenuating these symptoms in a non-treatment-seeking sample of cue-reactive, alcohol-dependent individuals. Subjects were 33 paid volunteers with current Diagnostic and Statistical Manual of Mental Disorders-IV alcohol dependence and a strength of craving rating 1 SD or greater for alcohol than water cues. Subjects were randomly assigned to gabapentin or placebo for 1 week and then participated in a within-subjects trial where each was exposed to standardized sets of pleasant, neutral and unpleasant visual stimuli followed by alcohol or water cues. Gabapentin was associated with significantly greater reductions than placebo on several measures of subjective craving for alcohol as well as for affectively evoked craving. Gabapentin was also associated with significant improvement on several measures of sleep quality. Side effects were minimal, and gabapentin effects were not found to resemble any major classes of abused drugs. Results suggest that gabapentin may be effective for treating the protracted abstinence phase in alcohol dependence and that a randomized clinical trial would be an appropriate next step. The study also suggests the value of cue-reactivity studies as proof-of-concept screens for potential antirelapse drugs.     

莫达非尼对睡眠剥夺条件下工作记忆的影响

目的:观察在睡眠剥夺条件下莫达非尼对工作记忆的改善作用,为此药在我军的应用策略提供实验依据。方法:18名健康男性志愿者,在两次睡眠剥夺实验中交叉服用莫达非尼和安慰剂,睡眠剥夺时间从第一天的07:00到第3d的07:00,并于第二天的0:00、12:00和第三天的0:00分别服用莫达非尼100mg或安慰剂。采用随机双盲设计给药,并在第一天的07:00、第二天的02:00和14:00以及第三天的02:00和07:00安排工作记忆测验。结果:工作记忆测验中,两组的反应时和正确率均有统计学差异(P<0.01),莫达非尼组的反应时要快于安慰剂组,正确率也要高于安慰剂组。莫达非尼对工作记忆的改善效果随着睡眠剥夺时间的延长而更趋明显。结论:莫达非尼对睡眠剥夺条件下个体的工作记忆有改善作用,是较为理想的睡眠剥夺对抗药物。     

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.     

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized,double-blind,placebo-controlled study

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness–Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.     

Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel.

We measured the effects of slow-release caffeine (SRC) and melatonin (Mlt) on sleep and daytime sleepiness after a seven-time zone eastbound flight. In a double-blind, randomized, placebo-controlled study, each of three groups of nine subjects was given either 300 mg SRC on recovery day 1 (D1) to D5 (0800) or 5 mg Mlt on preflight D-1 (1700), flight day D0 (1600), and from D1 to D3 (2300), or placebo (Pbo) at the same times. Nighttime sleep was evaluated by polysomnography and daytime sleepiness from measurements of sleep latencies and continuous wrist actigraphy. Compared with baseline, we found a significant rebound of slow-wave sleep on night 1 (N1) to N2 under Pbo and Mlt and a significant decrease in rapid eye movement sleep on N1 (Pbo) and N1-N3 (Mlt). Sleepiness was objectively increased under Pbo (D1-D6) and Mlt (D1-D3). SRC reduced sleepiness but also tended to affect sleep quality until the last drug day. In conclusion, both drugs have positive effects on some jet lag symptoms after an eastbound flight: SRC on daytime sleepiness, and Mlt on sleep.     

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.     

Trial of atenolol and chlorthalidone for hypertension in black South Africans.

Twenty-four black patients (Zulus) with hypertension participated in a double-blind, placebo-controlled cross-over trial of the efficacy of a beta-blocking agent (atenolol) 100 mg once daily as compared with chlorthalidone 25 mg once daily. The two drugs were also given combined at these doses and the effects compared with those of the drugs given alone. Atenolol as sole treatment had no appreciable effect on blood pressure as compared with placebo. Chlorthalidone produced a small decrease, but this was not statistically significant. Combining the two drugs, however, produced a significant reduction in blood pressure (mean lying blood pressure p < 0.001; mean standing blood pressure p < 0.0002). These findings suggest that beta-blockers should not be regarded as baseline treatment of hypertension in blacks.     

Improved hypnotic treatment using chlormethiazole and temazepam.

The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.