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Sleeping Pills, Insomnia, and Medical Practice: Report of a Study (1979)

Chapter:Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs

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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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Suggested Citation:"Appendix: Assessing the Hazards and Benefits of Hypnotic Drugs." Institute of Medicine. 1979. Sleeping Pills, Insomnia, and Medical Practice: Report of a Study. Washington, DC: The National Academies Press. doi: 10.17226/9934.
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APPENDIX ASSESSING HAZARDS AND BENEFITS OF HYPNOTIC DRUGS There are many complexities in evaluating the presumed benefits of hypnotic drugs. Some of these emerge when one considers the question: "What is at stake in not prescribing sleeping pills for a patient's com- plaints of insomnia?" The risk seems to be chiefly one of subjecting the patient to anticipatory distress while lying awake at night and/or dysphoria during the day after a poor night's sleep. Though there may also be the fear that loss of sleep will cause impaired cognitive and motor skills in the daytime, as yet no published reports have documented such deficits in various types of insomniac patients. In studies of experimentally induced sleep deprivation of normal volunteers, two full nights of sleeplessness are required in order to produce appreciable impairment of psychomotor skills such as tracking (a visual-motor skill related to driving). 1/-2/ Certain changes may be detected in the performance of very monotonous tasks by volunteers who have been acutely deprived of 2 1/2 hours or more of sleep for the two previous nights, but if the deprivation has been only two hours or less, even these subtle effects on psychomotor performance are absent. 3/ Thus, from a strictly objective point of view, the daytime benefits of hypnotic drugs would seem dubious, as their typical maximum effect is a shortening of sleep latency by 10-20 minutes and a lengthening of total sleep time by only 30-40 minutes. From a subjective point of view, of course, relief of daytime sleepiness by means of a nocturnal hypnotic would be valuable. Yet even daytime sleepiness is extremely variable among insomniacs and not directly correlated with their objective deficiencies in nocturnal sleep measures. 4/ Although there is little doubt that most hypnotic drugs promote drowsiness and have some effect on sleep, documentation of the benefits or efficacy of hypnotic drugs is meager and laden with difficulties in interpretation. For example, a series of studies in general medical hospital settings reveal that most hypnotic drugs are judged "satis- factory" by a majority of patients and their doctors, 5/-7/ but the basis of this satisfaction is not specified. Perhaps the hypnotic drug is providing a tranquilizing effect on the anxious patient sleeping in a strange and frightening place; or perhaps it provides some chemical insulation from intrusive noises during the night. In any case, it seems unwise to extrapolate to the presumed benefits for ambulatory insomniacs who actually complain of poor sleep. Studies of such patients reveal that hypnotic drugs usually do alter objective charac- teristics of their sleep, but to what extent these effects (on sleep latency, etc.) are clinically significant is not known. Unfortunately, reports of technologically advanced monitoring of drug effects in the sleep laboratory typically omit details of patients' subjective com- plaints, before, during or after treatment. From many of these reports a reader might get the impression that drug treatment is directed at sleep laboratory measures and not at insomnia problems. —155—

At the present time, the use of hypnotics is often intended to pro- vide symptomatic relief in many cases of insomnia of unknown etiology. How these drugs work is not understood. But even without explica- tion of specific mechanisms of action, efficacy studies could at least establish whether or not a hypnotic drug reliably alleviates the com- plaints of certain types of patients without increasing their risks. Unfortunately, until now objectively measured sleep parameters have not been related precisely to the complaint of the patient. Future studies which simultaneously monitor the effects of a drug upon sleep measures and any concomitant changes in the complaints of patients (both nocturnal and daytime) would have the greatest potential for accurately describing the drug's hypnotic efficacy. A. Approaches to the Study of the Effects of Hypnotic Drugs The following is a general framework for research on the hypnotics which includes various types of studies, questions that should be addressed in each, and measurements that could be taken to try to answer the questions. The "ideal hypnotic'' would be safe and effective. Evaluation of this drug would demonstrate that it would cause neither coma nor death when taken in overdose; it would not be attractive for abuse; it would not interact adversely with other medications; it would be free from such side effects as allergic reactions, respiratory depres- sion, and cardiovascular complications; it would be free of hangover effects, such as daytime drowsiness, memory and cognitive impairment, incoordination, and adverse mood changes; it would be safe for such special population groups as pregnant women, the elderly, and patients with pulmonary, renal, or liver insufficiency; it would not disrupt the order of natural sleep, including waveform characteristics; its onset and duration of action would be consistent with clinical use and need -- that is, it would enable patients to fall asleep quickly, to sleep through the night, and to wake at the desired time; although it would promote sleep, it would not anesthetize the patient so as to render him unresponsive to a full bladder, pain, telephone calls, fire alarms, a crying baby, or the smell of smoke; if needed for pro- longed use, neither tolerance nor dependence would develop, and upon cessation of treatment rebound insomnia would not occur; it would be inexpensive; it would not disrupt the normal physiological process associated with sleep or with circadian rhythms, such as changes in temperature and neuroendocrine responses; and it would effectively treat the problems of a wide variety of patients. No currently avail- able hypnotic fulfills all these criteria. The efficacy of hypnotic agents is particularly difficult to judge at this time. To say that a medical treatment is effective indicates that it cures or at least ameliorates some aspects of a specific disorder -156-

in a certain proportion of afflicted patients. This implies that the disorder -- even if its etiology is unknown -- can be defined, that the important measures of change in the patient's condition are known and that there are appropriate controls against which to compare this treatment (such as the natural history of the untreated disease, placebo treatment, or an established conventional treatment.) These criteria have not been met in the assessment of hypnotic drug treatment of insomnia. Little data is available which convincingly demonstrates that drug "X" is effective according to specific criteria in, say, 80 percent of patients with insomnia of type "Y" when treated under conditions "Z't. These types of specifications would be more useful than global statements that drug "X" is the best hypnotic. These issues are not merely academic, but are important ir guiding the physician in the clinical management of the complaint of insomnia. Hypnotic agents are administered to many different types of patients, under widely different co~ditio~s, and for varying periods of time. The executive flying from Washington to Tokyo, the enfeebled retiree living in a nursing home, the anxious spouse of an alcoholic, the hospi- talized preoperative patient, the agitated depressive, and the "chronic insomniac" all share the complaint of poor sleep but differ in their therapeutic needs. In short, the physician needs to know what he is treating when he decides to prescribe a hypnotic and needs relevant outcome measures with which to judge clinical effectiveness. Target Populations and Sample Selection Most of the research reported in the literature has been performed with normal young adult male subjects. Even when sleep-disturbed patients have been studied, the tendency has been to use relatively young patients. Future research with hypnotic drugs should take into account the different effects drugs may have on various populations that will use them. Such differences may be related to age, sex, ethnic background, pregnancy, and medical, psychiatric, or surgical problems. For example, hypnotic drugs are often taken by people who do not normally suffer from sleep disturbance, such as shift workers and travelers. Their responses are probably different from those with a chronic sleep disturbance. It would be unreasonable to expect a single drug to serve patients of all types. Therefore, when studying a particular drug, it is important to study subjects comparable to those who will use that drug. One potentially misleading aspect of hypnotic' efficacy studies has been the custom of establishing arbitrary sleep laboratory criteria for "insomnia," such as greater than 30 minutes sleep latency, less than six or 6 1/2 hours total sleep time, or greater than 30 minutes wake time after sleep onset. In early studies such criteria seemed reasonable in -157-

view of the fact that patients' complaints were often far worse than the objective findings. However, the sleep laboratory evaluations of insom- niacs reviewed for this study* clearly indicate that most persons who complain of insomnia do not meet these arbitrary criteria. In the only available hypnotic drug efficacy study that reported on details of its selection process, 330 "insomniac" volunteers were screened to obtain seven patients (less than 37) who met the objective criteria. 8/ Many hypnotic drug evaluations reviewed appear to have ignored such relevant characteristics of sample individuals as age and sex. Another important variable, weight, is also typically omitted from consideration, even though, for example, preliminary evidence suggests that flurazepam 30 mg may be an excessive dose for patients weighing less than 120 pounds. 8/ Because the drug testing is generally performed using standard dosages rather than on a mg/kg basis, a given compound would be expected to have a much greater effect when given to a 100-pound subject than a 200-pound subject. Since obesity may be a factor in pharmacokinetics, height should also be reported, but almost never is. Nighttime Measures of Hypnotic Effects and Adverse Effects The simplest subjective measures for each night of sleep include the subjects' own estimates of sleep latency, number and duration of awakenings, total sleep time, and restfulness of sleep. However, patients with sleep disturbance are known to be poor judges of their actual sleep. During periods of relatively disturbed sleep, they tend to exaggerate the disturbance, and during periods of drug induced sleep they correspondingly tend to exaggerate the improvement. Complementary to subjective impressions are the objective measures produced by all-night EEO tracings. In addition to recording intervals of sleep and wakefulness during the night, the EEG is also analyzed in 30-second or one-minute periods for each of five separate sleep stages (REM and stages 1, 2, 3 and 4 of Non-REM) and these are further analyzed to define various patterns for the entire night, such as percentages of the stages, latencies to the onset of the stages, duration of each sleep cycle and number of shifts among sleep stages during the night. Hypnotic drugs all produce disruptions in these phenomena, with possible (but far from certain) implications as to efficacy and safety. A hypnotic drug that affects sleep stages 3 or 4 may have implications for elderly people since these sleep stages normally decrease with age. Most hypnotics decrease REM sleep during one or more consecutive nights of *These are tabulated in the technical supplement to this report and summarized in Chapter 4. -158-

medication, and this is often followed by REM rebound upon discontin- uation of the drug. Although the full implications of these effects are not known, there is no question but that the normal mechanisms of sleep are upset in the process.* Unfortunately, in many study reports, the definition of such terms as "total wake time" or "sleep efficiency" is unclear. Similarly, there is no standardization of laboratory procedures at bedtime, or whether the subjects are awakened after eight hours or allowed to sleep ad libitum. Results from different laboratories are often not comparable because of these omissions. Adverse effects of a hypnotic drug on respiratory, cardiovascular, and neuro-endocrine physiology should be determined during nighttime monitoring. Effects on respiration are particularly important because a depression of respiratory function could have lethal consequences in patients suffering from sleep apnea or other respiratory difficulties. Artificial awakenings of the subjects should be included to evaluate the subjects' ability to become reoriented, reasonably alert, and capable of good mobility should these be necessary in real life situations when hypnotics are used. As stated earlier, the effect of a hypnotic should not be that of temporary anesthesia, nor should there be disorienting and amnesiac effects as a result of the drug. There is one recent report suggesting that flurazepam may cause such a sound sleep that the noise of home fire alarms might not awaken people in time to attend to their safety. This was not a problem with pento- barbital. 9/ There are reports that flunitrazepam (not yet marketed in this country) has powerful amnesia-inducing effects that could pose practical hazards in clinical use. 10/ Because people commonly mix alcohol with sleeping pills at bedtime, despite medical warnings, it could be useful to test combinations of new hypnotics with low doses of alcohol to see if especially deleteri- ous effects on nighttime physiology or psychomotor performance are demonstrable. Daytime Measures of Hypnotic Effects and Residual Adverse Effects There are two reasons why assessments of daytime functions should be included in the clinical evaluations of hypnotic agents. First is the necessity to determine the safety and side-effects of drugs. At *Even more highly sensitive reflections of drug activity may be obtained through the examination of EEG waveform activity. Waveforms of particular current interest are sigma spindles (which occur through- out non-REM sleep but are especially associated with stage 2) and delta waves (which are used to define stages 3 and 4~. -159-

present, such evaluations are commonly limited to monitoring a few variables in subjects' moods and physiological functions. The standard evaluation procedures should be expanded to include measures of addi- tional subjective effects and measures of certain behavioral functions. The subjective measures can contribute information on both the abuse potential of the drug and the mechanisms of the subjects' response to the drug. For example, it may be that a drug that produces subjec- tive euphoria has a greater abuse potential than a drug that does not have this effect, or that euphoria contributes significantly to a subject's retrospective positive assessment of the drug's effectiveness the night before. Measures of behavior such as cognition, memory, coordination, automobile driving skill, and alertness are necessary to determine whether important waking functions are impaired. The second reason for including assessments of non-sleep functions, and particularly behavioral functions, is the potential they offer for demonstrating heretofore undetected benefits of the drug. For example, increased sleep in insomniacs ought to lead to better daytime function- ing, although no study has ever demonstrated this. An appropriate battery of tests for the assessment of non-sleep functions would include measures of mood, psychomotor and cognitive functions, and daytime alertness. Since substantial psychopathology is found in many insomniacs, it would be interesting to determine the effect of hypnotic treatment on measures of emotional disturbance. Because daytime sleepiness is one of the most common side effects of hypnotic agents, daytime alertness requires special evaluation procedures. Both subjective and objective measures should be used. An instrument such as the Stanford Sleepiness Scale can provide subjec- tive ratings, while polygraphic monitoring during multiple daytime sleep-latency tests can provide objective measures. 11/ Assessing daytime psychomotor performance is of special concern because of potential hazards in driving or in operating heavy machinery. In recent years it has been recognized that there are several different paths to impaired psychomotor performance, each of which could result in potentially hazardous decrements in ability to drive automobiles or handle complex machinery. The following recommendations are offered with this potential public health issue in mind - especially since the hypnotics most commonly prescribed in North America and Europe (flurazepam and nitrazepam) produce active metabolites that, when taken nightly, remain present all day long at high levels. A battery of standard performance tests would include measures of gross motor coordination (balance board), fine motor coordination (Purdue Pegboard, symbol copying test), cognition (Digit Symbol Sub- stitution Test), perception (critical flicker-fusion threshold), short-se con memory and long-term memory. -160-

In the past decade, however, several tests have evolved from traffic safety oriented research that also should be included in the laboratory protocols for testing the residual effects of hypnotics. Ideally, a driving simulator should be included. 12/ In addition there should be difficult tasks requiring eye-hand coordination and tracking ability, as well as information processing tasks requiring divided attention. 13/-14/ Reaction time should be measured under various conditions -- especially in monotonous tests of vigilance versus drowsiness. 15/ Substantial impairment in any of these tests, even in the presence of adequate per- formance on other tests, could be indicative of a deficit with practical significance for traffic and industrial safety. 16/ Obviously, standard measures of mood and overall alertness should be included, 17/ as well as the subjects' own estimates of their daytime performance. An especially hazardous combination is the presence of impaired performance along with a subjective assessment of normal performance. Some authors have suggested there might actually be a small benefit to experiencing daytime sleepiness or other hangover effects of hypnotics -- these symptoms may serve to warn the subject that his body is still being influenced by these drugs. In two studies, subjects did not report a significant sense of impairment after noctur- nal use of nitrazepam, although their motor and attention skills were indeed decreased. 18/-19/ Subjects who had received a barbiturate -- butabarbital or amobarbital -- and subjects who had received flurazepam acknowledged their impaired performance as they were still somewhat sleepy during the test periods. 18/-19/-20/ Testing should be done at different times of the day, especially when it is known that a hypnotic or its active metabolites is long-lived. Blood samples to test for the hypnotic and its metabolites should accompany the testing to add further confirmation that drug effects are indeed related to pharmacokinetics. 19/-20/ All drugs should be tested for daytime interaction with alcohol. On some tests nitrazepam, flurazepam and diazepam have remarkable additive effects with alcohol, and in this dimension present potential problems greater than those posed by nightly consumption of barbi- turate hypnotics. 19/-20J-21/-22/ Assessments must be made of hypnotics not only in acute studies that would resemble the clinical situation of use for only one to three nights in a row, but also in situations that resemble chronic nightly use (7-14 days or more). Certain assessments of comparative safety made after one or two nights' administration might be reversed in the more chronic situation once the hypnotic with the long-lived metabolites has accumulated in the body (and indeed this appears to be the case in comparisons of flurazepam with barbiturate hyp- notics). 20/,23/ -161-

It has been learned in recent years that well-trained subjects, who have learned to perform well on the difficult coordination and attention tasks referred to above, are the ones in whom the investigation of potentially deleterious drug effects will be most productive. Inter- estingly, untrained (and presumably anxious) subjects will sometimes improve their performance if given sedative or anxiolytic medication, which helps them learn the task more rapidly than if their anxiety remains high. It is the well-trained subjects upon whom the deleter- ious effects of drugs can be most clearly seen; and, of course, the variable of practice on the complex task has already been accounted for. 22/ Drugs should be tested both in middle-aged and elderly volunteers and insomniac patients. Drugs deemed to have little or no residual effect at low doses in 20 year aids may have considerable effects at those doses in 40 year olds. 18/ As noted elsewhere in this report, most hypnotic medication is prescribed for middle-aged and elderly people, and yet most research is conducted on young adult student volunteers. Barbiturates seem to have a fairly constant level of ad- verse residual reactions with age (mainly, unacceptable daytime drow- siness), but benzodiazepines have an increasing level of adverse reactions with age. It has been estimated that the half-life of benzodiazepines is twice as long in someone over 70 as it is in some- one 20 years old. 24/ Overall Study Design Assessment of a hypnotic drug's effects would logically include four different types of studies described by Kay, et al: 25/ (1) pilot studies, in which potential drug effects are described; (2) dose-effect studies which establish minimum effective dosage, maximum tolerated dosage, therapeutic range, and relative potency in comparison to a standard drug; (3) short-term studies, in which acute tolerance, if any, is characterized and optimal dosage and characterization of the recovery from accumulated drug is established; and (4) long-term studies, in which maximum tolerance can be assessed, along with the nature of chronic toxicity, if any. Such studies will also reveal syndromes that may appear after the drug is withdrawn. In evaluating hypnotic drugs it would be useful to compare standardized measurements for each in relation to certain standard drugs. Distinctive patterns characteristic of each drug could then be obtained. Likewise, determination of approximately equivalent dosages of various drugs facilitates realistic comparisons in further studies. (Many studies have been biased in favor of one drug over another by using dosages which are grossly unequal in hypnotic potency.) -162-

Animal pharmacology, including sleep pattern analysis, obviously would precede the testing of drugs in man. Such animal testing should include comparisons with standard drugs. A broad range of effects should be evaluated in several species, including measures of anti-wakefulness, specific sleep mode promotion, toxicity and drug dependence. This might allow investigation of mechanisms of sleep induction or maintenance and allow distinctions to be made among the effects of different drugs.The pharmacokinetics of drugs in relation to such effects should be included and pursued in subsequent human studies. B. Daytime Residual Effects of Hypnotic Drugs Overview There is a growing body of evidence that hypnotics may continue to influence the nervous system throughout the day following nocturnal administration. This is manifested in changed performance on psycho- motor testing and in altered EEG patterns. The practical significance of these changes is as yet unclear. However, they point to the possi- bility that persons taking hypnotics may perform their daily tasks with diminished skill, and may potentially be more likely to suffer harm from accidents. The potential for adverse drug interaction with alcohol is also present, at least with flurazepam and nitrazepam, all day long. Particularly troublesome is the observation that subjects may be unaware of their decreased performance following hypnotic use. This would seem to put them at a potentially greater risk of harm when engaging in tasks requiring alertness and coordination such as opera- ting an automobile, airplane or industrial machinery. It is not clear from the available evidence that getting a good night's sleep is essential to maintaining skilled performance of psychomotor tasks, and there is some evidence to suggest that the residual deleterious effects of some hypnotic drugs on daytime functioning could outweigh any benefits which may be derived from a feeling of having slept well. More research is needed testing normals and insomniac patients at various times of the day with various doses of nocturnal hypnotics, as well as epidemiological studies of drivers and machinery opera- tors* who may be either insomniac or taking hypnotic drugs or both. *A prospective study of Israeli industrial accidents in relation to workers' sleep problems and/or hypnotic drug use was begun in 1978, under the direction of Dr. P. Lavie of Haifa University. -163-

Findings The half-lives of the commonly used hypnotics vary widely, but typically are much longer than the few hours needed to aid sleep. This may have implications for daytime functioning of persons who take this medication. After a single nocturnal dose of flurazepam, for example, its powerful metabolite, N-desalkylflurazepam remains in the body with a half-life of 50 to 100 hours. The following day it may have undesired effects on the person's alertness or coordination. If the drug is taken for several consecutive nights, there will be an accumulation of the drug in the body which potentially increases the risk of untoward effects during the day. 26/,24/ Alcohol ingestion during the day could also prove hazardous because of additive effects. _/ A variety of studies have examined the influence of hypnotics on daytime performance measures, including tests that measure finger tapping rate, simple auditory reaction time, complex visual reaction time, adaptive tracking tests, card sorting speed, and the digit-symbol substitution test. The latter two tests may be divided into different components intended to parse out drug effects on motor skills and on cognitive functions. A few laboratories have investigated coordina- tion skills directly with simulated driving. Most of the laboratory studies have examined the effects of the benzodiazepines or barbiturates on psychomotor tasks, compared to placebo, other hypnotics, alcohol, and combinations of the drugs with alcohol. No pharmacologic class of hypnotic has been shown to be benign in this regard. In one study, the changes in performance following single doses of hypnotics lasted in the range of 10 to 16 hours 27/ and in another 34 hours. 28/ There is also evidence that cumulative effects can occure One study found that following one night of administration of N-desmethyldiazepam (an active metabolite of diazepam) there were no performance decrements, but after seven nights there was decreased daytime performance in tests of visual-motor coordination. 29/ The benzodiazepines appear to impair motor skills particularly, while barbiturates mainly affect cognitive functions. 30/ Occasionally performance will be improved on some tasks. Such improvements are usually isolated findings, however, and not evidence of generally improved functioning. In one simulated driving test chronic administration of diazepam was associated with improved reaction time and slightly improved coordination when the simulated vehicle was going at a fixed speed. 21/ This may have been related to an anti-anxiety effect upon the untrained subjects. In the same study, however, the diazepam subjects -164-

drove faster and made more mistakes when they were allowed to control the speed themselves a manifestation, perhaps, of poorer self- control. Because of the widespread prescribing of flurazepam, it is particularly important to closely examine those studies which have measured its effects on daytime functioning. Four research groups, three in Great Britain and one in Finland, have established signifi- cant patterns of impairment, especially of eye-hand coordination, as a daytime residual effect from nocturnal doses of flurazepam.* In the first report, normal subjects received single doses of either 15 mg or 30 mg of flurazepam and were tested the next day with an assortment of psychological tests as well as an electroencephalogram. The electroencephalogram showed changes up to 18 hours following the administration of the drug; impairment on the symbol copying test was observed up to 12 hours following the dose of the drug. 30/ The symbol copying test is essentially a test of visual-motor coordination and speed, not requiring coding or complex cognitive skills. 31/,32/ Both doses of flurazepam significantly impaired performance on this test. The subjects also did poorly on the digit symbol substitution test that requires both motor function and cognitive skills. In the view of the authors, it was a motor impairment that flurazepam had induced. Anxious, insomniac patients who were tested in a British medical office practice on the eighth day after they had been receiving nightly doses of 30 mg of flurazepam manifested definite impairment of visual- motor coordination. Patients in the same study who received only 15 mg doses did not exhibit such impairment. 34/ At the Royal Air Force Institute of Aviation Medicine, volunteers' perfo~ance on reaction time and on an "adaptive tracking" test (similar to eye-hand coordination skills used by airplane crews) was impaired by one 30 mg dose of flurazepam until the early afternoon of the next day. _/ In later research, the R.A.F. researchers tested the hypnotic efficacy and residual effects of several drugs. They reported that a single 10 mg dose of diazepam was an effective hypnotic whose *In the United States, one small preliminary study revealed that both flurazepam and secobarbital adversely affected cognitive-associa- tion tasks and visual-motor performance. Secobarbital's daytime effects wore off with continued nightly administration. Flurazepam's daytime effects were not studied during prolonged treatment, nor were they followed up in subsequent reports. 33/ -165-

deleterious effects on normal volunteers' tracking performance was quite pronounced 2.5 hours after the dose, but had disappeared by 9.5 hours. 35/ This made diazepam relatively hazardous for daytime use by pilots, but clearly a safer hypnotic for occasional nocturnal use than would be flurazepam. Oxazepam and methaqualone were also free of any residual effects on performance nine hours after administra- tion. _ /-37/ Daytime impairment of performance resulted from a single nocturnal drug dose of nitrazepam and a large dose of pentobarbitone, 200 ma; these effects were somewhat more severe and longer-lasting than that produced by flurazepam. 28/ In Finland, normal volunteers were administered 30 mg of fluraze- pam for 14 nights and tested on the mornings after the 7th and 14th nights; they displayed significantly impaired psychomotor skills related to driving. 20/ Some subjects also received a standard dose of alcohol to drink prior to the morning's test -- equivalent to about three ounces of whiskey.* In this study subjects who received a placebo at night and alcohol in the morning showed significant impairment in a test of visual-motor coordination, but flurazepam alone taken the night before resulted in more mistakes on this test than did the morning alcohol alone. When subjects who had received flurazepam on the previous night also drank alcohol the following morning, the coordinative skills were the poorest of any combination studied. Other drugs in this study of nightly administered hypnotics were amylobarbit-one, glutethimide and methaqualone, with and without alcohol. Glutethimide and metha- qualone did not impair morning performance, nor did they contribute to impairment when combined with alcohol. Amylobarbitone alone did impair performance, though less severely than flurazepam alone; it also interacted with alcohol to result in further decrements. Significantly, a comparison group of drug-free subjects were tested after a night of partial sleep deprivation and severe sleep inter- ruption, and their coordinative skills were excellent. 19/-20/ The test used by the Finnish investigators for coordination was one in which there was a narrow illuminated track moving on a screen, requiring a subject to keep a black ball on the track by turning an automobile steering wheel. 13/ The number of *The dose of alcohol was sufficient to produce a blood alcohol level of approximately .04 grams percent. This is just slightly below the level for legal intoxication in Scandinavia which is 0.5 grams percent; in most of the United States, the blood alcohol level for legally inebriated drivers is 0.1 grams percent. -166-

deviations from the track was recorded. The subjects were well-trained beforehand, so that the effects of drugs and alcohol were clearly re- presented and were not contaminated by the process of learning the tasks. Drug effects are not as clearly demonstrable in novel situ- ations). 22/ (Actual automobile driving itself is usually a well- learned task.) What bearing might the above have on daytime functioning -- especially driving skills? First of all, it should be noted that blood level measurements taken during these Finnish studies con- fi~-~ned previous work showing that by the second week of consecutive nightly usage of the 30 mg dose the active metabolite of flurazepam, N-desalkylflurazepam, had accumulated to a level 4 to 6 times greater than on the first morning after use. _ /* Thus, a few drinks of alcohol at any time during a 24 hour period after one week of consecu- tive nightly usage of flurazepam could produce a deleterious additive effect on coordination. In causing these performance decrements, flurazepam closely resembles diazepam in that the main impairment is on eye-hand coordina- tion, rather than on attention tasks.** There are no epidemiological studies in which blood samples or reports of flurazepam have been sought from victims of traffic accidents (either drivers or pedestri- ans). But there are several studies in which diazepam has been measured and in which a level of significance has been attached to the role of diazepam in driving accidents. Inasmuch as the effects of diazepam and flurazepam are quite similar in test batteries -- and inasmuch as both of them show a very substantial additive effect with alcohol, resulting in sharply decreased performance -- it is reasonable to specu- late that nightly users of flurazepam put themselves at somewhat increased risk of daytime auto accidents. Recent calculations from Finland suggest that diazepam users are over-represented in that country among both drivers and pedestrians in urban traffic accidents that involved per- sonal injury or property damage. 22/ Among drivers, two and one-half times as many of those involved in traffic accidents had significant blood levels for diazepam or its major metabolite than did carefully selected control drivers (five percent vs. two percent). Among pedes- trians injured in accidental falls and hit by cars on the streets of *Amylobarbitone, glutethimide and methaqualone did not accumulate; blood levels on the 14th day were not significantly higher than on the first day. 19/-20/ **Alcohol, when taken alone in low doses, generally impairs coordination much less than it does performance of divided attention tasks. But clear dose-related impairment of eye-hand coordination is demonstrable when the tasks are rather difficult. 38/ -167-

Helsinki, use of psychotropic drugs (largely benzodiazepines) was associated with a relative injury risk 4.9 times the rate for non- medicated sober controls. 39/ The Finnish investigators have concluded that psychotropic drugs, particularly benzodiazepines, appear to have a role as contributing factors in personal injury traffic accidents. Of course, this role is definitely smaller than that of alcohol (one- fifth, in their estimate). In traffic fatalities -- as opposed to urban personal injury accidents -- they noted that "an over-representation of drug users" (other than alcohol) has not been convincingly demon- strated. 22/ It has been suggested that a mechanism by which the metabolites of diazepam or flurazepam might exert their deleterious influence on tests of visual motor coordination may be through impairment of eye move- ment in otherwise alert subjects. The first work in this regard was in 1963 when the inhibitory effects of benzodiazepines on saccadic (very rapid, small) eye movements was reported. 40/ In work recently completed in Finland it was demonstrated that 10 mg doses of diazepam caused sub- stantial impairment of divided attention tasks that require eye movement, but no such impairment of attention tasks in which eye movement was not essential. 41/ In the United States, it has recently been found that performance on difficult attention tasks is indeed impaired following administra- tion of diazepam. _ / In one prospective study, it was shown that these divided attention tasks seemed to have the clearest correlation with actual driving skills. _ / In the same prospective study of Helsinki bus drivers, coordination skills also correlated with the ability to avoid accidents. _ / The very recent evidence of impairment of attention as well as coordination skills by diazepam, plus the powerful interaction between these agents and alcohol gives the medical profession cause for concern that patients may not be adequately warned of hazards to them in traffic safety. In a study using a driving simulator in which subjects "drove" for 40 minutes starting 30 minutes after drug intake, 10 mg of diazepam increased the number of "collisions" in simulated emergency situations. 43/ Diazepam when given in combination with alcohol resulted in even more collisions, as would be expected; but a new phenomenon developed -- deviations off the road -- which had not been present when either alcohol or diazepam had been given alone. 43/ Such studies with driving simulators have not been performed with individuals who have been taking flurazepam; it may not be appropri- ate to generalize frog an acute experiment with diazepam. Nonetheless, the impairments on these tests are real, and the potential for practical consequences must be recognized. -168-

Of further interest is the finding that Wile certain anti- depressants — amitriptyline (Elavil(R) ~ and doxepin (Sinequan(R) )-- do not impair psychomotor test performance when taken alone, they do interact with alcohol in ways that are suggestive of appreciable decrements in driving skill s . 49 / Adding to the problem of convincing patients of the dangers of mixing these drugs with alcohol is the fact that individuals may not be able to correctly assess their functional impairment. In several of the studies cited, subj ects were asked to evaluate their perfor- mances after receiving the study drugged) or alcohol. In one study, subj ects receiving either flurazepam or amobarbital correctly sensed a decrement in their performance. 20/ In another, however, subj ects felt that N-desmethyldiazepam had no effect when there was a measur- able impairment of function. 29/ A further study reported that subj ects believed their performance on an adaptive tracking test had returned to normal at 16 hours after ingestion of pentobarbital or nitrazepam, whereas actually impairment continued to be demon- strable for at least an additional three hours. 28/ Some might erg ue that there should be a trade-off improved performance stemming from more satisfactory sleep offsetting the decrements due to the residual effects of the drugs. The small amount of evidence available does not support this hypothesis, however. Normal subj ects in one study receiving nitrazepam or butabarbital felt that they slept better, yet their performance was impaired. 44/ In another study, patients with anxiety neurosis and insomnia felt that their sleep was improved more by a week' s treatment with 20 mg N-desmethyldiazepam than by 200 mg amo- barbital, yet the patients on the former drug did significantly worse on daytime motor tasks. 45/ Thus, it is clear that sleep induced by hypnotics does not necessarily result in improved daytime performance, and considerable evidence shows that performance is often impaired . It has also been shown that subj ects taking nitrazepam, flurazepam or amylobarbitone may actually perform more poorly than subj ects who have in fact been partially deprived of sleep . 19 /~ / In one study of secobarbital, it was found that al though the drug lengthened subj actively reported sleep times of both normal volunteers and psychiatric patients, only the normals experienced undesirable "hangover" effects ~ sleepiness and difficulty in con- centrating ~ . 46/ The psychiatric patients did not report these phenomena any more often after secobarbital than after placebo; however, their background levels for sleepiness and concentration difficulties were already rather high. This difference between vol un Leer s and ps ychia tr ic pa tient s trig hi ig ht s the probl em of —169—

determining a genuinely pharmacological effect in a complex situation. As Hartmann recently pointed out, a drug's efficacy must be evaluated in appropriately selected insomniacs, but in order to be clear about drug-induced side effects studies of normal volunteers are essen- tial. _ / Another method of documenting residual effects of hypnotics is to review changes apparent on the electroencephalogram (EEG) when the subject is awake the next day. 30/,44/,48/ Such studies are often performed by separating the BEG signal into approximately five fre- quency ranges and determining the mean voltage in each range. In general, barbiturates and benzodiazepines tend to reduce the voltage in the lower frequencies (2.5 to 7.5 cycles per second); the barbi- turates, and sometimes the benzodiazepines, increase the voltage in the 13.5-26.0 cps range. These effects have been shown to last up to 18 hours after taking medication. No studies have been conducted for longer periods of time. In many cases, EEG effects last substantially longer than the drug-induced changes in psychomotor testing. Although their clinical significance is unclear at this time, they do show that changes in brain physiology clearly occur throughout the day following nocturnal hypnotic administration. C. Special Vulnerabilities to the Hazards of Hypnotics: Respiratory Difficulties, Kidney Disease and Pregnancy Elsewhere in this report, there are discussions of the special risks of prescribing hypnotics for certain groups of patients. These have included the elderly, depressed patients, patients with liver disease, alcoholics, and individuals who must operate complex machinery, such as industrial workers, motorists or pilOtse This section describes three other especially vulnerable groups: patients with respiratory difficulties, patients with impaired kidney function, and women of childbearing age who may be pregnant. Patients with Respiratory Difficulties Sleep apnea syndromes have been described in Chapter 4. Exacer- bation of respiratory difficulties and apneas during sleep have also been reported in patients with primary diagnoses of hypothyroidism, 50/ micrognathia, 51/ retrognathia, 52/ neurosurgical lesions, 53/ Shy- Drager syndrome, 54/ myotonic dystrophy, 55!-56/ poliomyelitis, 57/ and chronic obstructive pulmonary disease. 58/ As discussed in Chapter 4 in some detail, the association of sleep apnea with complaints of insomnia 59/ has been found in a number of sleep disorders centers. In addition, sleep at high altitudes has been linked with sleep apnea 60/-61/ and complaints of insomnia. 62/ -170-

For reasons of medical ethics, no experiment has ever been per-- formed directly testing the effects of hypnotic and sedative drugs on sleep-related respiratory disturbance. The central respiratory depressant effects of barbiturates, however, are well known. 63/ Other sedative hypnotics have also been found to have respiratory depressant effects, particularly when administered in repeated doses. 64/ The literature includes a number of case reports of patients with a known sleep apnea syndrome who need emergency resuscitative measures, including tracheotomy, when they suffered respiratory arrest after receiving pre-anesthetic medication. 65/,51/ Some researchers 66/ specifically caution against using pre-operative medications in such patients, and others 67/ have noted that "these patients are susceptible to respiratory arrest when small doses of sedative drugs are administered." These sleep-related respiratory dysfunctions are often un- diagnosed. In fact, sleep apneas have been found in some individuals whose only outstanding characteristic was that they snored 68/ or in normal, non-complaining individuals. 69/,70/ This poses a problem in the use of hypnotics. The apparently increased incidence of these occult sleep_related respiratory difficulties with advancing age 69/,71/ adds a new cautionary note in the prescribing of hypnotic and sedative drugs for elderly patients. In summary, a number of conditions, including the complaint of insomnia, have been associated with significant respiratory difficulties during sleep. The hazards in administering sedative-hypnotic compounds to such patients, whether their condition is known or occult, have not been fully evaluated. Nevertheless, the possible fatal response of such patients to hypnotic drugs (at non-toxic, therapeutic dosages) remains a contingency that must not be overlooked. Patients with Impaired Penal Function Impaired renal function is of particular concern with most commonly prescribed benzodiazepines because of their long-half lives and psychoactive metabolizes. This problem is evident not only when renal function is impaired in old age, but also when it is impaired by illness. In a cooperative study of more than 26,000 medical patients, Jick reported that renal impairment (as measured by the blood urea nitrogen concentration) was significantly correlated with adverse clinical effects of benzodiazepine hypnotics flurazepam, nitrazepam -- and of chloral hydrate. 72/ Interestingly, there was no association between renal impairment and adverse effects of penobarbital, secobarbital, and phenobarbital. -171-

Women of Childbearing Age In 1975, The Food and Drug Administration ordered that warnings must be added to all professional package inserts and advertising for benzodiazepines telling physicians that in view of teratogenic risk in the first trimester of pregnancy and "because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided." The warning alerts the physician to con- sider " the possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy" because many women do not realize they are pregnant until well into the first trimester . The basis for this action is reviewed in the September-November 1975 FDA Bulletin. 73/ 1~7O large-scale epidemiolog ical studies of a possible association of maj or birth defects with antenatal exposure to chlordiazepoxide and meprobamate had produced conflicting results. 74/,75/ Two other studies, 76/,77/ one in Atlanta and one in Finland, reported two to four-fold increases in risk of cleft lip with or without cleft palate in babies whose mothers had taken diazepam during the first trimester of pregnancy (or 4 cases per 1,000 live births, at most). This finding of weak teratogenicity needs substantiation, and a large scale epidemiolog ical study is now underway to pursue the matter. The study will not be completed until 1981 or 1982. 78/ It is possibly of related interest that diazepam was recently reported to directly and specifically inhibit the growth of embryonic chicken muscle in tissue culture. 79/ It has been suggested that barbiturates, especially phenobarbital, may be teratogenic. There has been controversy on this issue, however; at worst, teratogenic effects are of very low frequency. me investi- gators at the Boston University Drug Epidemiology Unit have calculated a slightly elvated standardized relative risk ( 1.29 ~ for cardiovascular anomalies after antenatal exposure to phenobarbital. 80/ Risks for cardiovascular anomalies among babies exposed to secobarbital and amobarbital were also elevated, but the total numbers of cases were so small as to make interpretation very difficult. More disturbing is a very recent report of a carefully designed, retrospective epidemiolog ical study of 127 children and adolescents with brain tumors. 81/ The results suggest, according to the authors, that as many as 8 percent of brain tumors in children and adolescents may be "attributable to use of barbiturates either by the child or prenatally by the mother." In their view, further research may establish that barbiturates (and other drug s) carry both teratogenic and carcinogenic risks for the developing nervous system of fetuses and children. —17 2—

In conclusion, the FDA warning about benzodiazepines in pregnancy probably should apply to all prescribing for women who may become pregnant. No drug has been proven 100 percent safe for fetuses, and so, if sleeping medication is not a matter of urgency (and it rarely is) hypnotics should be avoided altogether. D. Issues in the Long-term Use of Hypnotic Drugs Efficacy As noted in Chapter 2, during a given year at least one percent of the adult population uses a prescription hypnotic on a nightly basis for a period of two months or more. Yet' neither the effectiveness nor the risks of long term nightly use has been scientifically estab- lished. Only flurazepam and nitrazepam have been shown in sleep labor- atory studies to retain some favorable effects on objective sleep measures for as long as one month. Flurazepam, the most commonly pre- scribed hypnotic in the United States has not been studied beyond one month of continuous use. Most other hypnotics that have been studied in the sleep laboratory appear to lose their sleep-promoting properties within three to fourteen days. No hypnotic has had it cliniclal effects studied by sleep laboratory methods for more than four weeks and with more than ten insomniac subjects; nor have any ever been fully assessed with daytime measures of patients' mood, occupational performance, memory, cognition, psychomotor abilities and driving skills; nor has any evidence been presented demonstrating that chronic insomniacs are better off during the day as a consequence of having taken sleeping medication at night. There is some evidence to suggest that chronic use of hypnotics may actually exacerbate rather than ameliorate the sleep difficulties of some insomniac patients. In a comparison of ten chronic insomniac patients who had been taking various hypnotic drugs nightly from four months to ten years with 15 insomniac controls who were drug free, Kales and associates _ / found that the medicated patients had as great or greater difficulty falling asleep and staying asleep as did the unmedicated insomniacs. In every chronic drug patient, at least one of the key indices for objectively assessing insomnia -- sleep latency, wake time after sleep onset, or total wake time -- was elevated. Clinical investigators at other sleep laboratories have also suggested that hypnotics have become part of the problem rather than the solution for many insomniac patients -- some of whom appear to improve once their reliance on drugs is ended and they are drug free. -173-

In view of this, why is it that so many patients continue to regularly use prescription hypnotics? Unfortunately, available data are insufficient with which to answer that question. Aside from the study by Kales, 82/ no other published studies have been found that compare insomniacs with and without chronic hypnotic use. Since the subjects were not randomly chosen, it is possible that Kales investi- gated a biased sample of chronic hypnotic users, studying only those who were treatment failures or who were having difficulty. Eight of the lo patients took multiple doses each night. Clearly, those who regularly take low doses of hypnotics -- the subjectively satisfied patients -- are not likely to come to the attention of sleep researchers. Many responsible physicians report they have patients who have taken, for example, secobarbital 100 ma, nightly for many years without apparent difficulty and with subjective satisfaction. It is still an unanswered question, however, whether these patients are being helped or whether they continue regular use because of physical or psychic dependence or both. It is possible that a sedative or tranquilizing effect permits the patient to let himself fall and stay asleep -- the hypnotic drug induces a calm state of mind before and during sleep so that troubling thoughts do not intrude as much as they otherwise would. It is also possible that a powerful placebo effect is present, suggesting drowsiness to the patient. However, these drugs are certainly not physiologically inert placebos even when taken in low doses. Drug withdrawal insomnia or rebound insomnia has been well documented following abrupt withdrawal of both non- benzodiazepine 82/ and benzodiazepine hypnotics, 83/,95/ (but has not been reported following withdrawal of flurazepam). In patients who use sleeping medication for long periods of time, drug withdrawal insomnia may become a risk and contribute to their desire to continue regular use of hypnotics. This problem is espe- cially likely to occur in those who are taking multiple doses. Drug withdrawal insomnia has been attributed to several possible factors: to the patient's fear that he will be unable to sleep without the medication; to nightmares and intense dreaming that may accompany the REM rebound following withdrawal of REM sleep-suppressing drugs; or to over-excitability of the central nervous system following the withdrawal of a CNS depressant. When it is desirable to withdraw patients who have been using multiple doses of hypnotics, the importance has been emphasized of (1) gradual reduction in dosage, usually at the rate of about one therapeutic dose every week, and (2) careful education of the patient to expect transient psycho- physiological changes, such as increased dreaming, nightmares, and poor quality of sleep. 82/ -174-

There is little evidence that demonstrates the effectiveness of hypnotics with long term regular use. Although the most colon prescrip- tion is written for 30 pills, there is doubt that these pills would be effective if used nightly, at least in the case of nonbenzodiazepines. Also . these are enough pills, if taken alone, to be lethal in overdose . Rel lance on Drug s f or Sleep To is likely to develop nightly reliance on hypnotic drugs? Clift and his collaborators have conducted several studies in general practice settings in England, using the World Health Organization's broad definition of drug dependence. 84/-85/ Initially, the nightly drug dependent patients appeared to be older women who took single. Or, occasionally, double doses . (In contrast, patients severely depen- dent on barbiturates -- day and night -- tended to be young men . ~ Of the nightly hypnotic-dependent patients, 63 percent of the men and 52 percent of the women suffered from some chronic illness, including a high incidence of cardiovascular or orthopedic disorders and prior psychiatric illnessese About 94 percent of the hypnotic-dependent patients refused to discontinue the use of drugs. In two later studies, Clift and his co-workers studied the natural development of hypnotic drug dependence (nightly reliance on sleeping pills) in a prospective fashion. In one study, 50 consecutive adults with a primary complaint of insomnia were given hypnotics upon request. The selection of which nonbarbiturate was left to the discretion of the doctor: nitrazepam (43 patients), glutethimide (3 patients), and diazepam (4 patients). The mean age of the patients was 47 years at the onset; 34 were women, 16 men. At the end of six months, 17 of the sample still required regular prescriptions, while at the end of 12 months, 16 ~ 32 percent) did. By the end of the four years, 15 to 20 percent of the original patients were still dependent upon hypno tics . In a second study, 102 insomniac pa tients were randomly prescribed either amylobarbitone 200 mg or nitrazepam 5 ma. At the end of 12 weeks, 38 percent of the original group was still taking the hypnotic; at one year this was reduced to 8 percent. At the end of two years, about 8 percent ~ 6 of 79 patients who could be traced ~ still took the drug con- tinuously. However, if episodic users were also included, about 15 per- cent were taking the drug regularly. Nightly reliance on hypnotics developed equally of ten following prescription of nitrazepam or amylobar- bitone. Compared with patients who did not become dependent, the patient - who became dependent was more likely to be temporarily disturbed (even if this was judged to be a normal psychological reaction to a stressful life situation) and to show a tendency to increase the dose from one —175—

to two tablets nightly within the first two weeks. In this study, males were as likely as females to become dependent. Clift has suggested that the rate of hypnotic dependence can be reduced if the prescribing physician initially emphasizes that the hypnotic is not the solution to the patient's insomnia but only a temporary aid, if he limits the number of pills prescribed, and if he sees the patient in follow-up. Hazards It is generally not considered prudent medical practice to prescribe any medication for long periods of time without (a) a well understood indication, and (b) good evidence that the effectiveness of the drug is favorable in comparison with the natural history of the illness and the risks entailed in treatment. Because the definitions and natural history of insomnia are poorly understood at this time, the indications for use of a hypnotic are not clear. In addition, the evidence for long-tenm effectiveness of these drugs is lacking. A recent examination of some older data suggests that the long- tenm effects of hypnotics may be deleterious to health. 86/ Data from the American Cancer Society's prospective epidemiological study in 1959 show that the report by respondents that hypnotics were used "often" was associated with a 50 percent higher death rate at follow- up six years later than was the report of '7never" using sleeping pills. (This finding was unrelated to reported duration of sleep.) Although the meaning of this finding is far from clear and deserves further investigation, it does imply the possibility of long-term deleterious effects on the health of patients taking hypnotics. Since there is not a long history of clinical experience with the popular newer hypnotics, such as the benzodiazepines, possible effects from long-term toxicity are not known. It took over fifteen years to recognize the problem of tardive dyskinesia following the introduction of long-term anti-psychotic treatment with the pheno- thiazines. The administration of hypnotic agents undoubtedly affects normal physiology in ways not currently recognized. There is no way of judging the long-term consequences of these effects at this time (although there is no reason to assume that they will be as severe as tardive dyskinesia). The prolonged use of hypnotics poses problems in terms of good preventive prescribing practices. What happens if the regular user of sleeping pills becomes suicidally depressed, needs anticoagulant -176-

treatment, becomes pregnant, or develops chronic respiratory insuffi- ciency or sleep apnea? The risk of drug interactions increases with age as more drugs are used. The additive effect of hypnotics and alcohol is easy to overlook, as is the possibility that drug hangover (of which the patient may be unaware) may increase risk of daytime accidents. The risks of adverse residual daytime effects and nighttime confusion must be considered, particularly in the elderly. Some elderly patients are misdiagnosed as "demented" because of these side effects. Hypnotics may also increase the risk of becoming disoriented, frightened, or falling and suffering a fracture in the elderly. There is some danger that the widespread availability of hypnotics increases the risk of abuse and misuse by persons other than the patient. The patient's depressed wife may take them for suicide, his teenage son may use them for episodic intoxication, or his toddler may mistake them for candy. As suggested earlier in this report, the role of hypnotic use in suicide and accidents, as well as other causes of death, deserves further study. The risk of overdose in a suicidal attempt is apparently increased among patients who have become dependent on drugs for sleep. As Clift showed, patients with a history of psychiatric treatment or with con- current psychological distress are more likely to become dependent than those without. 85/ Moreover, both chronic insomniacs 87/,88/ and those who report using hypnotics 89/ are more likely to be depressed than others. In an English study of 100 suicides (44 of whom had used means other than drugs) Barraclough and associates 90/ found that half had been taking barbiturates regularly -- a third for more than two years, and a tenth for more than ten years. Even in a subgroup of 17 "impulsive" suicides, all had taken barbiturates regularly, usually for over a year. In the course of regular barbiturate prescribing, it was obvious that the physician's vigilance had been lowered. Many of the deceased had their prescriptions renewed repeatedly without even being seen by the doctor. This is a sobering reminder of the gravity of the problem of masked depression among general medical patients, especially among those with insomnia. In conclusion, it should be recognized that very little is known about the different types of patients who use hypnotics in conventional doses nightly, frequently, or infrequently on a regular basis. The risk/benefit ratios of long term hypnotic use have not been adequately weighed. Some current evidence suggests that the risks commonly out- weigh the benefits, though the reverse may be true for some sub-group of patients which as yet has not been studied. In view of the wide- spread long-term use of hypnotics, clinical investigation of the potential risks and benefits of this practice is required. -177-

E. An Overview of Available Studies of Hypnotic Drug Efficacy* There are insufficient data with which to judge the effective- ness of hypnotic treatment of "insomnia" or clearly measure the risk/ benefit ratios of these drugs in patients, especially in prolonged nightly treatment or in long-term intermittent use. No hypnotic agent has yet been comprehensively studied according to the criteria suggested earlier in this Appendix, which is not surprising since much recent progress has been incorporated into those expectations. Given the inadequacy of tests of hypnotic efficacy and safety, the results cited in the following overview of efficacy studies must be evaluated with great caution. Essentially, most investigators have been satisfied if their investigational drug shortens sleep latency, increases total sleep time or reduces wakefulness during the night. Yet, many investi- gators have studied normal volunteers rather than insomniac patients. With normal subjects who are already sleeping well, it is difficult to determine whether it will prove clinically significant that a drug shortens sleep latency, increases total sleep time, reduces wakefulness during the night, or increases subjective satisfaction with sleep. Similar limitations apply to studies of insomniac patients who actually sleep relatively well or whose sleep disturbance is not objectively established. A report that a drug is effective in prolonging sleep may be meaningless if the patients already sleep eight hours per night or if their sleep time was unspecified prior to treatment. In reports of studies of hypnotic drugs' effects on insom- niacs, investigators typically have failed to describe the patients' specific complaints (awakenings? difficulty getting to sleep?) and have neither indicated diagnostic possibilities about causes of the complaints, nor how the complaints of insomnia might be associated with difficulties (if any) in daytime sleepiness, mood, or performance. Furthermore, little attention has been given to the relationship, if any, between drug-induced changes in sleep measures and other meaning- ful clinical outcomes. Does a drug-induced increment of 30 minutes in total sleep time really make a difference to the insomniac and' if so, how? EEG~sleep laboratory reports indicate that the objectively demonstrable sleep-promoting effects of secobarbital, pentobarbital, and several other non-benzodiazepine drugs disappear after three to *The Technical Supplement to this report includes a comprehensive tabulation of 135 studies of hypnotic drug efficacy, both clinical studies (not using BEG procedures) and sleep laboratory studies. See also the review by Kay and associates. 91/ -178-

14 consecutive nights of treatment. However, there are very few clin- ical studies of the long-term effects of hypnotics, and no studies have been found of intermittent hypnotic drug use ~ which is probably the most common manner in which these drugs are taken). Thus, questions about subj ective relief of nocturnal distress have remained largely unexplored . Evidence to date suggests that in short term use, conventional doses of most of the available hypnotics do affect sleep more than placeboes do. The evidence is strongest for the barbiturates ~ seco- barbital, pentobarbital, and amobarbital, possibly phenobarbital and butabarbital ), methyprylon , and the teen zod ia zepines ~ f lurazepam and nitrazepam and possibly others such as triazolam, diazepam, and oxazepam) . Benzodiazepines In addition to the numerous reports of sleep prolonging effects of short-term administration of benzodiazepines, two long-term EEG sleep studies ~ on a total of 10 insomniac patients) suggested that flurazepam 30 mg tended to increase total sleep time or decrease wakefulness ~ according to the studies and the measures employed ~ with- out development of complete tolerance at the end of a month; nor did signs of physical dependence, such as "rebound insomnia ," appear immediately upon withdrawal of the drug. 92/-93/ In the study which included non-EEG measures, 93/ subj ective assessments of sleep latency and total sleep time improved, and there was no problem in subj ective sleepiness, ascertained 15 minutes after arising in the morning. Neither study otherwise measured daytime sleepiness, performance, mood, or subj ective satisfaction. Lack of tolerance to the hypnotic properties was al so reported in a non-EEG, one month study of fluraze- pam 15 mg in elderly insomniac patients. 94/ Patients reported significant benefits on two dimensions, onset of sleep and quality of sleep, as compared with placebo treatment. (Flurazepam was judged, however, to be significantly inferior to the iT~vestigational benzo- diazepine triazolam on duration of sleep). 94/ Absence of tolerance has also been reported with another ben- zodiazepine, nitrazepam, which is commonly used outside of the United States. In a ten week EEG sleep study conducted in 10 no ~ ~al volunteers with an average age of 57 years, it was found that a dose of 5 mg increased total sleep time by an average of about 35 minutes per night throughout the whole study. 95/ In contrast to reported resu] ts for flurazepam, however, significant rebound insomnia occurred during the first week of withdrawal. Subj ective estimates of sleep and satisfaction were not included, nor were there measures of daytime performance, mood, sleepiness, and so forth . —179—

At the Royal Air force Institute of Aviation Medicine oxazepam (Serax(R)) and diazepam (Valium(R)) were found to prolong total sleep time in healthy volunteers. 35/-36/ Both of these drugs were found to be free of residual effects nine hours after administration -- i.e., there was no impairment of performance on a difficult adaptive tracking test of eye-hand coordination. They were considered, there- fore, to be superior hypnotics for occasional use by pilots and others engaging in skilled professions, and definitely safer than the more commonly prescribed hypnotics, nitrazepam and flurazepam. The latter drugs, as described earlier in this Appendix, impaired performance well into the next afternoon (flurazepam) or early even- ing (nitrazepam) in these single dose trials. 28/ In these single dose studies, neither diazepam nor oxazepam altered the architecture of the sleep stages in any significant manner. 30 mg of oxazepam and lo mg of diazepam each lengthened total sleep time by about 35 minutes and 25 minutes, respectively. Diazepam shortened the sleep latency in normal volunteers by 11 minutes (from an average of 31 minutes down to an average of 21 minutes). No effect on sleep latency was observed with oxazepam. Although oxazepam is a rapidly metabolized "short-acting" drug with no metabolites, initially it is rather slowly absorbed from the intestine; therefore it has predictably little effect on sleep induction, but seems to aid in sleep ma~n- tenance. 24/ Barbiturate Hypnotics A detailed examination of the available studies reveals some of the limitations we have in generalizing about efficacy of hypnotic agents. For example, although secobarbital has been a popular and well established barbiturate hypnotic, current opinion about its effi- cacy is strongly influenced by information that tolerance develops quickly to its sleep-promoting properties. The most dramatic evidence for this has come from one sleep laboratory study in which eight insom- niacs received secobarbital 100 mg nightly for two weeks; placebos were administered before and after secobarbital. 96/ During the first three days, secobarbital was effective in significantly reducing wake time after sleep onset and total wake time, and in increasing the percent of sleep time; by the end of two weeks, however, sleep record- ings did not reveal any significant changes in any sleep measure compared with baseline, thus indicating that tolerance had developed. (Incidentally, only rather minor changes in sleep stages were noted during withdrawal, with little "REM rebound.") The design of this study is typical of modern sleep laboratory protocols. As with many such studies, its value could have been greatly enhanced if certain other information had been described: sex; psychiatric diagnosis (if any, other than "not psychotics"; -180-

diagnostic type of insomnia; past medications (including hypnotics); description of "wash out" period before beginning the study (if any); time of drug administration; total sleep time, whether patients were allowed to sleep late until they awakened naturally; information about subjective evaluation of sleep; and measures of daytime alertness, mood, and performance. Although total sleep time was not presented, it can be estimated to have been about 400 minutes during baseline, and to have increased to about 440 minutes during the first three nights of drug administration, after which tolerance developed. Since this group of patients was apparently sleeping relatively well before treatment, it is possible that secobarbital's effects would differ in magnitude and duration in patients with more severe problems. If they had received hypnotics recently, it is also possible they might have meta- bolized secobarbital rapidly and had less hypnotic effect or more rapid tolerance than patients who were truly drug-free. Subjective estimates of efficacy and daytime measures of mood and psychomotor performance would have been important with regard to the issue of tolerance as well as establishing the full range of benefits and side effects. The evidence for tolerance seems convincing but would be more so if it had been reported in other clinical studies. Two reports from the Boston Collaborative Drug Surveillance study provide some of the most favorable data supporting the efficacy of secobar- bital but these studies neither mention the issue of tolerance nor provide any information on duration of drug administration. 6/-7/ Their double blind study in hospitalized medical patients suggested that secobarbital was identical to flurazepam in efficacy and side effects, and that both drugs were superior to placebo. Since many physicians believe that secobarbital in low doses does retain its effectiveness for some patients for long periods of time, the issue of tolerance and efficacy may not be settled yet. The data cited for secobarbital are representative of data for other barbiturate hypnotics. Pentobarbital, for example, was noted as generally effective and relatively free of side of effects in the Boston Collaborative Study, again without a statement of duration of administration. 7/ In a sleep laboratory comparison of pentobarbital 100 mg and flurazepam 30 mg administered nightly for 28 nights to 4 insomniacs, each, both drugs were reported to effectively promote sleep initially, but tolerance developed to pentobarbital 97/ One exception to this tolerance was that pento- barbital effectively reduced the number of wakes throughout the drug period. Again, much desirable information was missing, as in the study of secobarbital. 96/ -181-

Nonbarbiturate, Nonbenzodiazepine Hypnotics The data base of research supporting the use of certain widely prescribed nonbarbiturate drugs as hypnotics is surprisingly meager, in particular in the cases of glutethimide (Doriden(R)), ethchlorvynol (Placidyl(R)) and methaqualone (Quaalude(R)~. This raises questions about relative efficacy and thus the risk/benefit ratio -- for these drugs. While glutethimide has been judged superior to placebo in some studies, it has been found to be inferior to these other commonly used hypnotics, in terms either of its sleep promoting effects or its side effects: secobarbital, 98/ methyprylon, 98/-99/ lorazepam, 100/ ethchlorvynol, 101/ and flurazepam. 7/ The EEG sleep effects in insomniac patients have been short lived, inconsistent, and disruptive of the stages of sleep. 103/,111/ Ethchlorvynol constituted seven percent of the prescriptions for hypnotics in 1977 and is widely advertised to the medical profession. However, its effects on sleep were not superior to placebo in two of three clinical (non-EEG) studies reviewed; 104/-105/ in the third, it induced sleep more promptly than placebo or glutethimide. 101/ The two available EEG sleep studies in insomniacs indicate that its effects were weak, short lived, and not statistically different from placebo 106/, 17/ although it did improve sleep latency and some other variables. These sleep laboratory studies only included four subjects each, and "statistical significance" may not be a clinically relevant parameter. Most disconcerting, however, was the report of adverse daytime effects on all four subjects in the most recent study of ethchlorvynol by Kripke and associates. 17/ These included loss of concentration, confusion, less vigor and alterations in mood. These side effects were not reported after administration of placebo. In two of the four subjects these effects were severe to the point of being disabling. The data reviewed for methaqualone suggest that it may be useful on a short-term basis, particularly for elderly patients. 107/-110/ In one study, however, methaqualGne was indistinguishable from placebo, and clearly inferior to secobarbital. 98/ In EEG studies, its effects have been inconsistent, weak, short lived and disruptive of the stages of sleep during and after treatment. 111/-113/,106/ In view of these observations on relative efficacy, the risk/ benefit ratios of glutethimide, ethchlorvynol, and methequalone need further consideration. As noted in Chapter 1 of this report, gluthe- thimide is thought to have a low margin of safety in overdose, 102/ and it has been used in addiction syndromes very similar to those of barbiturates. Methequalone is currently abused because of its -182-

reputed euphoriant and aphrodisiac properties; it has been associated with polyneuropathy. 114/ Its hypnotic effects, however, especially in the elderly do deserve further investigation. Ethchlorvynol may have considerable toxicity in therapeutic dosages, 17/ and it too has become attractive to drug abusers. 115/ Methyprylon (Noludar(R)) has been assessed fairly extensively in non-laboratory studies of chronic disease patients, psychiatric patients with sleep disturbance and short-term medical patients. In all studies reviewed, it was rated by patients or nurses to decrease various measures of sleep disturbance more than placebo; there are several favorable reports of relative efficacy compared to other drugs. 116/-117/,_/-99/ There have, however, been no studies lasting longer than two weeks. EEG documentation of its efficacy is lacking. One quality of interest about methyprylon is that it has a particularly short half-life. In sum, clinical studies have provided some promising data, but further EEG investigation is indicated. Despite the widespread popularity of chloral hydrate, much of the evidence reviewed suggests that it is only weakly effective, in comparison with placebo or other well known hypnotics. It has not apparently been shown to be effective in insomniac patients in a sleep laboratory study, aside from one report of initial reduction in sleep latency. 112/ This study was conducted, however, in insomniacs with little evidence of objective sleep disturbance. In normal volunteers, there is one study suggesting that chloral hydrate did increase total sleep time by 15 minutes per night over a one month period. 118/ Further studies are needed to assess its short and long term effects in moderately or severely affected insomniac patients, including comparison of 1000 mg and 500 mg doses. Comparisons of Efficacy While it is true that EEG sleep laboratory studies suggest the comparative superiority of benzodiazepines over barbiturates with nightly administration for two weeks or longer, other studies suggest that in short-term use barbiturates are equal or even superior to benzodiazepines. As mentioned earlier, in the Boston Collaborative Drug Surveillance Study judged secobarbital and flurazepam as equally effective for hospital patients. 5/ Phenobarbital was reported to be superior to nitrazepam in a three night study of psychiatric patients who had difficulty falling asleep because of disturbing thoughts. 119/ In another short term study, amylobarbitone had a greater hypnotic effect than chlordiazepoxide in psychiatric patients. 120/ Other studies indicate that amobarbital may be equal to nitrazepam 121/-123/ or flurazepam (over a 14 day period). 124/ Butabarbital has also -183-

been reported to be equivalent to nitrazepam. 125/-126/ In a clinical comparison of nitrazepam, secobarbital, methyprylon, and placebo (each administered in random order for five night blocks to elderly chronically hospitalized medical patients), nurses rated all the active drugs to be equally efficacious in sleep induction, duration, and quality as compared with placebo; 117/ the only difference was that nitrazepam 10 mg (but not 5 ma) caused more side effects than the other drugs. In one study of medical patients with respir- atory disorders, flurazepam was judged to be clinically superior to amobarbital, especially in those patients who had previously been treated with benzodiazepines. 127/ Further studies are clearly indicated to establish the relative advantages and disadvantages of these different drugs in specific populations or situations. Since it has been shown 92/ that the full hypnotic effect of flurazepam is not achieved until the second or third night of use, it is possible that an alternative drug would be superior to fluraze- pam when a hypnotic is to be used acutely or occasionally. Even more important is the possibility that drugs that are metabolized more rapidly than flurazepam would carry less risk of residual adverse effects. Such drugs include the barbiturate hypnotics, chloral hydrate, diphenhydramine, methyprylon, L-tryptophan and the shorter acting benzodiazepines (such as oxazepam and lorazepam). Future studies should attempt to clarify the relative benefits and risks of benzodia- zepines and other types of hypnotics in specific clinical situations. The sleep-promoting effects of "non-hypnotics" -- phenothiazines, tricyclic antidepressants, daytime anxiolytics and antihistamines -- need further study since these drugs appear to be used fairly often as sleeping aids in insomniac patients. Each type of drug has some limited research evidence supporting its utility, but none have been studied extensively. 128/-131/,35/-37/ As indicated in Chapter 1 of this report, the dietary supplement L-tryptophan has shown some promise as a mild hypnotic, 132/ but has not been evaluated for clinical use in comparison to standard drugs. -184-

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