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The most thorough and clinically relevant approach to hypnotic drug evaluation is one that balances the strengths and weaknesses of clinical trials and sleep laboratory evaluations. Advantages of clinical trials include the ability to evaluate large numbers of subjects and specific target groups and to thoroughly assess and quantify a drug's side effects, whereas sleep laboratory studies are very limited in all of these areas. Sleep laboratory studies however provide a rigorous, precise, and comprehensive profile of a drug's activity since there is more control over experimental variables and measurements are objective as well as continuous throughout the night. These benefits offset the shortcomings of clinical trials, which include a lack of objective measurements, less control over experimental variables, failure to evaluate a drug's effectiveness with continued use, and inattention to drug interaction and withdrawal effect. Several basic principles derived from sleep laboratory findings have been incorporated into both the clinical trials and sleep laboratory evaluations recommended in the new FDA Guidelines for the Clinical Evaluation of Hypnotic Drugs. These principles include provision for adequate baseline and withdrawal periods, use of multiple consecutive drug nights to assess a drug's effectiveness with continued use, and inclusion of an adequate washout period when a cross-over design is used. The guidelines do not emphasize either clinical trials or sleep laboratory studies at the expense of each other, but rather stress their complementary utilization.

This is the first controlled study to show a lack of relation between a positive history of sleepwalking or night terrors in adults and daytime EEG abnormalities. We recorded a standard clinical EEG on 35 adult sleepwalkers (SW), 35 adult night terror patients (NT), and 35 control subjects (CS). Three subjects in the SW group showed abnormalities: one during both the resting record (RR) and hyperventilation (HV), and two only during HV. None in the NT group showed any EEG abnormality. Two control subjects showed abnormalities of both RR and HV, and a third only during HV. The number of abnormal EEGs within each group was limited, and the three groups did not significantly differ from one another. Our results suggest that the daytime clinical EEG is of limited value in evaluating adults with the primary complaint of sleepwalking or night terrors. However, further all-night sleep EEG studies utilizing clinical montage are needed to investigate the temporal relationship of sleepwalking and night terror events to possible EEG abnormalities.

Fifty adults with either a present or past complaint of somnambulism were evaluated to determine the development and clinical course of their disorder as well as their personality patterns. Generally, when sleepwalking was outgrown, its onset was before age 10 years and its termination before age 15 years. Current sleepwalkers, compared with past sleepwalkers, started sleepwalking at a later age, had a higher frequency of events, and had episodes earlier in the night. Their episodes were also characterized by more intense clinical manifestations. Furthermore, current sleepwalkers demonstrated high levels of psychopathology, whereas past sleepwalkers had essentially normal psychological patterns. Specifically, the current sleepwalkers showed active, outwardly directed behavioral patterns, suggestive of difficulties in handling aggression. The clinical application of these findings is discussed and practical recommendations are given for the evaluation and management of sleepwalking.

The development and clinical course of night terrors and the personality patterns of patients with this disorder were evaluated in 40 adults who had a current complaint of night terrors. Compared with a group of adult sleepwalkers, the patients with night terrors had a later age of onset for their disorder, a higher frequency of events, and an earlier time of night for the occurrence of episodes. Both groups had high levels of psychopathology, with higher values for the night terror group. This sleepwalkers showed active, outwardly directed behavioral patterns, whereas the night terror patients showed an inhibition of outward expressions of aggression and a predominance of anxiety, depression, tendencies obsessive-compulsive/, and phobicness. Although night terrors and sleepwalking in childhood seem to be related primarily to genetic and developmental factors, their persistence and especially their onset in adulthood are found to be related more to psychological factors.

Nine patients with the Prader-Willi syndrome, ranging in age from 3 to 21 years, were examined clinically as well as studied in the sleep laboratory. They had striking disturbances of sleep-wakefulness patterns. All patients except one had the symptom of excessive daytime sleepiness. The most striking finding was the presence in five patients of rapid-eye-movement (REM) sleep occurring at sleep onset (SOREM). None of the patients had the condition of sleep apnea. One patient, however, demonstrated severe hypoventilation during REM sleep; the lowest value recorded for O2 saturation was 40%, with a consistent value below 50% for as long as ten to 15 minutes. Previous findings have indicated that the Prader-Willi syndrome is of hypothalamic origin. We hypothesize that both the SOREM and O2 desaturation findings in our patients with the Prader-Willi syndrome are also a result of hypothalamic changes.

DSM-III diagnoses were established for 100 patients with chronic insomnia. Principal and additional diagnoses on axis I and II (psychiatric and personality disorders) were extremely prevalent. Only five patients had a principal diagnosis on axis III (physical disorders). The most common diagnoses on axis I were dysthymic, anxiety, somatoform, and substance use disorders. Compulsive personality disorder or trait was the most common axis II diagnosis. Ninety-five patients had multiple diagnoses. This study confirms that patients with chronic insomnia have a high prevalence of psychopathology and characteristic internalizing patterns of anxiety, depression, obsessive-compulsiveness, phobia, and excessive somatic concerns.

Sleep and wakefulness patterns in daytime naps of 50 patients with narcolepsy/cataplexy were compared with those of 50 controls. Each subject was monitored polygraphically during 2 one-hour nap periods. A sleep-onset REM period in either of the 2 daytime naps was observed to have a higher diagnostic sensitivity (78%) than an abnormally shortened sleep latency (68%). However, the specificities of a sleep-onset REM period (88%) or abnormally shortened sleep latency (90%) were quite similar. When the occurrence of either a sleep-onset REM period or a shortened sleep latency was evaluated in either of the two naps, the overall sensitivity was increased to 84% while the specificity was decreased only to 80%. The limitations of and indications for the use of testing for sleep and REM latencies in the diagnosis of narcolepsy in clinical practice are discussed.

Following abrupt withdrawal of five benzodiazepine hypnotics, the presence of rebound insomnia on individual subject nights was evaluated in comparison to a placebo group. During the first three nights of withdrawal, the frequency of occurrence of rebound insomnia for drugs with relatively rapid rates of elimination (triazolam, midazolam, and lormetazepam) was significantly higher than that for the placebo control group. In contrast, the frequency of withdrawal sleep difficulty for two slowly eliminated hypnotics (flurazepam and quazepam) was similar to that of the placebo control group during each of five successive three-night segments of a 15-night withdrawal period. These findings, based on individual subject-night data, confirm and extend previous reports using group mean values that demonstrate a frequent, immediate, and intense degree of rebound insomnia following abrupt withdrawal of relatively rapidly eliminated hypnotic drugs and an infrequent, delayed, and milder degree of sleep difficulty following withdrawal of slowly eliminated drugs.

Although the initial sleep disorders classifications provided a framework for categorizing diagnoses, these early instruments had a number of limitations. Among their shortcomings were a lack of specific diagnostic criteria, limited clinical validation, and an overreliance on sleep laboratory findings. As a result, many of the diagnoses were not only poorly substantiated, but they lacked clinical relevance. Also, because of a fusing of diagnoses, a causal relationship was implied that may have been nonexistent and could misdirect the treatment focus. The ICD-10 represents a clinically based diagnostic classification. Furthermore, this classification system includes diagnostic criteria and encourages multiple diagnoses for a more complete description of the patient's clinical presentation. In addition, the ICD-10 allows for differentiation of psychogenic, developmental, and organic factors. Finally, it can be fully applied in the office setting, which allows physicians to maximize their interviewing and assessment skills to complete the diagnoses and subsequent treatment plans. Thus, this classification system strongly reinforces the doctor-patient relationship. It also facilitates consideration of the entire scope of the patient's problems in a truly biopsychosocial perspective. The prevalence of insomnia ranges across studies from 20 to 30% of the adult population. Before adulthood, its prevalence is below 2%. About 5% of adults complain of excessive daytime sleepiness. Among the conditions of excessive daytime sleepiness, narcolepsy has a prevalence of 0.1% and sleep apnea not more than 1% in the general adult population. Nightmares have a prevalence of about 5% in adulthood and 20% in childhood. Sleepwalking and night terrors have a prevalence of less than 1% in adulthood and 15 and 5%, respectively, in childhood.(ABSTRACT TRUNCATED AT 250 WORDS)

This is a summary of research studies indicating a primary role of psychotherapy in the etiology of certain sleep disorders. Thus, chronic insomnia is associated with high levels of psychopathology and a personality profile characterized by internalization of emotions. Also, a greater number of stressful life events occurs at the year of onset of insomnia. Two additional sleep disorders (sleep-walking and night terrors in adults) are similarly associated with high levels of psychopathology. Although these two disorders share many common clinical and psychopathological characteristics, their psychological profiles and psychopathological correlates differ considerably. Sleepwalkers show a high incidence of personality disorders with generally active, outward behavioral patterns, whereas night terror sufferers are mostly anxious, depressed and phobic with an inhibition of outward expression of aggression. Based on these research findings a series of therapeutic recommendations is presented for the effective management of patients with insomnia, sleepwalking or night terrors.

The development, clinical course, and electrophysiologic characteristics of narcolepsy were evaluated in 50 adults who had a current complaint of sleep attacks and cataplexy. In most of the patients, the first symptoms, usually excessive daytime sleepiness and sleep attacks, developed during childhood or adolescence. The condition was invariably chronic. Patients frequently had family histories of some disorder of excessive daytime sleepiness. In nocturnal sleep or daytime nap recordings, all but three of the patients demonstrated a rapid-eye-movement (REM) period at sleep onset. Sleep apnea was found in only one patient. Our findings indicate that sleep laboratory recordings to detect a sleep-on-set REM period are of little diagnostic value when the narcoleptic patient has cataplexy. Furthermore, narcoleptic patients require sleep laboratory evaluation for sleep apnea only when the presence of apnea is suggested by the sleep history.

The percentage of subjects with sleep apneic activity was significantly greater in a group of 60 healthy subjects who were 50 yr and older compared with a control group of 69 subjects who were younger than 50 yr. Sixteen of the older subjects (26.7%) and six of the younger subjects (8.7%) met the criteria for sleep apneic activity, i.e., 3-29 episodes per night. However, only one of the older subjects (1.7%) had enough sleep apneic activity (30 or more episodes in a night) to meet the definition of the condition of sleep apnea. In both age groups, sleep apneic activity (SAA) was slightly more prevalent in males than females. Older subjects with SAA were not significantly heavier than those without SAA but were so when compared with the younger subjects with SAA. In the 29 older subjects for whom hemoglobin O2 saturation (Sao2) was recorded, those with SAA had a significantly lower mean minimum Sao2 value (87%) than those without (92%).

The emotional and psychosocial correlates of narcolepsy were evaluated in 50 adults who had a current complaint of sleep attacks and cataplexy. The psychosocial consequences of narcolepsy were extensive; most patients reported that the condition seriously affected their interpersonal, marital, work, and social relationships. Many of these consequences were caused by others' misunderstanding of the symptoms of the disorder, which resulted in negative attitudes toward the patients. Th narcoleptic patients showed high levels of psychopathology compared with controls, but this difference is considered to be primarily a reaction to the disorder and its effects. The narcoleptic patients were overly concerned with emotional control, which appeared to lead to their generalized lack of expressiveness and tendency to build up emotional pressure. Based on these findings, recommendations are given for the psychosocial management of the narcoleptic patient.

In taking a sleep history, the physician determines the onset, course and clinical characteristics of the disorder; assesses the 24-hour sleep/wakefulness patterns; obtains additional information from the bed partner, and inquires about a personal or family history of other sleep disorders. The impact of the disorder on the patient's life is evaluated, and the attitudes of the patient and his family toward the sleep problem are assessed.

Two benzodiazepine hypnotics, one with an intermediate elimination t1/2 (temazepam, 15 mg) and the other with a long t1/2 (quazepam, 15 mg), were evaluated in 22- night sleep laboratory studies. The effectiveness and side effects of these benzodiazepines were assessed during short- and intermediate term use. Subjects were also assessed for the presence of rebound insomnia after abrupt withdrawal. Quazepam, 15 mg, was significantly effective in improving sleep both with short- and intermediate-term use, but the effectiveness of temazepam was considerably less. Although temazepam was effective for maintaining sleep with short-term use, there was rapid development of tolerance for this effect with intermediate-term use. Temazepam did not produce any behavioral side effects during either drug condition. The only side effect associated with quazepam was a significant degree of daytime sleepiness. After its withdrawal, temazepam was associated with some sleep and mood disturbance on the first withdrawal night, whereas quazepam had carryover effectiveness.

Ten of 114 psychiatric patients undergoing combined lithium-neuroleptic treatment exhibited somnambulistic-like episodes. These episodes are differentiated from nocturnal wanderings and epileptic attacks during sleep; they occurred within two to three hours after sleep onset and were characterized by the patients appearing confused and walking about in a quiet, detached and clumsy manner. Generally, there was amnesia for the event. Since sleepwalking occurs out of slow wave sleep, the increase in slow wave sleep induced by lithium and certain neuroleptics may represent a neurophysiological mechanism responsible for these patients' somnambulistic behaviour. The occurrence of grand mal seizures in two patients was probably unrelated to the somnambulistic-like episodes. However, persistence of the latter appears to be associated with drug-induced EEG irregularity.

A sleep laboratory hypnotic drug evaluation study was conducted in which 2 mg flunitrazepam, a benzodiazepine with a half life of intermediate duration, was administered nightly to 6 insomniac subjects for 4 consecutive weeks. The drug was effective with short-term use. However, tolerance developed for sleep maintenance during the intermediate- and long-term drug administration periods. Following drug withdrawal, a significant worsening of sleep above baseline levels occurred. These data are consistent with our previous findings of rebound insomnia following withdrawal of short- and intermediate-acting benzodiazepines.

The authors determined the prevalence of sleep disorders in a general population through a survey of 1,006 representative households in the Los Angeles metropolitan area. They found an overall prevalence of current or previous sleep disorders in adults of 52.1%. Specifically, they found a 42.5% prevalence of insomnia, 11.2% of nightmares, 7.1% of excessive sleep, 5.3% of sleeptalking, and 2.5% of sleepwalking. These conditions were often chronic and usually started early in life. Insomnia was more frequent in older people, particularly older women, and in people of lower educational socioeconomic status. Insomnia, nightmares, and hypersomnia were correlated with more frequent general physical and mental health problems.

Rebound insomnia and rebound anxiety are clinical conditions related to withdrawal of certain benzodiazepine drugs. Numerous studies of benzodiazepine and nonbenzodiazepine hypnotics conducted in our sleep laboratory demonstrated that rebound insomnia developed following withdrawal from benzodiazepines with a rapid or intermediate elimination rate. Several studies conducted by other investigators also indicated the development of rebound insomnia under similar conditions. Rebound insomnia and rebound anxiety are discussed in terms of their interrelationship, clinical implications, and receptor mechanisms. Evidence suggests that drugs producing rebound insomnia and rebound anxiety also show a more rapid development of tolerance and greater potential for drug dependence than benzodiazepines where the parent compound or its metabolites have a long elimination half-life.

Sleep stages and release patterns for growth hormone (GH), luteinizing hormone (LH) and prolactin were evaluated in two subjects during a three week period in which flurazepam 30 mg was administered nightly. Sleep stages were monitored throughout the placebo-baseline, drug and placebo-withdrawal conditions. Blood samples were obtained on nights three and four of baseline, after two and three weeks of drug administration and following extended drug withdrawal. In both subjects, flurazepam produced a marked suppression in stages 3 and 4 (slow wave) sleep which was maintained throughout the drug administration period. Following withdrawal, there was a slight increase in slow wave sleep above baseline levels. With all three hormones, no clear cut changes were observed in mean nightly output, pulse amplitude and pulse frequency from baseline to the drug and the withdrawal conditions. Thus, the decrease in slow wave sleep produced by administering flurazepam 30 mg was not accompanied by any clear cut changes in GH, LH or prolactin.

Lormetazepam, an investigational hypnotic, was evaluated for efficacy and withdrawal phenomena in doses of 0.5, 1.0, 1.5, and 2.0 mg in four separate sleep laboratory protocols, each including four placebo baseline nights, seven drug nights, and three placebo withdrawal nights. A moderate degree of efficacy was shown across the four doses, but this was quite variable. There was no dose-response effect for efficacy for either the first three or last three nights of this short-term administration period. In general, there was less efficacy on the later drug nights, indicating a potential for the development of tolerance over a relatively short period of time. Following drug withdrawal, there was a dose-related worsening of sleep above baseline levels (rebound insomnia). The peak degree of worsening of sleep following drug withdrawal was more than two times greater than the peak degree of improvement of sleep with drug administration.

In treating the symptomatology of patients who are chronically ill, it is likely that the physician will encounter a significant number of patients who have sleep disorders. This article has described an approach for the assessment, differential diagnosis, and clinical management of the most prevalent sleep disorders, which are often chronic in nature and have significant psychosocial or medical consequences for the patient and his or her family. We have emphasized the importance for the physician to complement his general medical and diagnostic skills by taking a careful sleep history from the patient (and, in some instances from the bed partner or caretakers). There is no justification for the physician to routinely request costly sleep laboratory hypnopolygraphic evaluations to screen patients with sleep disorders. However, in those instances where the sleep history is highly suggestive of sleep apnea, a sleep laboratory evaluation is indicated. By incorporating the use of the sleep history in the general evaluation of patients with sleep disorders, the physician is better able to develop rational pharmacologic and non-pharmacologic approaches to managing these patients, including the judicious use of medication as an adjunctive treatment.

Triazolam was administered to five psychiatric inpatients for a two-week period. This period was preceded by a one-week placebo baseline and followed by another week of placebo administration. All conditions were double blind. By the second week of active drug administration, psychopathology greatly intensified across all of the patients with the emergence of anxiety, memory impairment, confusion, paranoid ideation, and hallucinations. The drug-induced behavioral changes persisted during the initial withdrawal period, but then gradually subsided. Also following drug withdrawal, four patients showed a marked worsening of their sleeplessness for several nights.

Diazepam 10 mg was evaluated in a sleep laboratory study of six insomniac subjects. The protocol, which lasted for 18 consecutive nights, including four placebo-baseline, seven drug, and seven placebo-withdrawal nights, allowed for assessment of initial and short-term drug effects, side effects, and any withdrawal effects. With initial drug use, there was a significant improvement in sleep. Further, there was little evidence of tolerance developing at the end of the 1-week drug administration period. During drug administration there was a mild degree of daytime sedation reported. After abrupt termination of diazepam, there was a moderate degree of sleep difficulty on the sixth withdrawal night when total wake time was increased by 34% above baseline (not significant). On other nights, mild withdrawal changes were noted. These findings for the short-term administration and withdrawal of diazepam contrast with those for rapidly eliminated benzodiazepine drugs. The latter are characterized by a rapid development of tolerance and more frequent and intense withdrawal sleep disturbances.

Sleep patterns were evaluated in 100 normal men and women who did not have any complaints of a sleep disorder and who were divided into three broad age groups: 19-29, 30-49, and 50-80 years. Total laboratory recording time was held constant across all four study nights. The amount of nightly wakefulness was positively correlated with age; total wake time for the oldest age group was about two times that of the youngest group, due primarily to an increase in wake time after sleep onset, because sleep latency did not change with age. Within each of the three age groups, especially the two oldest groups, the greatest amount of wakefulness following sleep onset occurred in the final hours of the recording period. Sleep in men was characterized by a higher number of nocturnal awakenings, and in elderly men by a longer final awakening; however, other parameters of sleep efficiency did not differ considerably between the sexes.

Sodium salicylamide in doses of 650 and 1,300 mg was evaluated in two separate sleep laboratory drug evaluation studies of insomniac patients. Each study utilized a standard protocol of 10 consecutive laboratory nights consisting of four placebo nights for adaptation and baseline, three drug nights for short-term drug administration and three placebo nights for evaluating withdrawal. Neither dose had a clear-cut hypnotic effect in inducing or maintaining sleep. Sleep stages were not effected by drug administration or drug withdrawal. Both the objective findings and subjective estimates suggest that the 1,300-mg dose may have a slight sedative effect. However, when salicylamide is used as an ingredient in over-the-counter preparations, the usual dose is only 200-400 mg.

1. An experimental antidepressant was studied through sleep laboratory recordings, psychoendocrinological tests and clinical measurements in terms of its efficacy, side effects and effects on sleep. 2. The design included a four-week drug administration period, preceeded and followed by a one week placebo period. 3. In the presence of antidepressant efficacy, the drug did not disturb sleep induction and maintainance. 4. The only effect on sleep stages was an increase of REM sleep during the short-term drug administration period which is contrary to the REM supressant effect of most antidepressants. 5. This finding suggests that REM supression and antidepressant efficacy are not necessarily related. 6. Further, given that the only known action of the drug is its inhibitory effect on GABAergic transmission, one can speculate that GABA mechanisms may be involved in REM sleep modulation.

Brotizolam 0.25 mg was evaluated in a sleep laboratory study of 10 normal subjects. The study covered 10 consecutive nights and included 4 placebo-baseline nights, 3 nights on the drug and 3 placebo-withdrawal nights, which permitted assessment of initial drug effects, side effects and withdrawal phenomena, such as rebound insomnia. There was a significant increase in total sleep time with drug administration; the improvement in sleep occurred primarily in the first third of the night following the onset of sleep. During the day after nightly drug administration, the presence of rebound anxiety was suggested by an increase in reports of anxiety/tension as compared to baseline. Following drug withdrawal there was a significant increase in total wake time above baseline level, to 40% above baseline on the first and third nights of withdrawal.

The authors evaluated the development and clinical course of nightmares and the personality patterns of people with this dosorder by studying 30 adults who had a current complaint of nightmares. Nightmares usually began in childhood or adolescence and were chronic. Psychological factors played a major role in the development and persistence of nightmares, major life events were often associated with the onset of the disorder, mental stress usually increased the frequency of events, and psychological testing indicated relatively high levels of psychopathology. Nightmares sufferers in general were distrusful, alienated, sufferers in general were distrustful, alienated, and emotionally estranged, and many showed a chronic schizoid pattern of adjustment, but they were not overtly psychotic.

In the vast majority of patients with parasomnias, the evaluation can be accomplished in the office setting, based on information from the patients themselves and family members or other observers of the nocturnal events. Parasomnias are episodic sleep disorders that include sleepwalking, night terrors, and nightmares. All three conditions are more prevalent in childhood, when developmental factors appear to be responsible for their occurrence; in the much less frequent cases of a delayed onset or persistence in adulthood, psychopathologic states are often primary in their cause. Based on a number of clinical, physiologic, and etiopathogenetic similarities between sleepwalking and night terrors, these two conditions appear to fall along the same pathophysiologic and therefore nosologic continuum. They are both disorders of impaired arousal, characterized by various degrees of confusion, and they occur early in the night when slow-wave sleep predominates, whereas nightmares may occur at any time of the night, because they are closely associated with REM sleep. Another important issue relating to the assessment of parasomnias is to differentiate between nightmares and night terrors: in addition to the different time of night for their occurrence, nightmares are accompanied by much less anxiety, vocalization, motility, and autonomic discharge. Also, nightmare patients usually have vivid and elaborate recall for the event, whereas patients with night terrors are typically amnesic for their episodes, as are patients who sleepwalk. A mainstay in the management of sleepwalking and night terrors is instructing the patients and their family members to provide for adequate safety measures to prevent accidents that may occur during these events.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred subjects without any complaint of sleep disturbance were evaluated in the sleep laboratory for the presence of sleep apnea and sleep apneic activity (SAA). This sample, which had a representative proportion of women and men and a wide age distribution, included only subjects who were physically and mentally healthy and were not using any medication. None of the subjects had the clinical condition of sleep apnea, and only 12 percent of the subjects met the more liberal criterion for SAA. The prevalence of SAA was slightly higher in men than in women. SAA was positively and significantly correlated with increasing age. However, relative severity, as judged by the mean number of events and the duration of events, showed no consistent pattern in relation to age. Further, it was demonstrated that those subjects with SAA were significantly heavier than those without the activity. Neither smoking nor caffeine consumption was related to the presence of SAA. When the amount of each sleep stage was controlled for, SAA occurred significantly more often during REM sleep. A relatively small number of EEG arousals were related to SAA, with only about one-fifth of the events resulting in brief arousals.