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.

Daytime alertness in subjective and objective insomnia: some preliminary findings.

Daytime performance and alertness were examined in two groups of patients with disorders of initiating and maintaining sleep (DIMS) and a control group of self-described good sleepers. Individuals complaining of disturbed sleep that was verified by polysomnographic indices (objective DIMS) and a group with complaints of disturbed sleep in the absence of objective findings (subjective DIMS) were compared with normal sleepers. Nocturnal polysomnographic recordings documented increased sleep latencies and decreased sleep efficiencies for the objective DIMS group and essentially normal sleep for the subjective DIMS group. However, the subjective DIMS group showed impaired daytime vigilance compared with both the objective DIMS and control groups. Additionally, the subjective DIMS group demonstrated an atypical daytime alertness and a tendency toward lowered arousal during vigilance task performance. Insomniacs without clear objective findings of disturbed sleep, therefore, showed decrements commonly seen following sleep loss or sleep disturbance, whereas insomniacs with evidence of disturbed nocturnal sleep did not differ from the control group in terms of waking function.

Effects of lorazepam and its withdrawal on sleep, performance, and subjective state.

The effects of 3 mg lorazepam on polysomnographic recordings, performance, anxiety, and perceived sleep were examined. Six insomniac subjects slept in the sleep laboratory for 18 consecutive nights after having taken placebo or lorazepam. Polysomnographic data and subjective reports indicated hypnotic efficacy in terms of sleep initiation and maintenance. There was some evidence of rebound insomnia after drug withdrawal, although it was not evident from all measures. Clear performance decrements occurred during lorazepam use.

Hypersomnia, bithalamic lesions, and altered sleep architecture in Kearns-Sayre syndrome.

An 11-year-old boy with Kearns-Sayre syndrome developed hypersomnia associated with bithalamic lesions and had complete absence of sleep spindles on a nocturnal polysomnogram.

Role of hypnotic drugs in general practice.

General practice physicians commonly deal with patients who report experiencing insomnia. Advances in our understanding of insomnia should result in much more effective diagnosis and therapeutic intervention for insomnia patients at the primary care level. This presentation highlights the new knowledge of insomnia pertinent to general practice physicians and discusses the rational use of hypnotic medications in primary care.

Characteristics of narcolepsy in preteenaged children.

Narcolepsy is rarely diagnosed in preteenaged children. Its clinical and polysomnographic manifestations, some of which are unusual, are described in four children who were observed prospectively. The mean age at onset of hypersomnia was 10.2 years (range 8.4 to 11.2 years). Daytime naps among these children were lengthy, ranging from 20 to 120 minutes, and generally were considered unrefreshing. Cataplexy was present at the onset in all four children. Three of the four children were obese, with the concurrent nocturnal snoring prompting a misleading concern about obstructive sleep apnea syndrome in two children. The histocompatibility DR2 antigen was present in all four children. Significant behavioral manifestations appeared in all of them. The response to stimulant medications was, at best, modest. Narcolepsy may be difficult to diagnose in this age group. However, a careful history eliciting sleep/wake dysfunction (including cataplexy), leukocyte assays for the histocompatibility DR2 antigen, and serial polysomnographic studies may enable early recognition and treatment of this disease.

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.

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.

Physiological sleep tendency and ability to maintain alertness at night.

The maintenance of wakefulness test (MWT) and repeated test of sustained wakefulness (RTSW) were compared to the multiple sleep latency test (MSLT) during nighttime hours to evaluate differential sensitivity to variation in physiologic sleepiness/alertness. The degree of sleepiness varied by time of night and was further manipulated by varying prior sleep. Seven healthy normal sleepers were evaluated on the MWT, RTSW, MSLT, a digit symbol substitution test and the Wilkinson addition test in a protocol beginning at 2200 h and terminating at 0830 the following morning. A counterbalanced, crossover design compared an evening nap condition to a no-nap condition. The MWT and RTSW discriminated between nap and no-nap conditions, but the MSLT did not. This suggests that in some situations the MWT and RTSW may be more sensitive to changes in physiologic sleepiness/alertness than the MSLT. The data are discussed in terms of possible methodologic limits of the MSLT and the relationship between physiologic sleep tendency and the capacity to maintain alertness.

Acute administration of triazolam for the daytime sleep of rotating shift workers.

Ten rotating shift workers, who changed shifts every 1 to 4 weeks, slept in the laboratory during the first four daytime sleep periods of two consecutive tours of night shift. Prior to the first two sleep periods of one tour, the subjects were given 0.5 mg triazolam. Placebo was administered prior to sleep periods one and two of the other night shift tour. Neither drug nor placebo was given before the third and fourth sleep period of either tour of night shift. Conditions were counterbalanced among subjects. Polysomnography demonstrated that triazolam significantly increased total sleep time and sleep efficiency relative to placebo, primarily by promoting sleep maintenance. No adaptation to daytime sleep was seen during the four consecutive sleep periods without triazolam (placebo, then no drug). Triazolam did not appear to promote adaptation to daytime sleep on the 2 days following triazolam administration.

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.

Physiological sleep tendency on a simulated night shift: adaptation and effects of triazolam.

Daytime sleep and nocturnal sleepiness were examined in 18 normal sleepers (9 young adults, 9 middle-age adults) for 5.5 days following acute sleep/wake schedule inversion. Triazolam and placebo were compared in a counterbalanced, crossover design. Triazolam improved daytime sleep, but did not produce significant changes in sleep tendency at night. Physiological sleep tendency in the early morning hours (0200 to 0600) was profound, but decreased significantly within 3 to 4 days following sleep/wake inversion, irrespective of treatment condition. Nocturnal performance data generally were consistent with changes in physiological sleep tendency. We conclude that extending daytime sleep by an average of approximately 50 min per day via administration of a hypnotic does not appear to significantly reduce circadian sleep tendency in the early morning hours. Further, considerable adaptation, in terms of sleep tendency, occurred within a weak of simulated night shift despite a relatively constant daytime sleep pattern.

Sleepiness/alertness on a simulated night shift schedule and morningness-eveningness tendency.

This study examined the influence of morningness-eveningness on night shift sleepiness in 15 subjects. Sleepiness was assessed during a five-night protocol involving the multiple sleep latency test (MSLT), repeated test of sustained wakefulness (RTSW) and the Stanford Sleepiness Scale (SSS). Daytime sleep was estimated by sleep diaries and wrist actigraphy. The sample was divided by median score on the Horne and Ostberg Morningness-Eveningness Questionnaire. Physiological sleep tendency was significantly worse between 0030 and 0430 hours for the Morning Tendency group than for the Non-Morning Tendency group. The Morning Tendency group reported obtaining less daytime sleep than the Non-Morning Tendency group; however, there was no difference between groups in total daytime sleep estimated by actigraphy. This preliminary study suggests that morning types are sleepier during night shift hours than non-morning types.

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.

Somnofluoroscopy: cineradiographic observation of obstructive sleep apnea.

Systematic cineradiographic observation of the upper airway with simultaneous polysomnography, termed somnofluoroscopy, was performed for a relatively large sample of obstructive sleep apnea patients. These observations suggest that (a) the site of upper airway occlusion may be oropharyngeal, hypopharyngeal, or both; (b) upper airway dynamics appear to be consistent within a given patient and variable among patients; and (c) a passive mechanism results in occlusion rather than active muscular contraction. Somnofluoroscopy is a relatively simple procedure that may be helpful in the selection of treatment for individual sleep apnea patients.

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.

Sleepiness/alertness on a simulated night shift following sleep at home with triazolam.

Physiological sleep tendency during a simulated night shift schedule was examined in 15 middle-aged subjects following daytime sleep after administration of triazolam or placebo. A double-blind, counterbalanced, crossover design involving two tours of five laboratory nights and four daytime home sleep periods was used. Triazolam lengthened daytime sleep as measured by wrist actigraph and improved nighttime alertness as measured by the MSLT. Sleepiness was most profound during the early morning hours (0430 to 0630) but improved significantly across nights for both conditions. Repeated test of sustained wakefulness latencies and simulated assembly line task performance decreased slightly across the night, but there were no significant condition effects. Subjective data tended to support objective measures, although Stanford Sleepiness Scale ratings indicated that subjects did not perceive improved alertness at night after triazolam-aided daytime sleep.

Trends in the pharmacologic treatment of insomnia.

Data from the National Disease and Therapeutic Index for the time period 1987-1991 (IMS, America) were examined for recent trends in the pharmacologic treatment of insomnia. All medications given with the desired action of promoting sleep or sedation at night were categorized as benzodiazepine hypnotics, benzodiazepine nonhypnotics, antidepressants, or other. From 1987 to 1991, the following trends were found: (1) overall pharmacologic treatment for insomnia decreased by approximately 10%, (2) use of benzodiazepine hypnotics fell about 30% during this time period, (3) use of antidepressants for insomnia increased by 100%, and (4) the noted changes were somewhat stronger for institutionalized patients than for ambulatory patients. These changes in the pharmacologic treatment of insomnia may be related to widespread media attention and are not supported by scientific data.

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.