Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep.

Hypnotics that interact with the GABA(A) receptor have marked effects on the electroencephalogram (EEG) during sleep. It is not known whether the effects of hypnotics on EEG power spectra differ between the sexes. The effects of 5, 10 and 15 mg of gaboxadol (GBX) and 10 mg of zolpidem (ZOL) on EEG power spectra were assessed in a randomized, double-blind, placebo-controlled, 5-way cross-over design study using a phase-advance model of transient insomnia. Sleep stage specific EEG power spectra were computed in 36 men and 45 women. GBX enhanced power density in delta and theta activity in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and suppressed sleep spindle activity in NREM sleep. The increase of delta and theta activity in NREM and REM sleep was significantly larger for women than for men but the suppression of spindle activity did not differ between the sexes. After ZOL administration, no sex differences were observed in the reduction of delta and theta activity in NREM sleep, but the increase in sleep spindle activity in NREM sleep was greater in women than in men. These sex dependent and differential effects of GBX and ZOL may be related to their differential affinity for GABA(A) receptor subtypes and their modulation by neurosteroids.

A comparison of placebo and no-treatment during a hypnotic clinical trial.

OBJECTIVE: Sleep parameters commonly improve during placebo treatment in insomnia clinical trials. We examined whether the improvement seen with placebo was related to taking pills or other non-specific factors. METHOD: 95 insomniacs took either a placebo pill (pill+) or no pill (pill-) on nights of their choosing over 12 weeks. RESULTS: Pills were consumed on about half of the nights. Consistent improvement was seen with reduced reported sleep latency, wakefulness after sleep onset, number of awakenings, and total sleep time over the 12 weeks for both the pill+ and pill condition. A difference between pill+ and pill- was detected only for total sleep time, and this difference favored pill+. CONCLUSIONS: This study suggests that improvement seen during placebo treatment is more related to non-specific factors of participating in clinical trial than to pill taking behavior.

The challenge of chronic insomnia: is non-nightly hypnotic treatment a feasible alternative?

The adverse effects of insomnia on health and quality of life are matters receiving increasing attention. Yet, surveys have consistently shown that most people suffering from insomnia do not seek medical help, perhaps, in part, because of a concern of becoming dependent on hypnotic medication. The treatment of chronic insomnia poses a particular dilemma in that continuous hypnotic treatment is restricted in many countries to a maximum of 4 weeks, and behavioural treatment is not readily available. Non-nightly hypnotic treatment of chronic insomnia offers a promising alternative option for the many patients whose symptoms do not necessitate nightly drug intake, allaying fears of psychological dependence on medication and respecting regulatory constraints on hypnotic use while providing patients with adequate symptom relief. The practical feasibility and efficacy of this approach has been demonstrated with zolpidem using various treatment regimens and study designs. So far, six clinical trials have been completed on over 4000 patients. Published results show effective treatment of insomnia without any evidence of either adverse event associated with a discontinuous regimen or increased hypnotic use over the treatment period.

Zolpidem reduces the sleep disturbance of jet lag.

OBJECTIVE: To determine the degree to which zolpidem 10 mg would reduce the sleep disruption associated with rapid, eastward transatlantic travel. BACKGROUND: Subsequent to rapid transmeridian travel, individuals often complain of jet lag which includes transient disturbances in sleep patterns, alertness, appetite and mood. Disturbed sleep and impaired alertness appear to be the most debilitating symptoms of jet lag. METHODS: This multi-center, double-blind randomized, placebo-controlled, parallel-groups study involved 138 adult (mean age 44.9 years) experienced travelers while on their regular eastward transatlantic assignments originating in the US and crossing 5-9 time zones. Subjects were normal sleepers when not traveling and had to have traveled overseas at least twice during the last 24 months. Subjects were randomized to zolpidem 10 mg or placebo for three (optionally four) consecutive nights starting with the first nighttime sleep after travel. Sleep was assessed with daily questionnaires. RESULTS: A total of 130 subjects completed the study. Compared to placebo, zolpidem was associated with significantly improved sleep (statistically significant differences at nights indicated) longer total sleep time (night 1), reduced number of awakenings (nights 1 and 2), and improved sleep quality (nights 1, 2 and 3). Zolpidem was not associated with improvement in sleep latency. No unexpected or serious adverse events were reported and the most common adverse event was headache in both groups (9.2 and 17.6% for placebo and zolpidem, respectively). CONCLUSION: In seasoned travelers, zolpidem 10 mg produced significant improvement in sleep following rapid transmeridian travel.

Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia.

The present randomized, double-blind, placebo and active-drug controlled, crossover study assessed residual sedation after zaleplon 10 mg, flurazepam 30 mg (as an active control), and placebo, taken during a nocturnal awakening in patients with sleep maintenance insomnia. Twenty-two healthy sleep maintenance insomniacs (11 men; mean age, 42 y) received zaleplon, flurazepam, or placebo after an experimental awakening 3.5 hours after bedtime on two consecutive nights in each of three conditions. Residual sedation was measured with sleep latency testing (5 and 6.5 h postdrug), digit symbol substitution, symbol copying, and subjective sleepiness by visual analog scale, each twice each morning. Zaleplon did not differ from placebo on any measure of residual sedation; flurazepam showed significant sedation on all measures. No residual sedative effects were detected 5 or 6.5 hours after ingestion of zaleplon during the middle of the night by sleep maintenance insomniacs.

Eight weeks of non-nightly use of zolpidem for primary insomnia.

CONTEXT: Intermittent use (i.e., a few nights per week) of hypnotic medication is often recommended for the treatment of chronic insomnia despite an absence of efficacy and safety data using this regimen. STUDY OBJECTIVES: To evaluate the clinical efficacy and safety of intermittent pharmacotherapy for chronic insomnia. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel groups, clinical trial at six sleep research sites. PATIENTS: One hundred-sixty-three (115 women, 48 men; mean age 44.1+ SE. 0.9 years), DSM-IV-defined primary insomnia patients were randomized, 134 patients completed the study. INTERVENTIONS: Eight weeks of treatment with either zolpidem 10 mg or placebo. Patients were instructed to take medication when they felt they needed it, but at least three and no more than five times per week. MAIN OUTCOME MEASURES: Investigator and Patient Global Ratings were the primary outcome variables. Secondary measures from daily questionnaires to assess efficacy, rebound insomnia and drug taking behavior. RESULTS: The Investigator's Global Rating indicated that intermittent use of zolpidem produced a significantly better therapeutic effect and significantly reduced insomnia severity throughout the 8-week study relative to placebo. Zolpidem was found to be effective in initiating and maintaining sleep on nights taken, as compared to placebo, based upon the Patient's Global Ratings and all subjective sleep variables. No evidence of rebound insomnia was found on nights that zolpidem was not taken. The number of nights a pill was taken did not differ between groups, nor did frequency of pill taking change in either group across the duration of the study. There were no significant effects of treatment upon quality of life or neurocognitive measures. CONCLUSIONS: Zolpidem 10 mg is effective in treating insomnia when used intermittently, without evidence of discontinuation effects or increased frequency of pill taking.

Zolpidem for persistent insomnia in SSRI-treated depressed patients.

BACKGROUND: Depressed individuals effectively treated with selective serotonin reuptake inhibitors (SSRIs) often report persistent insomnia and require adjunctive sleep-promoting therapy. METHOD: Men (N = 40) and women (N = 150) with a mean age of 41.6 years who had persistent insomnia in the presence of effective and stable treatment (at least 2 weeks) with fluoxetine (< or =40 mg/day), sertraline (< or =100 mg/day), or paroxetine (< or =40 mg/day) for DSM-IV major depressive disorder, dysthymic disorder, or minor depressive disorder of mild-to-moderate severity (and score of < or =2 on item 3 of the Hamilton Rating Scale for Depression [HAM-D]) participated in this randomized, double-blind, parallel-group study. At study entry, patients were required to score < or =12 on the HAM-D. During a 1-week single-blind placebo period, patients had to report on at least 3 nights a latency of > or =30 minutes or a sleep time of <6.5 hours and clinically significant daytime impairment. Patients received either placebo (N = 96) or zolpidem, 10 mg (N = 94) nightly, for 4 weeks and single-blind placebo for 1 week thereafter. Sleep was measured with daily questionnaires and during weekly physician visits. RESULTS: Compared with placebo, zolpidem was associated with improved sleep: longer sleep times (weeks 1 through 4, p<.05), greater sleep quality (weeks 1 through 4, p<.01), and reduced number of awakenings (weeks 1, 2, and 4; p<.05), together with feeling significantly more refreshed, less sleepy, and more able to concentrate. After placebo substitution, the zolpidem group showed significant worsening relative to pretreatment sleep on the first posttreatment night in total sleep time and sleep quality, reverted to pretreatment insomnia levels on the other hypnotic efficacy measures, or maintained improvement (fewer number of awakenings). There was no evidence of dependence or withdrawal from zolpidem (DSM-IV criteria). Incidence rates of adverse events were similar in both treatment groups (74% and 83% for placebo and zolpidem, respectively), but 7 zolpidem patients discontinued compared with 2 placebo patients. CONCLUSION: In this defined patient population, zolpidem, 10 mg, was effectively and safely co-administered with an SSRI, resulting in improved self-rated sleep, daytime functioning, and well-being.

The direct economic costs of insomnia in the United States for 1995.

STUDY OBJECTIVES: To assess the direct economic costs of insomnia in the United States in 1995. METHODS: The costs of prescription medications were based on 1995 data compiled by IMS America, Ltd. (Plymouth Meeting, PA). Non-prescription medication expenditures were provided by Information Resources, Inc. (Chicago, IL). The costs of physician visits related to insomnia were estimated from unpublished data of the 1994 National Ambulatory Medical Care Survey conducted by the National Center for Health Statistics and from the America Medical Association Center for Health Policy Research. Several other sources were used for other cost estimates. RESULTS: Total cost for substances used to treat insomnia was $1.97 billion, less than half of which was for prescription medication. Health care services for insomnia totaled $11.96 billion, 91% of which is attributable to nursing home care. The total direct costs in the United States for insomnia in 1995 were estimated to be $13.9 billion. CONCLUSIONS: Increased efforts are needed in several domains to offset the cost of insomnia including clinical research on the consequences of untreated and treated insomnia, development and implementation of curricula to provide knowledge about sleep and sleep disorders for medical students, physicians, and other health professionals, education to increase public awareness of insomnia and sleep disorders, and more support for basic research on neural mechanisms involved in healthy and disordered sleep.

Ten-year trends in the pharmacological treatment of insomnia.

STUDY OBJECTIVE: To assess patterns of pharmacological treatment of insomnia during the period 1987-1996. DESIGN AND MEASUREMENTS: Data were obtained from the National Disease and Therapeutic Index (NDTI; IMS America, Ltd., Plymouth Meeting, PA) which samples office-based physicians in 24 specialties. Drug mentions, a measure of patient contacts in which drug therapy is recommended, with a physician-indicated desired action of "promote sleep" or "sedative night" were compiled for each year. Z-scores were calculated to determine statistical differences over time for total drug mentions, drug mentions by category (hypnotics, non-hypnotic benzodiazepines, antidepressants, or other), and for some individual drugs. RESULTS: Total drug mentions for the treatment of insomnia fell 24.4% from 1987 to 1996. From 1987 to 1996 hypnotic mentions decreased 53.7%, antidepressants increased 146%, "other" drugs decreased by 63.2%, and benzodiazepine non-hypnotics remained relatively unchanged. CONCLUSIONS: Since 1987, overall pharmacological treatment of insomnia has decreased substantially although surveys indicate a stable or increasing prevalence of sleep disturbance. There has also been a dramatic shift to use of antidepressants in lieu of hyponotics for the symptomatic treatment of insomnia despite a paucity of data regarding their efficacy and the potential for serious side effects.

Cognitive function following acute sleep restriction in children ages 10-14.

STUDY OBJECTIVES: Various aspects of human performance were assessed in children after sleep loss. PARTICIPANTS: Sixteen children (7 males, 9 females) between the ages of 10 and 14 years. DESIGN AND INTERVENTIONS: Children were randomly assigned to either a control (CTRL) group, with 11 hours in bed, or an experimental sleep restriction (SR) group, with 5 hours in bed, on a single night in the sleep laboratory. MEASUREMENTS: Both groups were evaluated the following day with a battery of performance and sleepiness measures. Psychomotor and cognitive performance tests were given during four 1-hour testing sessions at 2-hour intervals. RESULTS: A multiple sleep latency test (MSLT) documented shorter latencies for SR children than controls. Significant treatment differences were discovered in three of four variables of verbal creativity, including fluency, flexibility, and average indices. There were also group differences found on the Wisconsin Card Sorting Test (WCST), which may be indicative of difficulty learning new abstract concepts. Measures of rote performance and less-complex cognitive functions, including measures of memory and learning and figural creativity, did not show differences between groups, perhaps because motivation could overcome sleepiness-related impairment for these tasks. CONCLUSIONS: Higher cognitive functions in children, such as verbal creativity and abstract thinking, are impaired after a single night of restricted sleep, even when routine performance is relatively maintained.

The sleep of long-haul truck drivers.

BACKGROUND: Fatigue and sleep deprivation are important safety issues for long-haul truck drivers. METHODS: We conducted round-the-clock electrophysiologic and performance monitoring of four groups of 20 male truck drivers who were carrying revenue-producing loads. We compared four driving schedules, two in the United States (five 10-hour trips of day driving beginning about the same time each day or of night driving beginning about 2 hours earlier each day) and two in Canada (four 13-hour trips of late-night-to-morning driving beginning at about the same time each evening or of afternoon-to-night driving beginning 1 hour later each day). RESULTS: Drivers averaged 5.18 hours in bed per. day and 4.78 hours of electrophysiologically verified sleep per day over the five-day study (range, 3.83 hours of sleep for those on the steady 13-hour night schedule to 5.38 hours of sleep for those on the steady 10-hour day schedule). These values compared with a mean (+/-SD) self-reported ideal amount of sleep of 7.1+/-1 hours a day. For 35 drivers (44 percent), naps augmented the sleep obtained by an average of 0.45+/-0.31 hour. No crashes or other vehicle mishaps occurred. Two drivers had undiagnosed sleep apnea, as detected by polysomnography. Two other drivers had one episode each of stage 1 sleep while driving, as detected by electroencephalography. Forty-five drivers (56 percent) had at least 1 six-minute interval of drowsiness while driving, as judged by analysis of video recordings of their faces; 1067 of the 1989 six-minute segments (54 percent) showing drowsy drivers involved just eight drivers. CONCLUSIONS: Long-haul truck drivers in this study obtained less sleep than is required for alertness on the job. The greatest vulnerability to sleep or sleep-like states is in the late night and early morning.

Minimal rebound insomnia after treatment with 10-mg zolpidem.

This study examined rebound insomnia after discontinuation of chronic use of zolpidem (10 mg), a short elimination half-life imidazopyridine. The zolpidem group was bracketed by a placebo group and a positive control group taking 0.5 mg of triazolam (twice the recommended dose), which is known to produce rebound insomnia. Ninety-nine patients with sleep complaints that were polysomnographically documented participated in the study. After randomization, patients completed a 2-night, single-blind, placebo baseline period, a 28-night double-blind treatment phase, and a 3-night, single-blind, placebo substitution period. Polysomnographic and subjective sleep variables indicated a lack of rebound insomnia for the zolpidem group. The positive triazolam control group had rebound insomnia only on the first discontinuation night. There was no significant correlation between rebound insomnia and the level of initial insomnia, the degree of response to treatment in week 4, or the amount of tolerance that developed during drug use. During the 4-week treatment period, efficacy diminished for both drugs. From these data, it cannot be determined whether the lack of rebound insomnia with zolpidem is a result of drug dose or some property of the drug such as receptor selectivity.

Effects of triazolam on sleep, daytime sleepiness, and morning stiffness in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of triazolam upon insomnia and daytime sleepiness in patients with rheumatoid arthritis (RA). METHODS: Triazolam or placebo was administered during two 7 night periods to 15 patients with RA in a double blind crossover study. Polysomnographic recordings were conducted on the last 2 nights of each condition, and multiple sleep latency tests and mood and arthritis assessments were performed during the intervening day in each condition. RESULTS: In the triazolam condition, total sleep time was increased, daytime sleepiness was reduced, and morning stiffness was improved compared to placebo. Objective measures of sleep fragmentation were unchanged. Clinical arthritis assessments were similar during both conditions. CONCLUSION: Short term hypnotic therapy improves sleep in patients with RA and appears to improve morning stiffness and daytime sleepiness.

The effects of caffeine on simulated night-shift work and subsequent daytime sleep.

Thirty healthy volunteers were randomly assigned to either a caffeine or a placebo group to investigate the alerting effects of caffeine at night. Subjects adhered to a simulated night-shift schedule for 5 consecutive nights. On the first 3 nights, 2 mg/kg caffeine was added to decaffeinated coffee at 2220 and 0120 hours for the caffeine group. On nights 4 and 5 both groups received placebo. Each night, subjects completed five 60-minute sessions of a computerized simulated assembly line performance task (SALT), a multiple sleep latency test (MSLT) and questionnaires. Daytime sleep was recorded in the laboratory between 0900 and 1700 hours each day following nighttime testing. Caffeine decreased physiological sleep tendency on the night shift compared with placebo; however, the two groups performed at equivalent levels on the SALT. On nights 4 and 5, when both groups received placebo, there were no differences between the groups on the MSLT, suggesting the absence of a discontinuation effect. There were no differences on daytime polysomnograms between the groups.

Sleepiness and performance during three-day administration of cetirizine or diphenhydramine.

OBJECTIVE: The sedative effects of cetirizine (10 mg once daily), diphenhydramine (50 mg three times daily), and placebo, each administered during a 3-day period, were compared with objective measures of sleepiness and performance. METHODS: Twelve atopic subjects received each of the three treatments for 3 consecutive days in a double-blind Latin square design. Subjects received either cetirizine at 8:00 AM and placebo at 3:00 PM and 10:00 PM; diphenhydramine at 8:00 AM, 3:00 PM, and 10:00 PM; or placebo at all three times. Sleepiness was measured on days 1 and 3 with the multiple sleep latency test at 9:00 AM, 11:00 AM, 1:00 PM, 3:00 PM, and 5:00 PM. Performance was assessed with a 60-minute simulated assembly line task at 9:30 AM, 11:30 AM, 1:30 PM, and 3:30 PM. Nightly sleep duration was estimated with actigraphy. RESULTS: Compared with placebo and cetirizine, diphenhydramine produced marked impairment only on the first day of drug administration. The multiple sleep latency test and the simulated assembly line task values remained stable across days with cetirizine and placebo but improved with diphenhydramine, resulting in no differences among the three conditions on the third day. CONCLUSION: Unlike cetirizine, diphenhydramine produced acute impairment of alertness and performance. By the third day of administration, however, this impairment was no longer present, apparently because of development of tolerance to the sedative effects.

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.

Two- and 4-hour bright-light exposures differentially effect sleepiness and performance the subsequent night.

The effect of two durations of bright light upon sleepiness and performance during typical night shift hours was assessed. Thirty normal, healthy young adults participated in a 2-night protocol. On the 1st night subjects were exposed to bright or dim light beginning at 2400 hours, under one of the following three conditions: bright light for 4 hours, dim light for 2 hours followed by bright light for 2 hours or dim light for 4 hours. Following light exposure, subjects remained awake until 0800 hours in a dimly lit room and slept in the laboratory between 0800 and 1600 hours, during which time sleep was estimated with actigraphy. Throughout the 2nd night, the multiple sleep latency test (MSLT), simulated assembly line task (SALT) performance, and subjective sleepiness were recorded. The single, 4-hour exposure to bright light was found to significantly increase MSLT scores and improve SALT performance during the early morning hours on the night following bright-light exposure. No significant effects were noted with a 2-hour exposure. The most likely explanation for these findings is a phase delay in the circadian rhythm of sleepiness-alertness.

Effect of freezing on the concentration of drugs of abuse in urine.

Benzoylecgonine, 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-acid), phencyclidine, codeine, morphine, amphetamine, methamphetamine, and lysergic acid diethylamide were dissolved in urine, stored frozen in plastic tubes at -16 to -18 degrees C, defrosted, transferred to other tubes, and analyzed by gas chromatography/mass spectrometry (GC/MS); no significant loss of compound was observed, except for THC-acid, which showed an average loss of 11%, ranging from 0 to 34% of the total concentration. The loss is attributed to the decrease in solubility of the compound and to adherence to the side of the container during freezing.