Biomedical subjects
J D Kales
Publications and source records attributed to J D Kales.
Next-day memory impairment with triazolam use.
The prevalence, rate, and degree of memory impairment for next-day activities during a short, intermittent course of bedtime doses of triazolam, temazepam, and placebo were assessed in a double-blind parallel-group study. 5 of the 6 subjects in the triazolam group reported at least one episode of next-day memory impairment/amnesia, with a total of 12 episodes being reported for the 30 subject-drug nights (a rate of 40%). In the temazepam group there were no such episodes of memory impairment. Immediate and delayed recall were also tested and related to whether active drug or placebo had been taken the night before. Impairment of delayed recall was significantly and several times greater than that in the temazepam or placebo groups. Next-day memory impairment/amnesia after a bedtime dose of triazolam tended to increase with continued or intermittent drug use. Cognitive impairments associated with triazolam probably represent a spectrum of organic brain dysfunction, with memory impairment/amnesia and confusion being the commonest, and milder manifestations and hallucinations and delusions the more severe and less common, features.
Clonazepam: sleep laboratory study of efficacy and withdrawal.
Clonazepam 0.5 mg was evaluated in a sleep laboratory study of 6 insomniac patients. The 16-night protocol consisted of 4 placebo-baseline nights, 7 nights of drug administration and 5 placebo-withdrawal nights. Clonazepam produced a significant decrease in total wake time initially (nights 5-7), as well as with continued administration (nights 9-11). With later but not immediate withdrawal, significant rebound insomnia occurred, on the 3rd withdrawal night, both wake time after sleep onset and total wake time increased markedly, with the latter significantly increased. These findings are discussed in light of clonazepam's increasing use for panic disorder; specifically, due to its maintained efficacy, it has the advantage of avoiding interdose rebound anxiety which is frequently reported with use of alprazolam.
Diazepam: effects on sleep and withdrawal phenomena.
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.
Inpatient multidimensional management of treatment-resistant insomnia.
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Evaluation and diagnosis of sleep disorders patients.
Using the biopsychosocial model, physicians can thoroughly assess patients with sleep disorders in the office setting. A careful sleep history, drug history, general medical assessment, and psychiatric evaluation along with an appraisal of the interplay between the patient's condition and his environment can provide all of the elements needed for diagnosis and treatment formulation. The main components of the sleep history include: defining the specific sleep problem, assessing the disorder's clinical course, differentiating between sleep disorders, evaluating the sleep-wakefulness patterns, questioning the bed partner, and obtaining a family history of sleep disorders. The drug history provides important information regarding the role of various medications, which may cause sleep difficulty during their administration or following withdrawal. Implementing a complete medical assessment is necessary for the identification of certain medical conditions that may be associated with sleep disorders. Finally, a thorough psychiatric evaluation and assessment of the psychosocial consequences of the patient's disorder should be conducted. In general, sleep laboratory diagnostic studies are of limited usefulness. These studies are indicated primarily when sleep apnea is suspected or when the sleep attacks of narcolepsy are present in the absence of auxiliary symptoms.
Adverse reactions to benzodiazepine hypnotics: spontaneous reporting system.
The rates of reported adverse drug reactions involving the central nervous system were compared among patients taking any of three benzodiazepine hypnotics: flurazepam, temazepam, and triazolam. These rates, based upon data collected through the spontaneous reporting system of the Food and Drug Administration, were controlled for the number and size of new prescriptions for each drug. In general, triazolam had much higher overall rates than did the other two drugs. Hyperexcitability and withdrawal effects were greatest for triazolam and least for flurazepam. Amnesia was reported almost exclusively with triazolam. Rates for other cognitive as well as affective and other behavioral effects were also much greater for triazolam and about equal for the other two drugs. Finally, daytime sedation was reported slightly more for flurazepam than triazolam and least for temazepam which was also reported most frequently as lacking hypnotic effect.
Sleep disorders: sleep apnea and narcolepsy.
Symptoms of obstructive sleep apnea, a potentially life-threatening disorder, include excessive daytime sleepiness and sleep attacks, nocturnal breath cessation, and snorting and gasping sounds. These symptoms usually become manifest before age 40 and cluster within a few years. Most patients are obese, hypertensive men who eventually develop cardiovascular abnormalities. If sleep apnea is suspected based on clinical information, a sleep laboratory evaluation is indicated. For severe obstructive sleep apnea, tracheostomy is the most effective treatment. Narcolepsy, another sleep disorder, is a life-long and usually disabling condition. In most narcoleptic patients the first symptoms develop during childhood or adolescence, yet many years pass before the proper diagnosis is made. The presence of sleep attacks together with auxiliary symptoms, particularly cataplexy, is diagnostic. Treatment of narcolepsy includes stimulants in combination with therapeutic naps for sleep attacks and tricyclic drugs for cataplexy.
Sleep disorders: insomnia, sleepwalking, night terrors, nightmares, and enuresis.
All five sleep disorders reviewed in this article can be adequately evaluated in the physician's office by taking a sleep history and conducting a careful general medical and psychiatric assessment. Insomnia, the commonest sleep disorder, is more prevalent among women and elderly and psychosocially disadvantaged persons. Personality factors such as a tendency toward the internalization of emotions and the occurrence of stressful life events also play a major role in the development of chronic insomnia. A multidimensional approach is indicated for the treatment of chronic insomnia; hypnotic drugs should be used only as an adjunct to this treatment. In children, sleepwalking and night terrors (two manifestations of the same pathophysiologic substrate), nightmares, and enuresis are commonly related to developmental factors; counseling and reassurance of the parents is indicated. Psychopathologic disorders are usually present in secondary enuresis, as well as in sleepwalking, night terrors, and nightmares that occur in adulthood. Psychotherapy and the occasional use of psychotropic drugs may be necessary in the treatment given adults with these disorders.
Quazepam and temazepam: effects of short- and intermediate-term use and withdrawal.
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.
Lorazepam: effects on sleep and withdrawal phenomena.
Lorazepam, an anxiolytic drug, was evaluated in a 2-mg dose using a 16-night protocol including 7 nights of drug trial. Initially and with continued use the drug was moderately effective in inducing and maintaining sleep. Side effects included episodes of memory impairment and confusion in 2 subjects and group mean increases in daytime anxiety and tension with continued drug use. Following drug withdrawal, there was a marked and significant worsening of sleep above baseline levels (rebound insomnia) on the third night as well as significant increases in tension and anxiety the next day. The peak degree of withdrawal sleep disturbance was several times the peak degree of sleep improvement with drug administration.
Clinical selection of benzodiazepine hypnotics.
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Role of the sleep laboratory in the evaluation of impotence.
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Treatment of sleep disorders.
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Anorexia nervosa in a young man with Tourette's syndrome.
Successful treatment of Tourette's syndrome in a young man seemed to precipitate anorexia nervosa. The obsessional behaviors associated with Tourette's syndrome and the social isolation incurred by his illness may have predisposed this patient to the development of anorexia nervosa in response to the heightened anxiety of adolescence. The association between obsessive-compulsive behavior and Tourette's syndrome is described, as is the diagnostic difficulty posed by the somatic obsessiveness of males with anorexia nervosa. The importance of using the biopsychosocial model to integrate pharmacologic therapy and psychotherapy in treating complicated conditions, as illustrated by the patient, is emphasized.
Rebound insomnia and elimination half-life: assessment of individual subject response.
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.
Quazepam: sleep laboratory studies of effectiveness and withdrawal.
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