Hypnotic Efficacy and Safety

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Recently, the need for improvement in the evaluation of hypnotic efficacy, as well as for more rational prescribing practices, has received increased federal.
Sleep, 4(2): 125-128 © 1981 Raven Press, New York

Editorial

Hypnotic Efficacy and Safety Recently, the need for improvement in the evaluation of hypnotic efficacy, as well as for more rational prescribing practices, has received increased federal attention. In 1977, at the request of the White House and the National Institute of Drug Abuse, the Institute of Medicine (10M) initiated a study of sleeping pills, insomnia, and medical practice. The report of the study was published early in 1979 (Institute of Medicine, 1979) and among other things it recommended additional research on hypnotic efficacy and a national education program for both professionals and the general pUblic. Later in the year, Dr. Julius Richmond, the Surgeon General of the United States, announced "Project Sleep: The National Program on Insomnia and Sleep Disorders." In remarks at a Washington, D.C. press conference, the Surgeon General stated, "Project Sleep will be a major educational and research effort aimed at increasing the level of knowledge by physicians, their patients, and the public about the nature of insomnia and sleep disorders and their treatment. Our primary aim will be to influence physicians' diagnostic and treatment practices, including their prescribing habits. The second aim is to improve the knowledge, attitude, and pill-taking practices of all persons who use sleeping pills. The third is to identify the gaps in our medical knowledge of sleep disorders and medications with the research necessary to expand our treatment. " These are laudable goals, and the emphasis on sleeping pills is appropriately strong. Professional sleep researchers will have a vested interest in these problems and their expertise will be essential. Who else can determine what knowledge about sleeping pill use should be disseminated, and who else can identify the important gaps in this knowledge? As past members of the 10M study group, we would like to comment upon some of the key issues in the clinical evaluation of hypnotic drugs that have been considered during and since the review. Detailed references and supporting data for our comments are available in the Institute of Medicine report (Institute of Medicine, 1979) and technical supplement, a current book (Mendelson, 1980) and a review article (Gillin and Mendelson, 1981). Subject Selection in the Clinical Polysomnographic Evaluation of Hypnotics Studies of hypnotic efficacy have not considered the complexity of the complaint of insomnia, having failed to take into account its severity, duration, multiple causation, and the variety of objective and sUbjective complaints relating to both sleep and ensuing daytime function. Subject selection has often been based on arbitrary subjective and/or objective sleep parameter criteria (e.g., sleep latency greater than 30 min or total sleep time shorter than 6 hr). While there is much to commend attempts to quantify the nighttime sleep parameters of ins om-

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niacs, such selection procedures can incur serious difficulties. Results may not be relevant to the majority of patients encountered in clinical practice; for example, many insomniacs appear to have little objective sleep disturbance. A related problem is that it may be difficult to recruit subjects. In one study, arbitrary inclusion criteria necessitated screening 230 chronic insomniacs to find seven subjects who qualified (Dement et aI., 1978). Recent publication of the Diagnostic Classification of Sleep and Arousal Disorders (Association of Sleep Disorders Centers, 1979), the first standardized nosology for insomnia, should help to alleviate these problems by facilitating the development of more specific and/or more representative inclusion criteria. Certain groups of subjects deserve special evaluation. For example, elderly individuals are more likely to complain of insomnia and to take disproportionately high doses of hypnotics; they usually show different rates of metabolism and volume of distribution and are more likely to suffer from concomitant medical difficulties. Daytime Residual Effects and Sleepiness/Alertness Just as many insomniac complaints include daytime deficits, consideration of hypnotic effect on these symptoms is crucial. Investigators must note daytime residual ("hangover") effects such as impairment of psychomotor performance, attention, vigilance, daytime sleepiness, and alternations in waking EEG patterns. Simultaneous study of daytime and nighttime hypnotic effect is required; improved nocturnal sleep without associated alleviation of daytime sleepiness and fatigue is of questionable value. Pharmacokinetic data are helpful in interpreting effects of hypnotics administered at night on daytime sleepiness/alertness. Effects of Hypnotics on Nocturnal Physiology The extent of sleep disturbance and hypnotic efficacy should not be measured by EEG sleep stages only. Respiratory and cardiovascular parameters are of particular importance. Can a hypnotic be declared "beneficial" if it induces impaired breathing? A number of individuals, such as heavy snorers and sleep apnea patients, already have disturbed breathing during sleep. It is important to realize that such impaired breathing may exist independently of other symptoms in these patients, and is undiagnosed in the vast majority. It is therefore essential that the effect of hypnotics on borderline or clinically impaired breathing be specifically evaluated. Other Design Issues In addition to issues pertinent to any pharmacologic study (e.g., number of subjects, dose, duration of treatment, double-blind methodology, duration of drug-free pre-trial period, etc.), specific design questions confront the investigator who evaluates hypnotic efficacy. When and for how long should subjects be allowed to sleep? Do subjects choose their own bed and arising times or do they follow a set schedule? Do they awaken spontaneously or by alarm? When do they

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take medication? Is total recording time fixed (and, if it is, for how long) or ad libitum? Lack of standardization across studies impairs the ability of researchers to compare data from different laboratories. Reporting Issues Many publications omit basic information such as subjects' age, weight, sex, and past history of drug use or participation in previous studies, number of subjects per bedroom, as well as most of the methodologic issues already mentioned. Basic terms used in reports are left undefined (e.g., "wake time after sleep," "sleep onset," "REM latency"). In addition to those problems which result from the lack of widely accepted standards· for hypnotic efficacy study, journal editors frequently are reluctant to allow room for adequate characterization of subjects and their individual efficacy results. Confirmatory studies or studies with negative results rarely see the light of day because they are less exciting. Perhaps special journal editions or supplements could provide a mechanism for publishing such results. Finally, we suggest a publication of standard terms (compiled by an appropriately representative task force) perhaps preceded by a national consensus conference that would address the critical need for consistency of study parameters and reporting. Standards for Applying Efficacy Research Findings to Clinical Practice What does it mean to say a hypnotic is "effective?" In searching the literature we often find that a drug was declared "effective" although only trivial changes were documented. Although very small changes in sleep parameters may be statistically significant, the implications for clinical benefit are lacking. In addition, it is travesty to assume that a benefit exists, regardless of the changes in nocturnal sleep parameters, if the patient feels "zonked" during the day. Considering the frequency with which hypnotics are prescribed we find it astonishing that there is no general agreement concerning the indications for or the goals of hypnotic therapy. Investigators must develop clear indications for hypnotic therapy as well as precise and clinically meaningful criteria for successful treatment. Conclusion As recently as 1977, the Food and Drug Administration (FDA) issued guidelines for the evaluation of hypnotic efficacy (Food and Drug Administration, 1977). These constitute a commendable beginning, but the field of sleep disorders is moving rapidly and the need for updating existed almost before these guidelines were published. In September of 1980, an Association for the Psychophysiological Study of SleeplAssociation of Sleep Disorders Centers select committee, made up of basic and clinical researchers and representatives from pharmaceutical companies, composed a number of suggestions for revision of the current FDA guidelines.

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Most ofthese suggestions were similar to those enumerated above. We hope that they will be promptly incorporated. Such positive steps will improve the evaluation of hypnotic efficacy and should encourage the development and marketing of more effective sleeping pills. Finally, the best possible principles for hypnotic prescribing and use should be widely disseminated to professional and lay communities by Project Sleep. The time has arrived to bring about a clear relation between research studies on hypnotic efficacy and the use of hypnotics in clinical practice. The potential benefits to insomniacs all around the world are substantial and it is up to sleep researchers and sleep disorders specialists to do everything they can to improve hypnotic effectiveness and foster better clinical practice. Wallace B. Mendelson J. Christian Gillin William C. Dement References Association of Sleep Disorders Centers. Diagnostic Classification of Sleep and Arousal Disorders, First Edition, prepared by the Sleep Disorders Classification Committee, HP Roffwarg, Chairman, Sleep 2:1-137, 1979. Dement W, Carskadon M, Mitler M, Phillips R, and Zarcone V. Prolonged use offlurazepam: A sleep laboratory study. Behav. Med. 5:25-31, 1978. Food and Drug Administration. Guidelines for the Clinical Evaluation of Hypnotic Drugs. HEW Publication No. FDA 78-3051, 1977, 13 pp. Gillin J and Mendelson W. Sleeping pills: For whom? When? How long? In: GC Palmer (ed), Neuropharmacology of Central Nervous System and Behavioral Disorders, Academic Press, New York, 1981, pp 285-316. Institute of Medicine. Report of a Study: Sleeping Pills, Insomnia, and Medical Practice. National Academy of Sciences, Washington D.C., 1979, 198 pp. Mendelson W. The Use and Misuse of Sleeping Pills. Plenum Press, New York, 1980, 220 pp.

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