How representative are insomnia clinical trials?

OBJECTIVES: To address the question of how representative subjects studied in hypnotic clinical trials are of the broader insomnia population, this study assessed initial contact rates and reasons for inclusion and exclusion during recruitment to an efficacy trial and to a safety trial of Food & Drug Administration (FDA) approved hypnotics. METHODS: Otherwise heathy persons meeting Diagnostic Statistical Manual, Fourth Edition, Revised (DSM-IVR) criteria for insomnia were recruited. In one study, persons 32-65 yrs, were invited to a 12 month trial of nightly use of zolpidem or placebo. In the other, persons 21-64 yrs with driver's licenses were recruited to test the effects of a hypnotic on live on-the-road driving ability. In both studies screening was conducted through an initial telephone interview followed by a clinic visit. RESULTS: In the United States (US) study 13% (n = 410) of 3180 initial contacts and in the Netherlands (NL) study 67% (n = 53) of the 79 initial contacts proceeded to the clinic visit. Of those at clinic 25% of US and 37% of NL participants failed to meet additional insomnia criteria. Mental health exclusions accounted for 24% of US and 23% of NL participants and medical problems accounted for 23% of US and 9% NL exclusions. Finally 20% of US and 26% of NL participants were excluded for drug use/abuse histories. After all screening 4% of the initial US contacts and 0% of the NL contacts entered the study. CONCLUSIONS: These data suggest persons entering insomnia hypnotic clinical trials are a highly selected sample that is unlikely to be representative of the broad insomnia population or the population of potential medication users.

Effects of zaleplon or triazolam with or without ethanol on human performance.

Objectives and background: Given that non-selective gamma-aminobutyric acid (GABA) agonist hypnotics impair performance and potentiate the disruptive effects of ethanol, this study was done to determine the performance-impairing and ethanol-potentiating effects of zaleplon, a new selective GABA agonist hypnotic.Methods: Eighteen healthy men (12) and women (six), 31.5+/-5.6 years old, were studied. Each underwent six treatments of 2 days in duration, presented in a Latin square design with 2-12 recovery days between. The treatments were: placebo-placebo; placebo-ethanol; triazolam-placebo; triazolam-ethanol; zaleplon-placebo; and zaleplon-ethanol; with triazolam (0.25 mg) or placebo administered at 08:30 h, zaleplon (10 mg) or placebo at 09:00 h, and ethanol (0.75 g/kg) or placebo consumed from 09:30 h. Performance tests were completed each day at 10:30, 12:00 and 14:30 h.Results: Breath ethanol concentration (BrEC), tested 0.5, 2.0, 4.5 and 6 h post consumption, did not differ among treatments and peaked at 0.052%, declining to 0.037, 0.009 and 0.001%. Triazolam with and without ethanol impaired digit symbol substitution, symbol copying, simple and complex reaction times and divided attention performance relative to placebo-placebo treatment. It did so consistently at 10:30 and 12:00 h, and less consistently at 14:30 h. Zaleplon without ethanol impaired only digit symbol substitution and divided attention tracking, and only at 10:30 h. Zaleplon with ethanol impaired most measures at 10:30 and 12:00 h, but not at 14:30 h. Zaleplon without ethanol consistently differed from triazolam without ethanol in the extent of performance impairment. Zaleplon with ethanol began to differ from triazolam with ethanol in performance impairment on the 12:00 and 14:30 h test sessions. Ethanol itself impaired most measures at 10:30 h, fewer at 12:00 h and none at 14:30 h. All active drug treatments increased self-rated sleepiness compared with placebo-placebo. Triazolam without ethanol produced greater self-rated sleepiness than zaleplon without ethanol. The addition of ethanol to both drugs generally produced comparable levels of self-rated sleepiness.Conclusions: In an absolute sense, zaleplon produced less performance impairment and a shorter period of ethanol potentiation than triazolam.

Self-reported levels of sleepiness among subjects with insomnia.

Objectives: To determine the prevalence of sleepiness in a cohort of insomnia subjects. We evaluated if differential levels of subjective sleepiness predict systematic differences in the polysomnographic characteristics of these subjects.Background: Insomnia is prevalent among the adult population. While it has been speculated that sleepiness may be an important daytime consequence of insomnia, this has not been demonstrated.Methods: Sixty-two subjects with complaints of insomnia for at least 6 months were polysomnographically evaluated. Subjects were asked to self-report their level of sleepiness based on their experiences for the previous 7 days. Subjects were divided into three groups based on their level of sleepiness. Sleepiness was determined using the excessive daytime sleepiness scale of the Sleep/Wake Activity Inventory (SWAI-EDS).Results: Twenty-two percent of insomnia subjects were found to be sleepy on the EDS scale of the SWAI. The level of sleepiness was also found to predict difficulty initiating sleep both on the nocturnal scale of the SWAI, and on nocturnal polysomnography.Conclusions: This study established a base rate of sleepiness among a cohort of insomnia subjects. It also demonstrated a wide spectrum of sleepiness/alertness among subjects with insomnia. Differential levels of sleepiness were found to predict nocturnal sleep latencies.

Effects of an experimentally induced rhinovirus cold on sleep, performance, and daytime alertness.

STUDY OBJECTIVES: There is accumulating evidence that the common cold produces impairments in psychomotor vigilance. This has led some investigators to hypothesize that such illnesses may also have disruptive effects on sleep. While several self-report studies suggest that viral illness may influence sleep parameters, no studies have assessed polysomnographically recorded sleep following viral infections. DESIGN: Parallel control group comparison. SETTING: Sleep laboratory in a large urban medical center. PARTICIPANTS: Twenty-one men and women with susceptibility to the rhinovirus type 23. INTERVENTIONS: Nasal inoculation with rhinovirus type 23. MEASUREMENTS: Polysomnographically recorded sleep for five nights (2300-0700 h) post-viral inoculation. Twice daily (1030 and 1430 h) performance assessment during each experimental day using auditory vigilance and divided attention tasks. A multiple sleep latency test (MSLT) was performed daily for the duration of the study. RESULTS: In symptomatic individuals, total sleep time decreased an average of 23 min, consolidated sleep decreased an average of 36 min, and sleep efficiency was reduced by an average of 5% during the active viral period (experimental days/nights 3-5) compared with the incubation period. Psychomotor performance was impaired. These changes were significantly greater than those observed in asymptomatic individuals. CONCLUSIONS: The common cold can have detrimental effects on sleep and psychomotor performance in symptomatic individuals during the initial active phase of the illness.

Hypnotic effects of low doses of quazepam in older insomniacs.

To evaluate the efficacy and safety of reduced doses of the benzodiazepine agonist quazepam in older insomniacs, 30 men and women > 60 years old with chronic insomnia were randomly assigned to receive 0, 7.5, or 15 mg quazepam. After two placebo nights, each subject received the appropriate dose for seven consecutive nights, which was followed by two placebo recovery nights. Both doses increased total sleep time relative to placebo during the early (nights 1 and 2) and late (nights 6 and 7) treatment phases. The low dose reduced sleep latency during the late phase, whereas the high dose reduced sleep latency in both early and late treatment phases. These observed hypnotic effects for both doses did not diminish over the seven nights of repeated administration. There also was a continued hypnotic effect during the two nights of placebo recovery for both doses. Analyses of plasma concentrations of quazepam and its metabolites suggested the continued drug effects on sleep during recovery are due to the metabolite desalkylflurazepam. In the safety evaluation done by means of adverse drug event assessments and postsleep questionnaires, the adverse events reported were minimal and not drug or dose related.

The chronic efficacy of midazolam.

The chronic efficacy of midazolam 15.0 mg was studied in 2 male and 10 female subjects. Only subjects with a complaint of sleep latency insomnia which was verified by polysomnography were included in the study. Following a screening and adaptation period, subjects spent 3 consecutive nights in the laboratory during the weeks of the study. Placebo was administered 15 min before lights out on the initial 8 and final 2 nights, and midazolam for the intervening 35 nights. Midazolam significantly reduced sleep latency parameters and significantly increased total sleep time the entire 5 weeks of nightly administration. No within-night rebound insomnia, residual daytime effects, or rebound effects upon discontinuation appeared.

The dose effects of zolpidem on the sleep of healthy normals.

This study determined the dose effects of zolpidem in 12 healthy males with normal sleep patterns. Subjects spent 7 weeks, 3 consecutive nights per week, in the laboratory and had a 4-night washout between treatments. The first week was a screening and adaptation week. Then subjects received zolpidem (2.5, 5.0, 7.5, 10.0, or 20.0 mg) or placebo on the first two nights for each of the next 6 consecutive weeks. Treatments were organized in a Latin square design and administered in a double-blind fashion. On the third night of each treatment, subjects always received placebo. The 5.0 mg and larger doses of zolpidem significantly decreased latency to persistent sleep and wake before sleep. Sleep maintenance measures were not affected by zolpidem. The 7.5 mg and higher doses of zolpidem significantly increased total sleep time. The only significant sleep stage effect was a decrease in percent of rapid eye movement sleep at only the 20 mg dose. No consistent discontinuation effects were found. Zolpidem was hypnotically active at doses as low as 5.0 and 7.5 mg, and sleep stage effects occurred only at the 20 mg dose, thus separating the dose range of hypnotic and sleep stage effects.

Characteristics of individuals who do or do not seek treatment for chronic insomnia.

Survey data have shown that a minority of people who complain of insomnia receive medical treatment for this problem. Patients who seek treatment for insomnia at medical clinics and sleep disorders centers are a self-selected group who may not be representative of all individuals with insomnia. Fifty patients presenting to a sleep disorders center with an insomnia complaint were compared to 50 subjects with insomnia recruited through the newspaper for psychopharmacological studies. No differences in sleep parameters were found, but significant differences on psychometric measures and in daytime alertness were present. The implications of these differences are discussed.

Sedative effects of antihistamines.

The central effects of a newly developed, long-acting H1 antihistamine, loratadine (10 and 40 mg), were compared with those of a standard H1 antihistamine, diphenhydramine (50 mg three times a day) with measures of performance and daytime sleepiness (multiple sleep latency test). Sixteen healthy adults (six women and 10 men), 19 to 35 years of age, received each of the drugs and placebo for 2 days, separated by 5 days at home. Each day, the drug or placebo was administered at 8 A.M. and 12 and 4 P.M. Diphenhydramine was administered in three equal doses (50 mg), and loratadine was administered in a single dose followed by two placebo doses. Mean latency to sleep on tests done at 9 and 11 A.M. and 1, 3, and 5 P.M. was reduced significantly with diphenhydramine compared to placebo, whereas neither loratadine dose reduced sleep latency. Performance measured at 9:30 P.M. and 1:30 P.M. with a battery of tests, including reaction time, vigilance, digit symbol substitution, and symbol copying tasks demonstrated a significant reduction in symbols copied and digits substituted after diphenhydramine compared to both loratadine doses. These results demonstrate that loratadine (10 and 40 mg doses) did not have clinically significant central nervous system activity, whereas diphenhydramine increases sleepiness and disrupts performance efficiency.

Bimodality electrophysiologic evaluation of brainstem in sleep apnea syndrome.

Previous electrophysiologic studies in the sleep apnea syndrome (SAS) have used only a single modality (brainstem auditory evoked responses [BAERs]) and yielded conflicting, inconsistent, and inconclusive results. We utilized both BAERs and somatosensory evoked responses in 12 patients with SAS and found normal central conduction times in all patients. These data argue against a significant structural alteration in both rostral and caudal brainstem, insofar as the auditory and somatosensory pathways are concerned, in patients with SAS.

Chronic hypnotic efficacy of estazolam.

The chronic hypnotic efficacy of estazolam 2.0 mg was studied in five female and seven male subjects. Subjects with a complaint of insomnia verified by polysomnography were included in the study. Following a screening and adaptation period, subjects spent two consecutive nights a week in the laboratory. The protocol for medication was placebo for weeks 1, 2, 9 and 10 and estazolam for weeks 3-8. Estazolam 2.0 mg significantly improved sleep onset and total sleep time for up to six weeks of nightly administration without consistent recovery effects upon discontinuation.

Amnesic effects of lormetazepam.

Sixteen healthy men, age 18-35, each received lormetazepam (1.5 mg), flurazepam (30 mg), temazepam (30 mg) and placebo (double-blind in a Latin Square design) 30 min before bedtime for 2 consecutive nights followed by a 12 day washout between conditions. Three hours after drug (2.5 h after bedtime) subjects were awakened and administered a 16-item memory task. Fifteen minutes after the awakening subjects returned to bed, were instructed to go to sleep, and remained in bed for an additional 5.5 h. Immediately after the memory tasks, before returning to bed, subjects recalled almost all of the 16 items when placebo was administered before bedtime. Immediate recall was significantly poorer than placebo after temazepam and flurazepam, but not after lormetazepam. Morning recall was reduced significantly from the immediate nighttime level in each condition; this loss was smallest with placebo. All active drug conditions produced significantly greater amnesia than placebo. This amnesia was smallest after lormetazepam and greatest after temazepam, which differed significantly from each other. All active drugs significantly reduced latency measures of the return to sleep after the 15 min awakening; it was shortest with temazepam and longest with flurazepam. This study showed a relation between the hypnotic and amnesic effects of these drugs which is consistent with their pharmacokinetic properties.

Dose-related effects of estazolam on sleep of patients with insomnia.

The dose range of estazolam for hypnotic effects was studied in seven men and eight women (mean age 30.3 +/- 8.6 years) who complained of insomnia and had polysomnographic evidence of disturbed sleep. Patients slept in the laboratory and were monitored using standard polysomnographic techniques. Four consecutive nights in the laboratory with placebo, which served as baseline and screening nights, were followed by five 2-night drug administration periods separated by 5-day drug washout periods spent at home. Each of the patients received a sequence of four doses (0.25, 0.5, 1.0, and 2.0 mg) of estazolam and placebo administered according to a Latin square design and in a double-blind manner. Estazolam significantly increased total sleep time and reduced time awake during sleep in a dose-dependent manner. Sleep latency parameters were reduced systematically with increasing doses of estazolam, but these effects on sleep latency were not statistically significant. Increasing doses of estazolam had systematic and statistically significant effects on sleep stages. Subjective estimations of sleep were consistent with the polysomnographic findings bur were not statistically significant.

Effects of acute administration of brotizolam in subjects with disturbed sleep.

Effects of ingestion of brotizolam (0.25 and 0.50 mg) over 1-3 days on polysomnographic measures of sleep were assessed in patients complaining of insomnia. Brotizolam reduced latency to sleep, number of awakenings and wake during sleep, and increased total sleep time. It also increased stage 2 sleep and decreased slow wave and rapid eye movement sleep. Increasing the dose from 0.25 to 0.50 mg increased hypnotic efficacy, and there was a more consistent and reliable effect. Discontinuation of brotizolam had minimal effects on sleep compared with placebo over the 3 nights after acute administration. No side-effects or disruption of daytime function was found using questionnaires and objective tests of performance.