Daytime Sleepiness and Antihistamines

Transcription

1 Sleep, 7(2): Raven Press, New York Daytime Sleepiness and Antihistamines imothy A. Roehrs, Elizabeth I. ietz, Frank J. Zorick, and homas Roth Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan, US.A. Summary: A daytime nap procedure was used to evaluate the daytime sleepiness associated with antihistamines, as well as to assess their hypnotic potential. Healthy, normal subjects received diphenhydramine (150 mg), terfenadine (120 mg), and placebo and went to bed at 900, 1100, 2000, and 2200 h with the instruction to try to fall asleep, hey remained in bed for 60 min while standard sleep recordings were made. Across all conditions latency to stage 1 sleep increased significantly from nap 1 to nap 4 and the amount of sleep (all nonstage 1 sleep) decreased significantly. Over the four naps the mean latency to stage 1 sleep with diphenhydramine was significantly shorter than terfenadine and placebo, which did not differ. On the other hand, there were no differences among the drug conditions in the amount of nonstage 1 sleep. In sum, diphenhydramine at this dose produces sleepiness but shows little potential as a hypnotic, and accumulated sleep across the day makes people progressively more alert. Key Words: Diphenhydramine erfenadine-antihistamines-daytime sleepiness-hypnotic potential. One of the most commonly reported side effects associated with the use of antihistamines is sleepiness (1). Diphenhydramine, a particularly potent and effective HI blocker, produces complaints of sleepiness in a relatively large proportion (approximately one-half) of patients compared with other antihistamines (1). For that reason, it is also frequently prescribed as a sleeping pill (2). However, the capacity of any antihistamine to induce sleepiness during the day has never been objectively and directly assessed. In addition, the effectiveness of these medications as hypnotics has not been evaluated adequately. Daytime sleepiness can be evaluated objectively by the multiple sleep latency test (MSL ). he MSL measures the latency to electroencephalographic signs of sleep when individuals are given repeated opportunities to fall asleep at 2 h intervals across the day. It is felt that the MSL measures physiological sleep tendency as opposed to manifest sleep tendency (3). Physiological sleepiness (latency to stage 1) as measured by the MSL is a function of prior sleep and wakefulness and varies as part of a circadian system. Benzodiazepine hypnotics produce sleepiness (reduce latency to stage 1 sleep) at night, and long-acting compounds of this class continue to affect sleep tendency the following day as measured by the MSL (4). Whether or not antihistamines affect physiological sleep tendency is unknown. Even objective evidence that an antihistamine produces sleepiness (decreases latency to stage 1 sleep) does not imply it is an effective hypnotic. An effective hypnotic should induce Accepted for publication February Address correspondence and reprint requests to Dr. Roehrs at Sleep Disorders Center, 2921 West Grand Boulevard, Detroit, MI 48202, U.S.A. 137

2 138 A. ROEHRS E AL. sleep and maintain the sleep process. Benzodiazepine hypnotics both induce and maintain sleep \vhether during the usual nighttime hours or during the day (5,6). hey increase total sleep time while decreasing stage 1 and wake time. On the other hand, alcohol induces sleep but does not maintain it (7). Little is known about the hypnotic activity of antihistamines. hose processes promoting sleepiness may differ from those producing and maintaining sleep. hus, the fact that a compound produces sleepiness does not necessarily mean it will also be an effective hypnotic. By modifying the standard MSL the hypnotic potential of antihistamines can be assessed. First, subjects remained in bed for 60 min on each nap opportunity. In the standard MSL each test is terminated immediately at the first signs of sleep or after 15 min of sleep. his is done so that significant amounts of sleep cannot be accumulated across the day and possibly make people progressively more alert. However, whether accumulated sleep on naps will affect subsequent sleep latencies has never been tested. It has been shown that 2 nights of approximately 60 min additional sleep (from 7.3 to 8.5 h) increased daytime alertness (8). Accumulation of sleep on early naps, resulting from the 60 min bedtime, may affect latencies on later naps. However, although absolute sleepiness may be confounded by sleep accumulation, relative sleepiness can still be assessed. On the other hand, increased alertness is desirable for evaluating hypnotic potential as it models insomnia in the healthy normal. A second modification of the standard MSL was made to further increase alertness. Subjects were tested at those points on the 24 h sleep latency curve when healthy normals are known to be most alert, in the early morning ( h) and the early evening ( h) (9). It should be noted that this procedure can not be considered an evaluation of hypnotic efficacy, but it can give indication of hypnotic potential. he present study used a daytime nap test procedure to evaluate the objective sleepiness associated with diphenhydramine compared with terfenadine and placebo and to assess the hypnotic potential of these drugs. erfenadine is a histamine HI antagonist reported to have little, if any, central nervous system depressant effects, and thus, served as an active control (10). As noted previously, diphenhydramine appears to have sedating effects and is sometimes used as a hypnotic. MEHODS Subjects welve men between the ages of 20 and 27 served as paid volunteers. Subjects were screened by a Cornell Medical Index, a Minnesota Multiphasic Personality Inventory, and a general questionnaire regarding sleep habits and drug use history to eliminate anyone who had medical or psychiatric symptoms or sleep-wake complaints. Prior to and following the study, all subjects received a physical examination, laboratory tests, and electrocardiogram. Only subjects who had normal physical examinations, normal vital signs, no clinically significant laboratory findings, and no sensitivity to antihistamines were included in the study. All subjects signed an informed consent. Design Each subject experienced each of three drug conditions administered in a Latin Square design and in a double blind manner. he three conditions were terfenadine 120 mg (two 60 mg doses separated by a placebo dose), diphenhydramine 150 mg (three 50 mg doses), and placebo (three doses). All medications were packaged identically. Doses were administered at 0830, 1300, and 1930 h on days 1, 5, and 9 of the study. Days 2 to 4 and 6 to 8 served as washout periods. Sleep. Vol. 7. No

3 SLEEPINESS AND ANIHISAMINES /39 Procedure Subjects arrived at the sleep laboratory 30 min before the first drug administration. Electrodes were applied for the continuous monitoring of the electroencephalogram at the P3-A2 (with P4-Al as backup) and Oz-A2 placements, the bilateral electrooculogram, and submental electromyogram. At 0900, 1100, 2000, and 2200 h subjects retired to a quiet, dark room, laid down on a bed, and were instructed to try to sleep. Subjects stayed in bed for 60 min while sleep recordings were made. Between nap tests, subjects completed a short performance test battery consisting of a balance board task, the Purdue Pegboard, a mathematical test of addition and subtraction, the digit symbol substitution test, and the symbol copying test. Subjects also completed the Stanford Sleepiness Scale, the Clyde Mood Scale, and a side effects checklist. he whole performance battery lasted approximately 45 min. During the additional time, particularly between 1300 and 2000 h, subjects watched V or read. hroughout subjects were monitored to ensure that they did not nap except during the scheduled tests. he nap recordings were scored in 30 s epochs according to the standard criteria of Rechtschaffen and Kales (11). Latency to stage 1 was determined for each nap test. he total amount of sleep (all nonstage 1 sleep) for each 60 min test was calculated. Analyses of each single sleep stage (stage 2, 3-4, and REM) were not conducted since values for each separate stage on the 60 min nap were relatively small and variable. Comparisons among the three conditions were made using analyses of variance and post hoc t tests. RESULS As hypothesized, daytime alertness increased progressively across the four naps. Figure 1 illustrates this effect. Over all conditions, latency to stage 1 sleep increased significantly from a mean of 8 min on nap 1 to a mean of 37 min on nap 4 (F = 20.97, p < 0.001). he systematic nature of this effect is best seen in the placebo condition. Within the placebo condition, latency to stage 1 increased by approximately 10 min/nap (see Fig. 1). he accumulation of sleep on early naps also affected the amount of sleep obtained on subsequent naps. he mean amount of nonstage 1 sleep decreased significantly across the naps (F = 7.82, p<o.ool). On nap 1 it was 39 min whereas on nap 4 it was only 10 min. here were significant differences among the three drug conditions in sleep tendency (F = 7.81, p<o.oo1). he mean latency to stage 1 sleep across all naps for each condition is shown in Fig. 2. he shortest latencies were found in the diphenhydramine condition, 50 M A 40 o 3 S A G E 1 1 PLACEBO III ALL CONDo NAPS 4 FIG. 1. Mean latency to stage 1 sleep on each nap for all conditions and placebo alone. Sleep, Vol. 7. No.2, 1984

4 140 r A. ROEHRS E AL. FIG. 2. Mean latency to stage 1 sleep across all naps for diphenhydramine 150 mg (D 150), terfenadine 120 mg ( 120), and placebo (PLAC). 313 i1 I N 213 I) c A 10 G E 1 o o PLAC which differed from placebo and terfenadine (p<0.05). he terfenadine condition did not differ from placebo. On the other hand, there were no differences among drug conditions in the amount of non stage 1 sleep nor was there a significant interaction. Mean amount of nonstage 1 sleep across all naps was 31 min for the diphenhydramine condition, 25 min for the terfenadine condition, and 26 min for placebo. DISCUSSION hese results show that diphenhydramine does produce sleepiness compared with placebo and terfenadine. On the other hand, there were no sedative effects associated with terfenadine. After terfenadine, subjects were as alert during the day as after placebo. Because our nap procedure was a modification of the MSL in that tests were done only in the morning and early evening and sleep accumulated by allowing 60 min/nap, absolute statements regarding the level of sleepiness are not possible. Furthermore, subjects did not sleep in the laboratory the night before the daytime procedures and there is no verification of the quality and quantity of their previous night's sleep. However, it should be noted that subjects were almost 50% sleepier with diphenhydramine than placebo. How this level of sleepiness compares with that found during the day after nighttime use of a long-acting hypnotic or after sleep deprivation or restriction can not be determined. Although this study can not be considered an assessment of hypnotic efficacy, it is interesting to note that diphenhydramine decreased latency to stage 1 but did not increase the amount of non stage 1 sleep on the 60 min nap. his would suggest that diphenhydramine at this dosage (50 mg, three times a day) shows little potential as a hypnotic. However, before reaching conclusions regarding diphenhydramine's hypnotic efficacy, the appropriate and complete research must be conducted. hese results also confirmed the assumption that accumulated sleep across the day will make individuals progressively alert. Previous studies relating the quantity of nighttime sleep to daytime sleepiness showed that approximately 60 min of additional sleep increased alertness during the following day (8). Here, as expected, we found that the accumulation of sleep on naps will increase alertness as measured by latency to sleep on subsequent naps. In the two morning naps, subjects accumulated approximately 60 min of sleep. his sleep increased alertness on afternoon naps by 60%. Recent interest has focused on the relation of the continuity of sleep to daytime sleepiness. his is a concern because various sleep disorders are characterized by disrupted and discontinuous sleep. It is interesting that the 60 min of accumulated sleep in this study was Sleep, Vol. 7, No.2, 1984

5 SLEEPINESS AND ANIHISAMINES 141 not continuous. Approximately 40 min was obtained on nap I and 20 min on nap 2. he question then is what amount of continuous sleep is sufficient to affect daytime alertness. If sleep serves a restorative function, as is generally assumed, what is the minimal amount of continuous sleep necessary for the process to occur? Would one 60 min nap have the same effect on alertness as three 20 min naps? Surveys of napping behavior indicate that the usual nap is approximately 60 min long (12). But it is not clear what factors terminate these naps or whether they are continuous sleep. Experimental studies of the recuperative power of naps following sleep deprivation indicate that 42 min of sleep restores performance efficiency (13). However, performance measures and direct measures of sleepiness/alertness are not well correlated (4). Performance measures are more readily influenced by motivational variables than direct measures of sleepiness. REFERENCES I. Douglas WW. Histamine and antihistamines; 5-hydroxytryptamine and antagonists. In: Goodman LS, Gilman A, eds. he pharmacological basis of therapeutics. New York: Macmillan, 1975: Solomon F. Report of a study; sleeping pills, insomnia and medical practice. Washington, DC: Institute of Medicine, National Academy of Sciences, Dement WC, Carskason MA. Current perspectives on daytime sleepiness. Sleep 1982;5(S2):S Roth, Roehrs, Zorick F. Sleepiness: its measurement and determinants. Sleep 1982;5(S2):SI Nicholson AN. he use of short- and long-acting hypnotics in clinical medicine. Br J Clin Pharmacol 1981;11:6IS-9S. 6. Roth, Zorick F, Sicklesteel J, Stepanski E. Effects of benzodiazepines on sleep and wakefulness. Br J Clin PharmacoI1983;11:3IS-5S. 7. Kay DC, Blackburn AB, Buckingham JA, Karacan 1. Human pharmacology of sleep. In: Williams RL, Karacan I, eds. Pharmacology of sleep. New York: John Wiley and Sons, 1976: Carskadon MA, Dement We. Nocturnal determinants of daytime sleepiness. Sleep 1982;5(S2):S Richardson GS, Carskadon MA, Orav EJ, Dement WC. Circadian variation of sleep tendency in elderly and young adult subjects. Sleep 1982;5(S2):S Merrill Laboratories. Internal report on terfenadine, II. Rechtschaffen A, Kales A, eds. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information Service/Brain Research Institute, University of California at Los Angeles, Dinges OF, Orne EC, Orne M. Napping: symptom or adaptation? Sleep Res 1982;11: Dinges OF, Orne EC, Evans FJ, Orne M. Performance after naps in sleep-conducive and alerting environments. In: Johnson LC, epas OI, Colquhoun WP, Colligan MG, eds. he twenty jour hour workday: proceedings of a symposium on variations in work-sleep schedules. Washtington, DC: US Department of Health and Human Services, 1981; Sleep, Vol. 7. No