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.

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.

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.

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.

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.

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.

Simulated assembly line performance following ingestion of cetirizine or hydroxyzine.

Twelve healthy subjects participated in three daytime work periods, in a double-blind repeated measures Latin square design. Subjects received cetirizine (10 mg), hydroxyzine (25 mg), or placebo at 0800. Performance was measured each day during eight 50-minute test periods on a simulated assembly line task between 0830 and 1700. Before entry into the study, subjects were trained to a minimum 80% correction rate on the performance task. Performance decrements were consistently associated with hydroxyzine but not with cetirizine. Subjects made fewer correct responses with hydroxyzine compared with both cetirizine and placebo. Subjectively, participants reported feeling sleepier and performing worse during the hydroxyzine condition than following placebo. Cetirizine, however, did not differ from the other two conditions on self-assessments of alertness or performance. These findings support the hypothesis that objective measures of human functioning are more specific than are subjective measures.

Sedative effects of ethanol at night.

The sedative effect of 0.7 g/kg of 100% ethanol, ingested at 9:30 PM, was investigated to examine the combined effects of ethanol and circadian sleepiness/alertness levels. Fourteen healthy young adults participated in a placebo-controlled, double-blind crossover design. Each subject, on two separate occasions (placebo or ethanol), completed multiple sleep latency testing and the repeated test of sustained wakefulness as objective measures of physiological sleep tendency, and completed the Stanford Sleepiness Scale as a measure of subjective sleepiness. The results indicate that a moderate dose of ethanol significantly increases physiological sleepiness during early morning hours even in individuals that are relatively alert at these times. Therefore, the marked reduction in alertness and related performance deficits that normally occur at night are worsened by ethanol ingestion. Sleepiness, due to any cause, and ethanol may well be a dangerous combination.

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.

Transient insomnia associated with a 3-hour phase advance of sleep time and treatment with zolpidem.

A 3-hour phase advance of sleep time was employed to produce a model of transient insomnia. The degree to which this manipulation was effective varied substantially among young, healthy normal sleepers. Zolpidem, an imidazopyridine hypnotic compound, was effective in reversing the sleep disruption in those individuals displaying transient insomnia in this model.

Effect of caffeine on physiological sleep tendency and ability to sustain wakefulness at night.

Marked sleepiness occurs during typical night shift work hours and this reduced alertness is associated with marked performance deficits. The effect of caffeine (versus placebo) upon sleepiness at night was studied using objective measures of physiological sleep tendency and ability to sustain wakefulness. Both measures show caffeine to reduce sleepiness at a single dose roughly the equivalent of two to four cups of coffee. Despite impressive objective differences in alertness with caffeine, subjects did not consistently differentiate between drug conditions on subjective alertness assessments. The use of CNS stimulants to promote alertness during night shift hours should be considered, particularly for occupations for which alertness is critical.

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.

Management of obstructive sleep apnea: comparison of various treatment modalities.

From July, 1982 through March, 1986, 253 patients with moderate to severe sleep apnea (OSA) were treated and had polysomnographic assessment of treatment. The treatment modalities were: 1. uvulopalatopharyngoplasty (UPP), 2. nasal continuous positive airway pressure (CPAP), 3. tracheostomy, 4. medication (tricyclic antidepressants), 5. tongue retaining device (TRD), and 6. orthodontic device. Uvulopalatopharyngoplasty was performed in 98 patients. The patients were categorized according to post-treatment improvement in the apnea/hypopnea index (A+HI) and severity index (SI) into good, moderate, and poor responders. There were 37 (37.7%) good, 33 (33.6%) moderate, and 28 (28.5%) poor responders in this group. Twenty-four patients underwent tracheostomy. Eighteen (75%) patients continue to have their tracheostomies without complications (mean follow-up time 32 months). One hundred thirty-eight patients were evaluated with CPAP. Of the 100 patients who began home CPAP use, 53 continue to use CPAP successfully at 18 months. Medical treatment (tricyclic antidepressants) was used in 35 patients. The response to this modality was generally poor. Six patients were fitted with TRD. The compliance to this device was poor, although two have had significant improvement in their apnea. An orthodontic appliance was used in two patients with one responding successfully.

Further evaluation of uvulopalatopharyngoplasty in the treatment of obstructive sleep apnea syndrome.

Since its introduction in 1981 uvulopalatopharyngoplasty (UPPP) has become an alternative surgical approach to permanent tracheostomy in treating obstructive sleep apnea (OSA). However, the criteria for selecting candidates for this procedure are unclear and the prediction of a positive response remains an enigma. This article presents the experience with UPPPs performed on 35 patients who had moderate to severe OSA. Criteria for patient selection included apnea severity, cardiopulmonary sequelae, and clinical symptomatology. All but two patients demonstrated clinical improvement, although there was considerable variability in the degree of response. Patients were classified as good or poor responders on the basis of the severity index (SI), which represents the number of apneas and hypopneas per hour of sleep resulting in oxygen saturation below 85%. A greater than 50% improvement in the SI was considered a good response. Twenty-three patients (65.7%) were good responders and the remaining 12 (34.3%) were poor responders. The need for permanent tracheostomy was obviated in 16 of 32 patients presenting with disabling daytime sleepiness or severe cardiopulmonary sequelae. Therefore it appears that UPPP is useful for treating most OSA patients.

Relationship of ventricular ectopy to nocturnal oxygen desaturation in patients with chronic obstructive pulmonary disease.

Sudden death and oxyhemoglobin desaturation are known to occur during sleep in patients with chronic obstructive pulmonary disease. The present study was undertaken to determine the frequency with which nocturnal oxygen desaturation promotes an increase in ventricular ectopic activity, since such a relationship could represent a potential pathophysiologic mechanism for sudden death during sleep. Forty-two clinically stable subjects with moderately severe obstructive airways disease, mean ratio of one-second forced expiratory volume to forced vital capacity = 51 +/- 12 percent, underwent overnight polygraphic sleep study. Oxyhemoglobin saturation was monitored by ear oximetry, and electrocardiographic leads CC5 and CM5 were employed for arrhythmia detection. Premature ventricular complexes were detected in 27 (64 percent) of the subjects and were complex (multifocal, repetitive, or both) in 17. No significant relationship between premature ventricular complex frequency and arterial oxygen saturation was detected for the group as a whole. In part, this result can be attributed to the relatively mild hypoxemic stress experienced by the 22 subjects in whom arterial oxygen saturation remained greater than 80 percent. In contrast, six (30 percent) of the 20 patients who had desaturation to less than 80 percent showed a greater than 150 percent increase in premature ventricular complex frequency with oxygen desaturation. These results suggest that nocturnal hypoxemia, if of sufficient magnitude, is capable of increasing ventricular ectopy during sleep in a substantial number of patients with chronic obstructive pulmonary disease.

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.

Myocardial stress. Exercise versus sleep in patients with COPD.

Epidemiologic investigation has revealed that patients with pulmonary disease are at increased risk of dying during the early morning hours. To provide a pathophysiologic explanation for these excessive nocturnal mortality statistics, we tested the hypothesis that episodes of arterial O2 desaturation during sleep can produce as severe a stress on the maintenance of myocardial O2 balance as maximal exercise in patients with chronic obstructive pulmonary disease (COPD). Thirty-one subjects with COPD underwent both overnight sleep and treadmill exercise study to their dyspnea-limited maximum. During both activities, systemic blood pressure was directly recorded and myocardial oxygen consumption (MVO2) estimated from the pulse rate (HR) - systolic blood pressure (SBP) product. Arterial O2 content (CaO2) was calculated from hemoglobin concentration and arterial O2 saturation (SaO2) measured by ear oximetry. Using these data and the Fick principle, myocardial blood flow (MBF) was continuously estimated during both exercise and sleep. During sleep, mean SaO2 was 88 +/- 7 percent while the average of the lowest SaO2 recorded for each subject was 71 +/- 14 percent. Episodes of nocturnal oxyhemoglobin desaturation produced consistent elevations in SBP frequently accompanied by an increase in HR. Because this hemodynamic response resulted in increased MVO2 at precisely the times when arterial O2 contents were low, high demands for MBF were generated. The average of the highest individual values for MBF during sleep was 244 +/- 144 (ml/100 g LV/min). This value was not significantly different from the value of MBF = 281 +/- 91 (ml/100 g LV/min) determined for maximal exercise. This finding suggests that the demand for coronary blood flow during episodes of nocturnal hypoxemia can be transiently as great as during maximal exercise in patients with COPD.