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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

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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-

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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-

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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-

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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-

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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-

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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-

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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-

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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-

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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-

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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-

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29 30 32 33 34 35 36 37 38 Tansella, M., Zimmermann-Tansella, C., and Lader, M., The residual effects of N-desmethyldiazepam in patients. Psychopharmacologia 38: 31-90, 1974. Bond, A.J. and Lader, M.H., The residual effects of flurazepam. Psychopharmacologia 32:223-235, 1973. Kornetsky, C., Vates, T.S., and Kessler, E.K., A comparison of hypnotic and residual psychological effects of single doses of chlorpromazine and secobarbital in man. Journal of Pharmacology and Experimental Therapeutics 127:51-54, 1959. Kornetsky, C. and Orzack, M.H., A research note on some of the critical factors on the dissimilar effects of chlorpromazine and secobarbital on the digit symbol substitution and the continuous performance tests. Psychopharmacologia (Berl.) 6:79-86, 1964. Bixler, E.O., Kales, A., et al., The effects of hypnotic drugs on performance. Current Therapeutic Research 15:13-24, 1973. Salkind, M.R. and Silverstone, T., A clinical and psychometric evaluation on flurazepam. British Journal of Clinical Pharmacology 2:223-226, 1975. Nicholson, A.N., Stone, B.N. and Clarke, C.H., Effect of diazepam and fosezepam (a soluble derivative of diazepam) on sleep in man. British Journal of Clinical Pharmacology 6:533-541, 1976. . Borland, R.G., Nicholson, A.N., and Wright, C., Behavioral sequela of methaqualone in man in the monkey (macaca mulata). British Journal of Clinical Pharmacology 2:131-141, 1975. Nicholson, A.N. and Stone, B.N., "Hypnotic Activity of 3-Hydroxy, N-desmethyldiazepam (oxazepam), British Journal of Clinical Pharmacology 5:469-472, 1978. Linnoila, M., Erwin, C.W., et al., Effects of alcohol on psycho- motor performance of men and women. Journal of Studies on Alcohol 39:745-758, 1978. -188-

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39 40 41 42 43 44 45 46 48 Ertama, L., Honkanen, P. and Kuosmanen, P., Drugs as a risk factor in accidental falls. Proceedings of the Seventh International Conference on Pharmacology, Paris 1978. (New York: Pergammon Press), (in press), 1978. Gentles, W. and Thomas, E.L., Effect of benzodiazepines upon saccadic eye movements in man. Clinical Pharmacology and Theraceutics 12: 563-574, 1971. Ertama, L., Hakkinen, S., Linnoila, M. Unpublished. Moskowitz, H. Unpublished. Linnolia, M., and Mattila, M.J., Drug interaction on driving skills as evaluated by laboratory tests an dby a driving simulator. Pharma- kopsychiatry 6:127-132, 1973. Bond, A.J. and Lader, M.H., Residual effects of hypnotics. Psychopharmacologia 25:117-132, 1972. Tansella, M., Siciliani, O., Burti, L. Schiavon, M. and Zimme`-man- Tansella, C., N-desmethyldiazepam and amylobarbitone sodium as hypnotics in anxious patients: Plasma levels, clinical efficacy and residual effects. Psychopharmacologia 41:81-85, 1975. Bloomfield, S.S., Tetreault, L., Lafreniere, B. and Bordeleau, J.M., A method for the evaluation of hypnotic agents in man, Journal of Phamacology and Experimental Therapeutics 156:375-382, 1967. Hartmann, E., The Sleeping Pill (Yale University Press: New Haven), 1978. Malpas, A., Rowan, A.J., Joyce, C.R.B. and Scott, D.F., Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium. British Medical Journal 2:762-764, 1970. -189-

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