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Sleep, 5:S46- S52 © 1982 Raven Press, New York Pharmacological and Medical Considerations in Hypnotic Use T. Roth, F. Zorick, R. Wittig, and T, Roehrs Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan The purpose of this presentation is to provide a survey of the clinical use of hypnotics. To this end, we shall first discuss the relation of pharmacokinetic properties and the clinical effects of hypnotics. The second part will present some guidelines for hypnotic use based on current knowledge of sleep disorders medicine. There is much confusion over the definition of a sedative/hypnotic. For the purpose of the present overview, a sedative/hypnotic is defined as any compound that promotes sleep (sleepiness-drowsiness, falling asleep, and staying asleep) and inhibits wakefulness (awakening, maintaining wakefulness, and functioning while awake). Many different groups of drugs (e.g., barbiturates, tricyclics, antihistamines, benzodiazepines) can be and are used as hypnotics. Of the various drug classes, benzodiazepines are the most commonly used compounds (1) and, therefore, will be discussed more extensively than other classes. To understand the effects of hypnotics, one must first recognize that hypnotic drugs do not simply affect rapidity of falling asleep and time of waking. In fact, they have multiple effects. Those biological processes currently known to be affected by hypnotics are: (a) sleep architecture, (b) sleep physiology, (c) sleep pathophysiology, and (d) sleep efficiency. Effects on Sleep Architecture. Virtually all psychotropic drugs affect sleep stages, suppressing stage 3-4, the rapid eye movement (REM) stage, or both. A thorough review of the effects of psychotropics on sleep stages is beyond the scope of this paper, and can be found in an article by Kay et aL (2). Benzodiazepines were once thought to have no effect on REM sleep; however, it is well documented that benzodiazepines, like all other sedative hypnotics, suppress REM sleep. Overall, benzodiazepines have dose-related effects on virtually all sleep stages (3). They decrease stages 1,3 -4, and REM. In comparison with other psychotropics, they suppress delta sleep (stage 3-4) as much as any other drug group. On the other hand, they are mild REM suppressants as compared with tricyclic antidepressants (4). Although the clinical effect of increasing or decreasing sleep stages is currently not well understood, the effect of drugs on sleep Address correspondence and reprint requests to Thomas Roth, Ph.D., Sleep Center, 512 NCP, Henry Ford Hospital, 2799 w. Grand Boulevard, Detroit, Michigan 48202. Key Words: Hypnotics-Sleep disorders-Pharmacokinetics. S46 HYPNOTIC USE S47 stages needs to be documented and further investigated. Certain sleep disorders-night terrors, enuresis, somnambulism, and sleep apnea-have been associated with different stages of sleep (5). Clearly, drugs that affect sleep stages have the potential to affect these disorders. Effects on sleep physiology. Determining the effects of psychotropic drugs on physiological function is a major factor in the assessment of drug safety. Typically, their effects on cardio-respiratory functioning are emphasized. Although there is increasing evidence that sleeping physiology and waking physiology are in some cases quite different, little work has been done on the effects of hypnotics on physiology during sleep (6). This is important, because hypnotics have the greater part of their effect on sleeping physiology. One of the few studies done on this topic was reported recently (7). The authors evaluated the effects of two benzodiazepines (triazolam 0.5 mg and flurazepam 30 mg) on heart rate during sleep in healthy volunteers and found that both of these benzodiazepines produced small, but statistically reliable, increases (4- 5 bpm) in heart rate during both REM and non rapid eye movement (NREM) sleep. In contrast, waking heart rate after oral administration of benzodiazepines is not affected, according to previous reports. Although these increases in heart rate are not clinically significant, this study suggests that hypnotic drugs may affect sleep physiology differently from waking physiology. Therefore, inferences from studies of waking physiology may be quite misleading. Effects on sleep pathophysiology. In referring to effects on pathophysiology, we mean the effects of hypnotics on physiological function characteristic of specific sleep disorders. Much is said about the effects of various drugs on nocturnal myoclonus and sleep apnea. However, there are no systematic data demonstrating differential effects of hypnotics on sleep disorders. Recent work on the effects of central nervous system suppressants has shown that they increase the frequency and the duration of apnea episodes in sleep. This has been demonstrated for alcohol (8) as well as benzodiazepines (9). Although these data are of critical importance in using hypnotics, there are several limitations to these data, which must be understood. First, it is essential to understand that central nervous system (CNS) suppressants have only been shown to exacerbate apnea, not create it. There are no data to suggest that a patient with normal respiration during sleep will develop apnea if given a hypnotic. The question arises as to whether a patient with compromised respiration (i.e., snoring) may become fully obstructed if given a hypnotic. Second, the consistency of this effect is unclear. Reports on the effects of benzodiazepines on apnea are all single case studies. No statistical data on a large group of patients have been reported to date. In fact, anecdotal reports have been presented showing that some patients actually show a decrease in the number ofapneas when given benzodiazepines. This inconsistency of results may be due to (a) the night-to-night variability of infrequent apneas (10), (b) differences among patients with different types of apnea (central versus upper airwaY-ll), and (c) differences among patients with regard to severity of apnea. Finally, it is unclear how benzodiazepines affect apnea. One hypothesis is that they are suppressants of respiration during sleep. An alternative explanation is that they aggravate apneas by increasing hypoxic and hypercapnic arousal thresholds. Sleep, Vol. 5 (Suppl. I), 1982 S48 T. ROTH ET AL. This latter explanation is more appealing, as benzodiazepines do not actually create apnea, but only make it worse. Further, benzodiazepines are known to increase other sensory thresholds (e.g., auditory awakening thresholds). Since apneas are a relatively common occurrence in sleep, especially in the elderly (12), it is critical that research be carried out to clarify the relation between hypnotics and disturbed breathing during sleep. Further, there is no systematic research on the effect of hypnotics on other specific sleep disorders, such as restless legs syndrome, periodic leg movements during sleep, circadian dysrhythmias, or parasomnias. Effects on sleep efficiency. Sleep efficiency is an index of the time in bed spent asleep, and is reflective of both sleep induction and sleep maintenance. Sleep induction refers to the ability of a hypnotic to induce sleep, and is usually measured by latency to stage 2 or latency to persistent sleep (first 10 min of continuous sleep). Sleep maintenance refers to the drug's ability to keep a patient asleep after sleep onset. This is usually measured by the number of awakenings and total time awake after sleep onset. Virtually all hypnotics studied, if given in adequate dosages, improve at least sleep maintenance and typically produce more rapid sleep induction as well. It is most important to recognize that all effective hypnotics also impair waking functioning as long as they are pharmacologically active. Measures of psychomotor functioning show significant decreases when subjects are awake (13). These drugs also decrease the patients' ability to respond to the external environment, as shown by increases in auditory awakening threshold (14). Overall, it is difficult to select a hypnotic solely on the basis of efficacy. The mqjor differences lie in their side effects and safety. Pharmacological properties. To understand the reciprocal relationship between efficacy and safety, it is important to review the various pharmacological and clinical characteristics of hypnotics, as well as their interrelation. Those pharmacological properties that are clinically important include toxicity, rate of absorption, rate of elimination, and potential for interaction with other drugs. No drug is free of toxic effects. An index referred to as the therapeutic index, or the margin of safety, is used to describe the relative safety of drugs. Therapeutic index is defined as the ratio of the dose producing lethal effects in 50% of the population to the dose producing therapeutic effects in 50% of the population. In other words, the larger the index the safer the drug is. The benzodiazepines, as compared with all other sedative hypnotics, have larger therapeutic indices (IS), which is one reason they have become the preferred hypnotic. But it should be noted that these indices have not been determined in studies on patients with insomnia or with regard to combination with other drugs. The indices may be quite different under these varying conditions. Another important characteristic is rate of absorption. A drug that is rapidly absorbed and thus becomes effective with a minimum of delay is less likely to encourage increased dosing when the patient is not sufficiently sedated after administration. Drugs taken by mouth are absorbed for the most part from the gastrointestinal tract. When in solid form, the dissolution of a drug becomes the limiting factor in its absorption. Studies have assessed the effect of pharmaceutical formulation (e.g., soft capsule versus hard-shelled capsule) on blood levels. Dif- Sleep, Vol. 5 (Suppl. I), 1982 HYPNOTIC USE S49 ferent formulations have been shown to produce differences in blood levels within 20 to 30 min of administration, which then disappear within 60 min (16). The critical question is, what is the clinical significance of that difference in rate of absorption, particularly for patients with complaints of difficulty in falling asleep? In addition to rate of initiation, the duration of drug action is also of clinical importance. Metabolism and elimination rates are thought to control the termination of drug effect; however, the distribution of a drug is also important, particularly with single doses and highly lipid-soluble agents (17). This whole process, by which the activity of a drug is terminated (distribution, metabolism, and elimination), is described in terms of various half-lives. Half-life, in simple terms, can be defined as the time in which half of the drug is eliminated from the body. With the various benzodiazepines there are great differences in half-life, which varies from 3 to 100 h (18). The clinical significance of half-life, with respect to both effects on sleep following a single dose or repeated doses and functioning the next day, has been documented. In general, hypnotics with longer half-lives (greater than 24 h) show increased efficacy with two or three nights of administration (19) and increased daytime residual effects. Shorter-acting hypnotics have consistent effects on sleep with multiple administration and little or no daytime residual effects. A final pharmacological consideration is the extent of drug interaction. It is recognized that the activity of a drug may be modified by the presence of other drugs. Drug interactions can arise from an alteration of the absorption, distribution, metabolism, or elimination of one drug by another. For example, when two drugs compete for plasma protein binding sites, one is displaced, making it available in greater concentration to receptors, which then may produce a more intense effect. On the other hand, a drug that induces metabolizing enzymes can increase the rate of metabolism of other drugs, which then decrease in their effect. Since ethanol is often combined with benzodiazepines, whether intentionally to improve sleep or inadvertently, when an individual with residual blood levels after nighttime use drinks the following day, their interaction has been investigated extensively. Generally, when combined with ethanol, sedative effects of benzodiazepines are increased both at night and during the next day. Long-acting benzodiazepines, which remain in the body for up to 100 h, may present a particular risk in this regard. Clinical properties. The clinical properties that are important in comparing the various hypnotics include (a) sleep induction, (b) sleep maintenance, (c) production of daytime residual amounts, (d) tolerance development, and (e) withdrawal effects. By and large, the pharmacological properties of the various hypnotics determine these clinical characteristics. Sleep induction capacity is the ability of the medication to reduce the latency to sleep. This clinical effect is determined largely by the absorption characteristics of the drug. The capacity of a hypnotic to maintain sleep refers to its ability to reduce the number of awakenings from sleep and the time spent awake and to increase the total time spent asleep. The half-life of a drug primarily determines this clinical effect. Obviously, if a drug is cleared from the system quickly, its sleep mainte- Sleep. Vo/. 5 (Suppl. I). 1982 S50 T. ROTH ET AL. nance capacity is minimal. For patients with a sleep induction problem only, this is nut a criticai issue. On the other hand, for patients with sleep maintenance problems this is an important question. A daytime residual effect is present when there is disruption of a patient's ability to function during the day following nighttime use of a hypnotic. As noted earlier, effective hypnotics also impair waking function while pharmacologically active. Thus the presence of a residual effect of a hypnotic is related to the half-life of the drug. A number of studies have shown that drugs, or their active metabolites, with long half-lives (greater than 24 h) compared with shorter-acting drugs produce decrements on a variety of performance tests and increase the probability of falling asleep on daytime nap tests (20). Tolerance development is simply the decline in efficacy with repeated administration of a given dose of a drug. Tolerance is related to a drug's capacity to induce drug-metabolizing enzymes or to produce changes in receptor sensitivity; it occurs with repeated use of all nonbenzodiazepine hypnotics. The benzodiazepine hypnotics remain effective with repeated administration-a second reason for their popularity (21). A final clinical issue is that of withdrawal effects (22). There is considerable confusion regarding the use of the term withdrawal. In using this term we mean those changes in sleep and daytime function which occur following discontinuation of the drug. Research has shown that discontinuation after repeated use of alcohol, barbiturates, and related hypnotics is associated with a rebound effect. That is, sleep is more disturbed after drug discontinuation than it was before administration. Whether such a rebound effect follows the discontinuation uf benzodiazepine hypnotics is unclear. Studies have shown some disturbed sleep following withdrawal, and some reports have maintained that such a recurrence of symptoms is unique to short-acting benzodiazepines. Adequate studies have not been carried out to resolve these issues. / Indications for use of hypnotics. Clinically effective use of hypnotics requires not only selecting the most appropriate medication but also understanding the nature of insomnia. Given the current understanding of insomnia, it becomes clear that hypnotics are appropriate for selected patients (23), and patients using them should be carefully monitored. The single most appropriate use of hypnotics is for transient situational insomnia. Situations such as acute stress, environmental change, and jet lag often result in sleep disturbance. The short-term use of hypnotics in these situations is clearly indicated. Some clinicians even argue that the acute use of hypnotics may, in some cases, prevent the development of a persistent problem of initiating and maintaining sleep. The chronic use of hypnotics is a more complicated issue. There currently exists little or no information on the efficacy and safety of hypnotics when taken for over one month. Despite this lack, some speculations can be made. First, it must be recognized that chronic use of hypnotics should not be undertaken until a thorough sleep evaluation (including polysomnography) has been done. After an evaluation has been performed and the degree of sleep disruption has been documented, a clinical trial with hypnotics can be undertaken with certain patients. Specifically, patients with the diagnoses of persistent psychophysiological insomnia, nocturnal myoclonus, and insomnia as- Sleep, Vol. 5 (Suppl. I), 1982 HYPNOTIC USE S5] sociated with selected psychiatric problems often may benefit from a trial with hypnotics. Contraindications for use of hypnotics. There are four situations in which hypnutics are clearly contraindicated. Patients with disturbed sleep associated with sleep apnea should not be given hypnotics. Despite the fact that the precise relationship between sleep apnea and hypnotics is not well understood, there are sufficient data to indicate that hypnotics have a potentially negative effect on patients with sleep apnea. Patients who are known to use alcohol excessively should never be given hypnotics. It is well known that alcohol potentiates the effects of hypnotics. Even the high safety margin associated with benzodiazepines is reduced when they are used in combination with alcohol. The teratogenic effects of psychotropics are always a major concern. Clearly, pregnant women should avoid the use of hypnotics. This is especially critical in the first trimester. Finally, people who are subject to being aroused and required to function in the middle of the night should avoid hypnotics. As mentioned previously, all hypnotics that promote sleep increase awakening thresholds and impair the ability to function adequately when awake. Special situations. In certain situations, hypnotics are not clearly contraindicated, but should be prescribed with caution. Hypnotic use in elderly patients always requires careful monitoring. Elderly patients present potential problems because of their high incidence of sleep apnea (12). Furthermore, these patients metabolize certain hypnotics more slowly, placing them at a greater risk of drug toxicity. As the elderly also awaken more frequently during the night, having hypnotics in their systems increases the likelihood of accidents. Heavy snoring is frequently associated with sleep apnea. Any patient, regardless of age, who reports loud snoring should receive a followup evaluation soon after hypnotics are initiated. Similarly, patients with lung disease often show disturbed respirations during sleep. Evaluation of the effects of hypnotics on respiration during sleep is necessary with these patients. Normal drug metabolism and elimination is necessary for safe and effective use of hypnotics. Patients with kidney or liver disease should be carefully monitored for drug toxicity. Misuse of medications is also a concern for the clinician. This is especially important when medications are used chronically. Patients who are a suicidal risk or have a tendency to abuse drugs should be carefully monitored. Finally, some hypnotics remain pharmacologically active after the patient gets out of bed. Patients who have skilled jobs (e.g., pilots, drivers, air traffic controllers) should be carefully monitored for morning "carry-over" effects. Survey data on hypnotic use indicate that the majority of patients with insomnia do not take any medications to help them sleep. In fact, hypnotic prescriptions have decreased dramatically from 1971 to 1980. Despite this, many people continue to write about the overuse of these drugs. The seeming contradiction between these two observations reflects the fact that hypnotics are not so much overused as they are misused. They are probably underused for transient situational insomnia and overused in treating patients with chronic insomnia of undetermined origin. The rational use of hypnotics is dependent upon the increasing Sleep. Vol. 5 (Suppl. /). 1982 S52 T. ROTH ET AL. sophistication of clinicians in the differential diagnosis of the insomnia complaint. Only when the cause of the sleep problem is unmasked wiU ciinicians be able to develop a rational treatment plan and to use hypnotics in a way that will be of maximum benefit to the patient. REFERENCES 1. Mendelson WB. The use and misuse oj sleeping pills. New York: Plenum, 1980. 2. Kay DC, Blackburn AB, Buckinham JA, Karacan I. Human pharmacology of sleep. In: Williams RL, Karacan I, eds, Pharmacology oJsleep. New York: John Wiley, 1976:83-211. 3. Roth T, Zorick F, Sicklesteel J, Stepanski E. Effects ofbenzodiazepines on sleep wakefulness. Br J Clin Pharmacol1981; 11:31-5S. 4. Vogel GW. A review of REM sleep deprivation. Arch Gen Psychiat 1975; 32:749-61. 5. Association of Sleep Disorders Centers. Diagnostic classification oj sleep and arousal disorders, first edition, prepared by the Sleep Disorders Classification Committee, HP Roffwarg, Chairman, Sleep 1979; 2:21-57. 6. Orem J. 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