Rebound insomnia: a new clinical syndrome.

Rebound insomnia followed the withdrawal of three benzodiazepine hypnotic drugs, each of which had been administered in a single nightly dose for only short-term periods. The intense worsening of sleep is attributed to the short duration of the action of these drugs. A hypothesis involving benzodiazepine receptors in the brain is proposed in which there is a delay or lag in replacement of endogenous benzodiazepine-like molecules after the abrupt withdrawal of exogenous drugs.

Cigarette smoking associated with sleep difficulty.

A group of 50 smokers experienced greater sleep difficulty than a group of 50 nonsmokers matched by age and sex. The two groups did not differ in personality patterns or drug consumption. Also, sleep patterns significantly improved in a group of eight chronic smokers when they abstained from cigarette smoking. These findings are consistent with reports on the stimulant effects of nicotine.

Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men.

The aim of this study was to investigate, in normal young men, whether gamma-hydroxybutyrate (GHB), a reliable stimulant of slow-wave (SW) sleep in normal subjects, would simultaneously enhance sleep related growth hormone (GH) secretion. Eight healthy young men participated each in four experiments involving bedtime oral administration of placebo, 2.5, 3.0, and 3.5 g of GHB. Polygraphic sleep recordings were performed every night, and blood samples were obtained at 15-min intervals from 2000 to 0800. GHB effects were mainly observed during the first 2 h after sleep onset. There was a doubling of GH secretion, resulting from an increase of the amplitude and the duration of the first GH pulse after sleep onset. This stimulation of GH secretion was significantly correlated to a simultaneous increase in the amount of sleep stage IV. Abrupt but transient elevations of prolactin and cortisol were also observed, but did not appear to be associated with the concomitant stimulation of SW sleep. Thyrotropin and melatonin profiles were not altered by GHB administration. These data suggest that pharmacological agents that reliably stimulate SW sleep, such as GHB, may represent a novel class of powerful GH secretagogues.

Effectiveness of hypnotic drugs with prolonged use: flurazepam and pentobarbital.

This study represents the first attempt to rigorously evaluate the effectiveness of hypnotic drugs under conditions of prolonged use. Flurazepam, 30 mg, and pentobarbital, 100 mg, were separately evaluated in identical 47-night sleep laboratory drug evaluation studies on insomniac subjects, which included 4 weeks of drug administration. Flurazepam was found to be effective in inducing and maintaining sleep over all treatment conditions. With long-term use, only a slight loss of effectiveness was suggested. Flurazepam also produced a moderate decrease in REM sleep and marked decrease in eye movement density and stage 4 sleep with short- and intermediate-term use. While the decreases in both REM sleep and eye movement density lessened with long-term use, stage 4 sleep remained markedly suppressed. No rebound was noted in any of these parameters after withdrawal. Pentobarbital was found to be effective in inducing and maintaining sleep only with short-term drug administration. This strongly suggests that it is of limited value for insomniac patients who require nightly medication beyond short-term use. Pentobarbital caused a minimal decrease in REM sleep with short- and intermediate-term administration, and slight rebound following withdrawal. Stages 3 and 4 sleep were decreased with short-term use and increased above baseline levels after withdrawal.

Lorazepam-efficacy, side effects, and rebound phenomena.

Lorazepam, 4 mg, was evaluated in an 18-night sleep-laboratory study involving five insomniac subjects. Hypnotic effectiveness and effects on sleep stages and related parameters were assessed. Placebo was given on baseline nights 1 to 4, lorazepam on nights 5 to 11, and placebo was given again on withdrawal nights 12 to 18. Subjective and objective data clearly demonstrated that lorazepam was effective for both inducing and maintaining sleep. Sleep latency was reduced from a baseline value of 34.6 min to 17.9 min (P less than 0.01) and total wake time was reduced from 75.9 to 38.5 min (P less than 0.01). On the third and fifth nights of drug withdrawal total wake time rose above baseline levels (termed rebound insomnia) and sleep latency increased by 77% and 60% over baseline (P less than 0.01). Subjective estimates of daytime anxiety also increased above baseline (rebound anxiety) during the withdrawal period. All subjects experienced severe hangover and varying degrees of impaired functioning during the first 3 days on drug. Three subjects also experienced anterograde amnesia during the day after the first drug night. These side effects diminished in intensity over the course of the study. Our results suggest that while 4 mg lorazepam may be effective in inducing and maintaining sleep, this dose induces clinically significant side effects that are followed by consistent rebound phenomena after withdrawal.

Dose-response studies of quazepam.

Quazepam, an investigational benzodiazepine, was evaluated in doses of 7.5, 15, and 30 mg in a 12-night protocol including four nights of drug trial. All three doses were effective in inducing and maintaining sleep, with the highest degree of effectiveness after the first drug night. Carry-over effectiveness, which was seen after withdrawal of all three doses, persisted throughout the withdrawal period after the 30-mg dose. Quazepam's effects during both drug use and withdrawal appeared to be dose related; 15 mg induced a greater reduction in wake time after sleep onset than the 7.5-mg dose, and 30 mg induced even greater differences in both wake time after sleep onset and total wake time. Subjective reports of improved sleep were in general agreement with the objective data at each dose level. Side effects appeared to be dose related in terms of severity. The efficacy and comparatively less severe side effects of the 7.5- and 15-mg doses of quazepam suggest that these doses may be optimal when the drug is considered for the adjunctive treatment of insomnia.

Comparative effects of prazosin and hydrochlorothiazide on sexual function in hypertensive men.

Evidence suggests that there may be differences in the incidence of drug-induced sexual dysfunction among the antihypertensive agents. This study assessed objective and subjective aspects of sexual dysfunction in hypertensive male patients in relation to two antihypertensive agents--prazosin and hydrochlorothiazide. A total of 12 hypertensive patients were evaluated in a crossover study utilizing a sleep laboratory to obtain polysomnographic evaluations of sleep patterns along with changes in nocturnal penile tumescence and buckling pressure. Objectively, no significant changes were observed between the two antihypertensive agents in relation to rapid eye movement-related sleep architecture, serum testosterone levels, or penile blood flow. Decrements in buckling pressure and subjective aspects of sexual dysfunction were greater during hydrochlorothiazide treatment than during prazosin treatment. Both drugs were effective in controlling blood pressure.

Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings.

Previous studies on the effects of gamma-hydroxybutyrate (GHB) on the sleep and clinical response of patients with narcolepsy are reviewed. New information on 48 patients treated with GHB for as long as 9 years is presented. These studies indicate that 2.25 to 3.00 g of GHB, taken in conjunction with a low dose of a stimulant during the day, rapidly alleviate the symptoms of narcolepsy in most patients. Tolerance does not develop to this treatment regimen; neither have any patients discontinued the treatment because of side effects. In poor responders, daytime drowsiness and not cataplexy has been the most common residual symptom. Sleep studies reveal that GHB induces REM followed by slow wave sleep. Although total sleep time at night may be unchanged, sleep is less fragmented. GHB appears to be effective because it can induce the symptoms of narcolepsy and contain them at night. It is noteworthy, therefore, that the central biochemical changes induced by GHB also appear comparable to those found naturally in narcolepsy.

Computerized adjustable versus fixed NCPAP treatment of obstructive sleep apnea.

An automated positive airway pressure device that monitors respiratory patterns and provides dynamic, real-time, relational pressure has been developed for the treatment of obstructive sleep apnea (OSA). The purpose of this study was to compare self-adjusting pressure to classical nasal continuous positive airway pressure (NCPAP). Subjects were newly diagnosed patients with a minimum respiratory disturbance index (RDI) of 15 episodes per hour who had undergone NCPAP titration and been using classical NCPAP at home on a nightly basis for at least 2 weeks. Patients then underwent repeat standard polysomnographic (PSG) evaluations for 2 nights using a self-adjusting pressure mode and a standard NCPAP mode randomly assigned in a single-blind crossover fashion. Eight males and four females (n = 12), aged 48.4 +/- 12.2 years [mean +/- and standard deviation (SD)], completed the study. During initial diagnostic PSG, the RDI was 57.3 +/- 30.8 episodes per hour. The RDI and minimum oxygen saturation for both treatment nights were significantly improved from those of the diagnostic PSGs (p < 0.001). The subjects spent 63.1 +/- 34.2% of total sleep time below prescribed pressure while on automatic pressure Percent of total sleep time in stage 3/4 sleep was significantly higher during self-adjusting pressure, at 8.6 +/- 7.5%, compared to standard NCPAP, at 4.6 +/- 6.0% (p < 0.05). Computerized adjustable nasal positive airway pressure effectively controls OSA, fluidly providing the minimal pressure necessary to control respiratory events without causing sleep disruption.

Comparative effects of sleep on a standard mattress to an experimental foam surface on sleep architecture and CAP rates.

The comparative effects of sleep patterns and rates of cyclic alternating patterns (CAP rate) in a high quality innerspring mattress were compared to those on a unique foam support mattress in 10 normal subjects. Results showed no differences in sleep stages, number of wakes, or total sleep time between the two conditions. CAP rates were significantly reduced on the foam surface. CAP rate was sensitive to the first-night effect on both surfaces, but was blunted on the foam mattress.

Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients.

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.

Feasibility of an every-other-night regimen in insomniac patients: subjective hypnotic effectiveness of quazepam, triazolam, and placebo.

BACKGROUND: Rebound insomnia, a worsening of sleep difficulty beyond baseline levels, can complicate the physician's attempt to use regularly scheduled drug holidays in the management of insomniac patients. Quazepam, a benzodiazepine with a long half-life, has been shown to exhibit carryover effectiveness for the first night or two following withdrawal. This finding suggests a potential utility for an alternate-night drug regimen in which the withdrawal features of the compound serve as a potential benefit. METHOD: A randomized, double-blind, three-compartment, parallel-group design of 5 weeks' duration, comparing quazepam 15 mg, triazolam 0.5 mg, and placebo, was conducted in 65 insomniac subjects. This study was a nonpolysomnographic study utilizing sleep questionnaires. RESULTS: No differences were noted between quazepam and triazolam on treatment nights. Evidence of carryover effectiveness with quazepam and rebound effects with triazolam were noted on off-treatment nights. CONCLUSION: The efficiency of alternate-night therapy with quazepam should be rigorously evaluated using polysomnographic determinations.

Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients.

Trazodone (150 mg to 400 mg) was administered to six depressed patients with significant sleep disturbances in an 8-week single-blind study design. Patients were evaluated psychologically by means of the Hamilton Rating Scales for Anxiety and Depression. Polysomnographic monitoring in the sleep laboratory was conducted at each of the time points corresponding to the psychiatric evaluations. Five of the six subjects completed treatment. Patients showed a significant improvement in symptoms of depression and in their polysomnographic-determined sleep architecture. There was a 44% improvement in persistent sleep latency, decreasing from a mean +/- SD of 51.0 +/- 59.3 minutes at baseline to 28.5 +/- 24.2 minutes after 5 weeks of active treatment. Total sleep time improved 14% from 387.1 +/- 59.2 minutes at baseline to 441.3 +/- 23.7 minutes after 5 weeks. Stage IV sleep more than doubled with an increase of 153% from 1.9 +/- 3.0% at baseline to a more normal 4.8 +/- 5.5%. There was no change in percentage of rapid eye movement (REM); however, REM latency increased 28% from a mean of 74.6 +/- 35.9 minutes at baseline to a mean of 95.6 +/- 28.8 minutes. Sleep efficiency improved from 80.6 +/- 12.3%, considered clinically significant insomnia, to 91.9 +/- 4.9%, which is well within normal sleep patterns.

Comparative amnestic effects of benzodiazepine hypnotic agents.

The effects of triazolam 0.5 mg and temazepam 30 mg on immediate and delayed recall in normal and insomniac subjects were evaluated in three separate, randomized, placebo-controlled, parallel group studies. Neither drug caused significant impairment of immediate recall. In the tests of delayed recall, triazolam caused a consistent anterograde amnestic effect. No significant impairment of delayed recall was observed in the temazepam study. Anterograde amnesia is thought to be a dose-related effect of benzodiazepines. Compounds with high benzodiazepine receptor affinity such as triazolam are thought to cause this type of amnesia more often than the lower-affinity compounds such as temazepam.

Comparative efficacy and safety of nortriptyline and fluoxetine in the treatment of major depression: a clinical study.

The safety and efficacy of nortriptyline and fluoxetine were compared in a double-blind, randomized, multicenter 5-week trial involving 205 outpatients with acute major depression of moderate severity. Seventy-two nortriptyline and 84 fluoxetine patients completed at least 2 weeks of medication and were included in the efficacy analysis; all patients were evaluated for side effects. Average total scores on the Hamilton Rating Scale for Depression (HAM-D) for both treatment groups declined from 22-23 at baseline to 11.5 at the conclusion of the 5-week period. At Week, 5, 71% of nortriptyline patients and 65% of fluoxetine patients were much or very much improved. Fluoxetine was associated more frequently with nausea (p less than .05), while nortriptyline was associated more frequently with dry mouth (p less than .05). These results are discussed in the context of selecting between nortriptyline and fluoxetine for a particular depressed patient.

A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia.

BACKGROUND: Zolpidem is a short-acting, nonbenzodiazepine hypnotic with rapid onset of action. Even though it is not a benzodiazepine, it binds to one of three types of central benzodiazepine receptors, showing selective binding to the type 1 benzodiazepine receptor subtype. Therapeutic hypnotic dosages do not disturb normal sleep patterns (sleep architecture). METHOD: A randomized, double-blind, placebo-controlled, parallel group multicenter trial was conducted to determine the effectiveness of 10 mg and 15 mg of zolpidem in the long-term (35 nights) treatment of chronic insomnia in 75 patients. Sleep stage effects and motor and cognitive effects during the 35-night treatment period and the 3-night posttreatment period were also investigated. RESULTS: Within the first week of treatment, 10 mg of zolpidem had a significant effect on latency to persistent sleep and sleep efficiency. Efficacy was maintained throughout the 35 nights of drug administration. There was no evidence of residual effect with 10 mg of zolpidem. Stage 3-4 sleep was preserved at both the 10-mg and 15-mg zolpidem dosages. There was no evidence of tolerance at either dose and no significant treatment differences between the 10-mg zolpidem group and placebo in latency to persistent sleep or sleep efficiency during the posttreatment period. Also, the 10-mg zolpidem dosage was judged by the patients to have helped them fall asleep. Similar results were observed with the 15-mg zolpidem dosage. However, there were significant decreases in REM sleep at Weeks 3 and 4 with 15 mg of zolpidem compared with placebo. Overall, incidence rates of treatment-emergent adverse events in the zolpidem groups were similar to those in the placebo group. CONCLUSION: This is the first sleep laboratory study using a parallel placebo group to demonstrate efficacy for longer than 4 weeks with a hypnotic agent. In this study 10 mg of zolpidem was found to be safe and effective for the long-term treatment of chronic insomnia, demonstrating hypnotic efficacy without affecting sleep stages or producing tolerance effects, rebound effects, or detrimental effects on psychomotor performance. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.

The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy.

Thirty patients with polysomnographically confirmed narcolepsy were treated with GHB (gamma-hydroxybutyrate) for up to 30 weeks. The number of nightly awakenings significantly decreased, while Stages 3 and 4 sleep substantially increased. The clinical symptoms of cataplexy, sleep paralysis, hypnogogic hallucinations, daily naps, and sleep attacks all showed significant improvements. Daytime sleepiness, while not completely eliminated, was controlled with lower doses of stimulant medication than patients were taking before the study. No patient developed tolerance to the drug, and no serious side effects were noted.

Lack of amnestic effects of clorazepate on geriatric recall.

Significant amnestic effects in young adults have been found with the short-acting sedative-hypnotic triazolam and the intermediate-acting lorazepam, but not with the longer-acting clorazepate. The effects of placebo and clorazepate 3.75 and 7.5 mg were compared in 43 nonanxious geriatric subjects. Results were consistent with earlier studies, and no significant impairment of immediate or delayed recall was found.

Differential amnestic properties of short- and long-acting benzodiazepines.

It has been demonstrated previously that orally administered lorazepam can cause anterograde amnesia in young adults. In this study, the effects of 7.5 and 15 mg clorazepate and 1 and 2 mg lorazepam on recall were compared in 74 healthy adults. Word list presentation tests were administered to subjects at selected intervals to measure immediate and delayed recall. Statistically significant memory impairment was found with 2 mg lorazepam during both immediate and delayed recall testing. Clorazepate produced no statistically significant amnestic effects. The data suggest that benzodiazepines differ in their potential for causing memory impairment.

Anterograde amnesia with oral lorazepam.

The use of intravenous benzodiazepines often results in amnesia for events subsequent to drug administration (anterograde amnesia). To asses the effects of oral administration, a single 2 mg dose of lorazepam was given to 6 normal subjects. No substantial effect on immediate recall of word lists was seen in comparison with 6 placebo control subjects. However, the active drug significantly hindered the delayed recall of words. These findings indicate that lorazepam, taken orally as a daytime tranquilizer, can have amnestic action.