Hyperarousal in insomnia and hypnotic dose escalation.

BACKGROUND: Given concerns about the abuse liability of hypnotics, this study assessed hyperarousal in people with insomnia and its relation to hypnotic self-administration over 12 months of nightly hypnotic use. METHODS: Ninety-five subjects with insomnia (age 32-64 years) underwent screening nocturnal polysomnogram (NPSG) and Multiple Sleep Latency Test (MSLT) the following day and, then, were randomized to receive zolpidem 10 mg or placebo nightly for 12 months. NPSGs and MSLTs were conducted and urine was collected (0700-1500 h) and analyzed for norepinephrine (NE) levels during months one and eight on study medication. A subset (n = 54) underwent hypnotic self-administration assessments in months one, four, and 12. RESULTS: Mean daily sleep latency on screening MSLT was distributed across the full range of MSLT latencies (2-20 min). The highest screening MSLT latencies were detected in subjects with higher NE levels, compared to those with the lowest MSLT latencies. In the subset undergoing self-administration assessment, those with the highest MSLT latencies chose more capsules (placebo and zolpidem) and increased the number of capsules chosen in months four relative to month one, compared to those with the lowest MSLT latencies. CONCLUSIONS: These data show that some insomniacs are hyperaroused with high MSLT/NE levels and, compared to low MSLT/NE insomniacs, they increase the number of capsules (zolpidem and placebo) self-administered on months four and 12 relative to Month one.

Effects of rapid versus slow accumulation of eight hours of sleep loss.

The present study assessed alertness, memory, and performance following three schedules of approximately 8 hr of sleep loss (slow, intermediate, and rapid accumulation) in comparison to an 8-hr time in bed (TIB) sleep schedule. Twelve healthy individuals aged 21-35 completed each of four conditions according to a Latin Square design: no sleep loss (8-hr TIB for 4 nights; 2300-0700), slow (6-hr TIB for 4 nights; 0100-0700), intermediate (4-hr TIB for 2 nights; 0300-0700), and rapid (0-hr TIB for 1 night) sleep loss. On each day, participants completed a multiple sleep latency test (MSLT), a probed-recall memory task, a psychomotor vigilance task, a divided attention task, and the Profile of Mood States. "Rapid" sleep loss produced significantly more impairment on tests of alertness, memory, and performance compared to the "slow" accumulation of a comparable amount of sleep loss. The impairing effects of sleep loss vary as a function of rate, suggesting the presence of a compensatory adaptive mechanism operating in conjunction with the accumulation of a sleep debt.

Scoring reliability of the multiple sleep latency test in a clinical population.

STUDY OBJECTIVES: To determine intrarater and interrater scoring reliability of the multiple sleep latency test (MSLT) in a population of sleep clinic patients. DESIGN: N/A. SETTING: Urban sleep center. PATIENTS: 200 consecutive sleep center patients (diagnoses included: obstructive sleep apnea, narcolepsy, periodic-limb-movement, and individuals with no diagnosis). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: MSLTs were recorded and scored according to standard clinical procedures. One of four clinical polysomnographers and one of seven polysomnographic technologists scored each MSLT. All MSLTs were then rescored by the same polysomnographer. The intrarater reliability coefficient for mean MSLT score was .87 and interrater reliability was .90. Coefficients for the mean number of REM onsets during the MSLT were .81 for intrarater and .88 for interrater reliability. Intrarater and interrater agreement (kappa coefficients) for the presence of at least one REM onset during the MSLT was .78 and .86, respectively. For the presence of greater than one REM onset, a kappa of .78 was obtained for intrarater agreement and .91 for interrater agreement. CONCLUSIONS: The clinical MSLT displays excellent interrater and intrarater reliability estimates for both sleep latency and REM onset scores in a sleep-disordered population.

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.

Electrophysiological assessment (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in humans.

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal-sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low-dose stimulant drugs, the stimulatory effect of ethanol was mild.

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.

Etiologies and sequelae of excessive daytime sleepiness.

Excessive daytime sleepiness (EDS), the primary complaint of patients seen in sleep clinics, affects up to 12% of the general population. The effects of EDS can be debilitating and even life threatening. Patients with EDS may exhibit psychosocial distress, decreased work or school performance, and increased risk for accidents. The differential diagnosis of EDS requires objective assessments, such as polysomnography and the Multiple Sleep Latency Test. There are four major causes of EDS: (1) central nervous system (CNS) pathologic abnormalities, such as narcolepsy and idiopathic CNS hypersomnia; (2) qualitative or quantitative sleep deficiencies, such as sleep apnea and insufficient nocturnal sleep; (3) misalignments of the body's circadian pacemaker with the environment (eg. jet lag or shift work); and (4) drugs, which can increase sleepiness either therapeutically or as a side effect. Depending on etiology, management strategies for EDS include extension of time in bed, naps, surgery, various medical devices (eg, oral appliances, continuous positive airway pressure), and pharmacotherapy. Pharmacotherapy is generally achieved with stimulants, such as amphetamine sulfate, methylphenidate, and pemoline or newer, safer compounds like modafinil.

The Sleep-Wake Activity Inventory: a self-report measure of daytime sleepiness.

The purpose of this study was to develop a valid multidimensional self-report measure of sleepiness. There were 554 subjects who completed the inventory. The structure of the Sleep-Wake Activity Inventory (SWAI) was derived from principal components analysis. The independent predictive strength of the factors was assessed by forward stepwise regression analysis with the average sleep latency on the Multiple Sleep Latency Test (MSLT) as the dependent variable. The scores on each of the factors were also compared by the level of sleepiness determined by the MSLT (pathological, diagnostic gray area, and normal). Factor analysis showed the existence of six factors on the SWAI (Excessive Daytime Sleepiness [EDS], Psychic Distress, Social Desirability, Energy Level, Ability to Relax and Nocturnal Sleep). The EDS factor was the best predictor of average MSLT. It was also able to differentiate pathological levels of sleepiness from both the diagnostic gray and normal levels of sleepiness. EDS factor scores were sensitive to changes in sleep physiology as improved scores followed normalization of sleep-disordered breathing. The SWAI was shown to be easy to complete, have a multi-dimensional structure, have a EDS factor useful in the prediction of average MSLT scores, be sensitive to differential levels of sleepiness, and change as a result of effective treatment.

Level of sleepiness and total sleep time following various time in bed conditions.

The effects of various time in bed (TIB) conditions on daytime sleepiness and total sleep time (during a 24-hour enforced bedtime) were investigated. Thirty-two healthy male subjects participated in the study. Subjects were assigned to one of four groups to balance average screening multiple sleep latency tests (MSLT). Subjects were randomly assigned to spend 8, 6, 4 or 0 hours time in bed. They underwent the same TIB condition twice with at least 7 days between the two sessions. Following their assigned time in bed conditions, subjects were counterbalanced to have a standard MSLT and a 24-hour enforced bedtime protocol. To assess the effect of TIB on the MSLT, the sleep latencies were submitted to a four (TIB condition) by four (nap test) multivariate analysis of variance. The sleep latencies were shorter for those subjects in the 0-hours condition when compared to the other three conditions. Also, the sleep latencies of those subjects in the 4- and 6-hour conditions were comparable but different from those of subjects in the 8- and 0-hour TIB conditions. To assess the effect of TIB on the 24-hour enforced bedtime, the total sleep time during this period was submitted to a six (4-hour block) by four (TIB condition) multivariate analysis of variance. Subjects slept more following 0 hours TIB when compared to the other three conditions. There were no statistically significant differences between the 8-, 6- and 4-hour TIB conditions. Across conditions, subjects slept more during the first 4 hours when compared to blocks 2, 3, 4 and 5. Blocks 1 and 6 were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Issues in drug-related performance impairment.

Performance impairment associated with alcohol, drugs, and medical disorders is of increasing concern to clinicians. Understanding and assessing performance impairment associated with a particular drug or condition is complex and requires careful, critical evaluation of the literature. Awareness of the issues involved enhances the ability of the clinician to assess risks for a given patient and of a given medical therapy. Important study variables are described that should be considered when evaluating the literature pertaining to performance impairment. The clinical relevance of the results of performance studies is also discussed.

Long-term study of the sleep of insomnia patients with sleep state misperception and other insomnia patients.

OBJECTIVE: The objectives were 1) to investigate differences among patients with subjective insomnia (sleep state misperception), patients with objective findings of insomnia, and normal volunteers and 2) to assess the consistency of the sleep findings during a 2-month period. METHOD: Twenty-one subjects were studied. Subjects with sleep state misperception (N = 7) had insomnia complaints for more than 1 year, no objective sleep disturbance, and sleep efficiency of 90% or greater (on the diagnostic screening sleep recording), while subjectively estimating that sleep time was less than 6.5 hours. Subjects with objective insomnia (N = 7) met the same subjective criteria, but objectively sleep efficiency was 85% or less. Normal subjects (N = 7) had no insomnia complaints and objective sleep efficiency of 90% or greater. All subjects were recorded on 2 consecutive nights three times with a 3-week period between each pair of nights (6 standard all-night polysomnographic sessions of 8 hours). A subjective sleep questionnaire was administered after each sleep recording night. RESULTS: Sleep stage variables (percentages) were similar between the two insomnia groups, and both were different from the normal subjects. Sleep continuity variables were disturbed in the objective insomnia group, but they were similar in the sleep state misperception and normal groups. Both insomnia groups rated their sleep as inadequate on the questionnaires and differed from the normal subjects. The distinct sleep patterns of each of the three groups did not vary over the 6 nights of assessment. CONCLUSIONS: Sleep state misperception may be a prodromic or transitional state of sleep dysfunction between normal sleep and the sleep pattern of objective insomnia.

Biperiden administration during REM sleep deprivation diminished the frequency of REM sleep attempts.

Sixteen subjects were assigned to a group using either placebo or biperiden, with eight subjects in each group. Both groups were studied for one acclimatization night, one baseline night, four nights of rapid eye movement (REM) sleep deprivation and two recovery nights. All the subjects received either placebo or 4 mg biperiden 1 hour before sleep during the four nights of REM sleep deprivation. During the baseline and the recovery nights both groups received placebo capsules. The results showed that REM sleep time during the REM sleep deprivation was reduced by 70-75% below the baseline night in both groups. The number of attempts to enter REM sleep was significantly reduced by biperiden as compared to placebo for each of the four REM sleep deprivation nights. Because the total sleep time in the biperiden group was reduced, the number of REM sleep attempts was corrected by the total sleep time. The adjusted number of REM sleep attempts was also significantly reduced in the biperiden group. REM sleep latency showed a reduction in the placebo group, whereas in the biperiden group REM sleep latency was unchanged throughout the deprivation nights. In the recovery night REM sleep time was increased in both groups, with no differences between the groups. The REM sleep latency showed a reduction in the first recovery night in both groups that persisted through the second recovery night. The above findings support the role of biperiden as a REM sleep suppressive drug.

Issues in the use of benzodiazepine therapy.

In selecting a hypnotic for the symptomatic management of insomnia, clinicians should look for those that most favorably balance sleep induction and sleep maintenance with potential adverse side effects. While all benzodiazepines have demonstrated efficacy in nocturnal sedation, the side effects of different compounds--and different doses of the same compound--vary greatly. The most common adverse effects associated with benzodiazepines are residual sedation, anterograde amnesia, and rebound insomnia, which are also related to the insomnia complaint itself. Therefore, careful evaluation of the dose of a benzodiazepine hypnotic is the key to effective treatment of insomnia without inducement of adverse effects. The most common side effects of hypnotics and their relation to drug dose are reviewed.

Enforced 24-hour recovery following sleep deprivation.

The pattern of recovery sleep after sleep deprivation was investigated in healthy young adults. Six subjects experienced three experimental conditions (0, 24, and 48 hr sleep deprivation) in a Latin Square design. The recovery period consisted of a 24-hr enforced time in bed during which subjects were polysomnographically recorded beginning at 0800. To assess the differential effects of the deprivation conditions, the total sleep time on the 24-hr recordings was submitted to a six (4-hr block) by three (deprivation condition) multivariate analysis of variance. Subjects slept more following the 24- and 48-hr conditions when compared to the 0-hr condition. Across conditions, subjects slept more during the first 4 hr when compared to the remaining five blocks. Importantly, there was a significant interaction of sleep deprivation by 4-hr block. In block 1 sleep was differentially recovered between each condition with more sleep being recorded following longer hours of deprivation. In block 2 subjects in the 24- and 48-hr conditions slept comparable amounts and significantly more than those in the 0-hr condition. In blocks 3 and 4 only the 48-hr condition exhibited significantly more sleep than the 0-hr condition. However, significantly less sleep was found in block 6 following the 48-hr condition. Overall, subjects recovered 72% and 42% of the total amount of sleep lost during the 24- and 48-hr conditions, respectively.

HLA DR2 in narcolepsy with sleep-onset REM periods but not cataplexy.

To determine the association of HLA DR2 in patients with narcolepsy without cataplexy, a case-control study was performed. Patients receiving the diagnosis of narcolepsy without cataplexy had excessive daytime sleepiness (EDS) and polysomnographic findings consistent with narcolepsy but no clinical evidence of cataplexy. Of 28 patients identified, 12 agreed to return for HLA typing. Respondents did not differ from nonrespondents in demographic, clinical, or sleep laboratory data. The comparison group was 503 individuals, those 30 years and older, on the Michigan Kidney Transplant Registry. The odds ratio obtained from logistic regression indicated a strong association between narcolepsy without cataplexy and HLA DR2. To control for potential confounding variables, multivariate models were constructed to explore the joint effects of HLA DR2 and each one of the covariates (age, sex, and race), their possible combinations, and the effect of all three covariates. The odds ratios decreased minimally and the association between the disease and HLA DR2 remained significant.

A review of the safety profiles of benzodiazepine hypnotics.

Although over 20 years of clinical experience with benzodiazepine hypnotics have demonstrated their relative safety, flurazepam, temazepam, triazolam, and quazepam do not have identical safety profiles. Dose-related central nervous system (CNS) depression such as daytime sedation and psychomotor impairment may be expected because they are an extension of the therapeutic action of these agents. Therefore, drug dose is an important factor in determining the expected frequency and severity of these side effects. Also, it is important for a clinician not to assume that these unwanted CNS effects relate only to the length of a drug's half-life. Half-life does appear to be an important determinant of the presence or absence of rebound insomnia.

Subjective and polysomnographic characteristics of patients diagnosed with narcolepsy.

In order to better characterize the subjective and polysomnographic findings in patients with narcolepsy, a follow-up questionnaire was mailed to all patients diagnosed with the disorder at the Henry Ford Hospital Sleep Disorders and Research Center. The questionnaire inquired regarding the present, previous, and change in status for the constellation of narcolepsy symptoms. Memory problems, problems of daytime function, and nocturnal sleep disturbance were included among the questions related to the symptomatic constellation. By definition, all patients were symptomatic of daytime sleepiness and were diagnosed with narcolepsy only if there were two or more rapid eye movement (REM) onsets documented on the polysomnographic evaluation. A high percentage of patients reported nocturnal sleep disturbance, which was one of the symptoms with the latest reported onset. Retrospective comparison of questionnaire responses to the clinical polysomnography revealed significantly more sleep maintenance difficulties in the group of patients reporting this symptom on the questionnaire. Patients with disturbed nocturnal sleep reported taking more naps during the day, although the Multiple Sleep Latency Test (MSLT) failed to show differences in sleep latency. Interestingly, this group of patients was found to have a significantly higher number of sleep onset REM episodes on the MSLT. Finally, the findings are discussed as they compare to studies that required the presence of cataplexy as part of their inclusion criteria.