T. Roth, Ph.D., T. Roehrs, Ph.D., G. Koshorek, J. Sicldost^, B.A., and

Size: px

Start display at page:

Download "T. Roth, Ph.D., T. Roehrs, Ph.D., G. Koshorek, J. Sicldost^, B.A., and"

Bryce Elliott
6 years ago
Views:

1 T. Roth, Ph.D., T. Roehrs, Ph.D., G. Koshorek, J. Sicldost^, B.A., and F. Zorick, M.D. Detroit, Mich. The central effects of a newly developed, long-acting H, antihistamine, loratadine (10 and ), were compared with those of a standard H, antihistamine, diphenhydramine (50 mg three times a day) with measures of performance and daytime sleepiness (multiple sleep latency test). Sixteen healthy adults (six women and 10 men), 19 to 35 years of age, received each of the drugs and placebo for 2 days, separated by 5 days at home. Each day, the drug or placebo was administered at 8 A.M. and 12 and 4 P.M. Diphenhydramine was administered in three equal doses (50 mg), and loratadine was administered in a single dose followed by two placebo doses. Mean latency to sleep on tests done at 9 and 11 A.M. and 1, 3, and5 P.M. was reduced significantly with diphenhydramine compared to placebo, whereas neither loratadine dose reduced sleep latency. Performance measured at 9:30 P.M. and 1:30 P.M. with a battery of tests, including reaction time, vigilance, digit symbol substitution, and symbol copying tasks demonstrated a significant reduction in symbols copied and digits substituted after diphenhydramine compared to both loratadine doses. These results demonstrate that loratadine (10 and doses) did not have clinically significant central nervous system activity, whereas diphenhydramine increases sleepiness and disrupts performance efficiency. (J ALLERGY CLIN IMMUNOL 1987;80:94-8.) Many clinically useful antihistamines that bind to Hphistamine receptors also pass the blood-brain barrier with relative ease. Neuropharmacolt^y studies suggest the central effects of antihistamines may be related to antagonism of histaminergic pathways in the brain that participate in control of wakefulness and sleep.'- ^ Increased daytime sleepiness (or reduced alertness) is a frequent complaint of persons using antihistamines. Daytime sleepiness/alertness now can be measured directly by the MSLT, a recently developed objective measure of sleepiness/alertness.' The MSLT measures the latency to electroencephalographic signs of sleep when individuals are provided with an opportunity to fall asleep in a quiet, dark bedroom. In tests administered at 2-hour intervals throughout the day, most healthy adults demonstrate a circadian rhythm of sleepiness/alertness with maximal sleepiness (short latencies) at midday and maximal alertness (long latencies) in the morning and early evening." The validity of this measure has been documented in a number From the Sleep Disorders and Research Center, Henry Ford Hospital, Etetroit, Mich. Received for publication June 30, Accepted for publication Jan. 24, Reprint requests: Thomas Roth, Ph.D., Henry Ford Hospital, Sleep Disorders aind Research Center, 2921 W. Grand Blvd., Detroit, MI Abbreviations used MSLT: Multiple sleep latency test TID; Three times a day SSS: Stanford sleepiness scale of experimental and clinical conditions,''' that is. throughout the day, sleepy people consistently have short latencies to sleep, and well-rested, alert people do not. Furthermore, depressant drugs of the central nervous system alter MSLT measures in the expected direction. Benzodiazepine hypnotics reduce sleep latency at night, and long-acting compounds of this class continue to effect sleep latency the following day. How antihistamines affect daytime sleepiness has not been thoroughly studied. A recent study used latency to electroeacephalograf^ic sleep as the measure of the sedating effects of antihistamines. Reduced sleep latencies at 9 and 11 A.M. and 8 and 10 P.M. were found with diphenhydramine (50 mg TID) con:^>ared to placebo treatment, whereas terfenadine (120 mg), an H, antagonist that does not cross the blood-brain barrier, did not produce sleepiness." However, because of the secondary purpose of the study, the latency tests in that study were not conducted during the midday when in most adults tibe circadian rhythm of alertness reaches its daytime nadir." TTjus, the time course of

2 VOLUME 80 NUMBER 1 Sedative effects of antihistamines 95 TABLE I. Nocturnal sleep measures 10 mg Diphentiydramine (tsomg) TST (min) SI Lt (min) No. of awakenings WASO (min) % Stage REM 439 (36.4) 25.3 (30.4) 3.6 (2.8) 18.1 (18.9) 13.0(7.1) 57.0 (5.7) 7.8 (6.3) 22.1 (4.6) 452 (12.3) 13.3 (6.2) 4.6(3.1) 16.3(11.5) 12.3 (5.6) 58.5 (6.3) 8.0 (5.7) 21.2(4.6) 449 (20.8) 18.9(15.1) 3.5 (2.3) 13.2 (9.9) 11.2(5.3) 59.1 (7.9) 7.4 (5.8) 22.4 (4.8) 449 (20.4) 17.7 (14.7) 4.2 (2.2) 11.0(5.5) 11.9(6.2) 57.5 (6.3) 8.6 (5.7) 21.9(4.3) TST = total sleep time; SI Lt = latency to stage 2 sleep; WASO = wake time after the onset of sleep; REM = rapid eye movement. Diphenhydramine was administered as 50 mg TID. Data are means (standard deviation) of the 2 days of each treatment. TABLE H. Daytime sleep latency TO mg Diplienhydramine (150 mg) Mean Latency Latency 9 A.M. 11 A.M. 1 P.M. 3 P.M. 5 P.M. 9.5 (3.3) 8.5 (3.0)* 10.4 (4.4) 8.9 (4.6) 6.9 (4.4) 7.3 (5.4) 9.8 (4.6) 7.8 (3.4) 9.5 (5.7) 7.2 (3.7) 10.9 (5.7) 10.9 (6.0) 6.7 (2.6)t 7.3 (3.6)* 5.9 (3.3) 5.2 (4.4)t 5.7 (3.4)t 9.4 (6.3)* 10.3 (3.3) 10.5 (5.4) 8.1 (5.1) 11.0(5.5) 8.3 (3.6) 12.2 (5.6) Data are mean (standiad deviation) minutes of the 2 days of each treatment. Diphenhydramine was administered as 50 mg TID. *p < 0.05 compared to placebo, tp < 0.02 compared to placebo. antihistamine-induced daytime sleepiness has not been carefully examined. This study compared the daytime sl^piness and performance effects of a new, long-acting H, antihistamine, loratadine (10 and ), with those of a standard H, antihistamine, diphenhydramine (50 mg, TID). As noted above, increased sleepiness has been demonstrated with diphenhydramine, whereas loratadine in animal studies appeared to be a selective peripheral H, antagonist and thus should be free of sedating effects of the central nervous system.' Since the amount of prior sleep and wakefulness affects level of daytime sleepiness,' nocturnal time in bed before each daytime evaluation was controlled, and sleep was monitored to correct for possible systematic differences in sleep time between conditions. IMEm(K>S Subjects Sixteen healtiiy, normal sleeping, and alert young volunteers (10 men and six women) (mean age 29 years) served as subjects. Each subject signed an informed consent and was paid for participation. After a physical examination, laboratory tests, and a screening nocturnal polysonuiopam and MSLT the following day (standard sleep recordings described below), qualified subjects were entered into die study. Procedure Each subject received either loratadine, 10 mg, loratadine, diphenhydramine, or placebo accotding to a doubleblind, Latin squiae design. Subjects received each treatment for 2 days, spending 5 days at home between treatments. On each day, subjects received medication at 8 A.M. and 12 and 4 P.M. TTie diphenhydramine dose was 50 mg, whereas die loratadine doses were administered at 8 A.M. followed by two placebo doses. Before each laboratory day, subjects slept in the laboratory (11P.M. to 7A.M.) with polysomnogr^y to eftsure adequate sleep before the experimental treattnents. Standard electroencephalograms (always including a midline occipital placement), elechomyograms, and etectro-ocul(^rams were recorded during the 8 hours in bed.'" Subjects arose at

3 96 Roth et al. J. ALLERGY CLIN. [MMUNOL JULY 1987 TABLE III. Subjective ratings of sleepiness 10 mg Diphenhydnmine (150 mg) Mean Latency Latency 9 A.M. 11 A.M. 1 P.M. 3 P.M. 5 P.M. 1.7(3.3) 1.7 (4.4) 1.9(1.2) 1.7 (4.6) 1.6(5.7) 1.7 (5.7) 1.8 (3.0) 1.7(4.6) 2.0 (5.4) 1.6(3.4) 1.9(3.7) 1.8(6.0) 2.0 (2.6)* 1.7(3.6) 2.3 (3.3)* 2.0 (4.4) 2.2 (3.4)* 1.9(6.3) 1.6(3.3) 1.6(5.4) 1.6(5.1) 1.6(5.5) 1.5(3.6) 1.8(5.6) Diphenhydramine was administered as 50 mg TID. Data are mean (standard deviation) minutes of the 2 days of each treatment. *p < 0.01 compared to placebo. TAMJ IV. Daytime performance parameters 10 mg D^riMHM^iWiiiie (ISO mg) Plaoribo Reaction time SRT (A.M.) SRT (P.M.) CRT (A.M.) CRT (P.M.) (95.7) (99.2) (136.5) (123.2) (154.5) (136.9) (165.0) 673.4(144.1) (147.7) (82.7) (138.7) (90.9) 538.5(108.1) 530.6(112.9) 701.6(116.8) (118.0) Vigilance RT (A.M.) RT (P.M.) ERR (A.M.) ERR (P.M.) 801.6(328.1) (337.1) 1.5(2.3) 1.6(2.7) (378.9) (350.6) 2.0 (2.9) 1.7(2.1) (373.0) (338.5) 2.2 (2.7) 2.2 (2.8) (331.9) (312.4) 1.7(2.4) 1.5 (2.2) Psychomotor DSST (A.M.) DSST (P.M.) SCT (A.M.) SCT (P.M.) 66.6 (10.9) 63.3(12.1) (23.3) (24.0) 66.1 (10.9) 65.2(11.9) 136.4(21.4) 134.4(21.7) 61.4(14.8)* 6L8(15.0) (18.8) (23.8) 65.3 (13.5) 64.0(14.0) 131.9(23.2) (27.8) SRT = simple reaction time; CRT = complex reaction time; RT = reactichi time; ERR = errors; DSST = digit symbol substitution test; SCT = symbol o^^g test. Data are mean (standard deviaticxi) of the 2 days of each treatment. Reaction time data are minutes and seccnids, and paper and pencil data are number of correctresponses.diftenhydtamine was administered as 50 mg TID. *p < 0.05 compared to placebo. 7 A.M., bathed, dressed, and ate a light breakfast that included a noncaffeinated beverage. Iti (Meparation for the MSLT, they were instructed to lie down on a bed in a dark, quiet room and try to fall asleep at 9 and 11 A.M. and 1, 3, and 5 P.M. Standard electroencq)faalo^ains (always including an Oz placem^t), electromyograms, and electrooculograms were reccsrded during the latency tests. Each latency test was concluded after 20 minutes of wakefulness, two consecutive epochs of stage 1 sleep, or one epoch of another sleep stage. Before each of the five latency tests, subjects completed the SSS (a subjective rating of sle^ness). The subjects selected one of the seven statements betow that best described the subject's present level of sleepisess/at^lness. Stanford sleepiness scale 1. Feeling active and vital, alert, wide awake 2. Functioning at a high level, but not at peak, able to concentrate 3. Relaxed, awake, not at fiiil alertness, responsive 4. A li^ foggy, not at peak, let down 5. Foggiaess, beguming to lose interest in [etsaiijing awake, slowed down 6. Sleepiness, pr^er to be lyit^ down, figtaing steep, woozy 7. Almost in a reverie, sleep onset soon, lost soi^tes to stay awake Perfonnazice was evaluated at 9:30 A.M. and 1:30 P.M. with a battery of tests, inclo^sg ^i^ie and comfriex le-

VOLUME 80 NUMBER 1 Sedative effects of antihistamines 97 action time, 40 minutes of auditory vigilance, and digit symbol substitution and symbol copying tasks.

4 VOLUME 80 NUMBER 1 Sedative effects of antihistamines 97 action time, 40 minutes of auditory vigilance, and digit symbol substitution and symbol copying tasks. The screening day served as the training on this performance battery. Between latency and performance testing, subjects were asked to stay out of bed, stay awake, and not to consume caffeinated beverages; they were monitored to ensure compliance. All dependent measures were analyzed with repeated measures analyses of variance, followed after this by t test comparisons when it was appropriate. RESULTS Nocturnal sleep The nocturnal polysomnograms scored according to the standards of Rechtshaffen and Kales'" and averaged during the 2 days of each treatment did not reveal differences among the treatments on any parameter evaluated, including total sleep time, latency to sleep, number and duration of awakenings after sleep onset, and percentages of various sleep stages (Table I). Consequendy, measures of performance and daytime sleepiness were not adjusted for differences in the prior amount of sleep. Daytime sleepiness The latency to sleep on the daytime latency tests (averaged during the 2 days) for each treatment is presented in Table II. There was a significant reduction (increased sleepiness) in mean latency to sleep (F = 7.82; df = 3,45;p < 0.01) with diphenhydramine differing from placebo (p < 0.01) and both loratadine doses (p < 0.01 and p < 0.02). The low loratadine dose did not differ from the placebo dose or from the large loratadine dose. Although the high loratadine dose did not differ from the low loratadine dose, it did differ from the placebo dose (p < 0.04). Separate analyses of each of the five latency tests were conducted to determine the temporal pattern of sleepiness. These latencies also are presented in Table II. Diphenhydramine produced increased sleepiness compared to placebo on all latency tests except the 11 A.M. test (9 A.M.,p < 0.04; lp.m.,p < 0.01; 3 P.M., /? < 0.01; 5 P.M., p < 0.02). It also differed from both loratadine doses at 1 P.M. {p < 0.01 and p < 0.04) and from the low dose at 3 P.M. (p < 0.01). There were no differences on any of the five tests between placebo treatment and either loratadine dose. The results of subjective ratings of sleepiness with the SSS paralleled the MSLT results. The SSS ratings are presented in Table III. The average of the five SSS ratings demonstrated reliable differences between loratadine, 10 mg, and diphenhydramine (p = 0.03) and between diphenhydramine and placebo (p = 0.01). In both comparisons, subjects rated themselves as being sleepier with diphenhydramine. No other comparisons of mean ratings produced reliable differences. The analyses of each of the five ratings separately indicated the increased sleepiness that was experienced at 11 A.M. and 3 P.M. Daytime performance The performance data were analyzed in the same manner as the MSLT data. Those data are presented in Table IV. The vigilance and reaction time tasks demonstrated no effect of treatments. On the performance battery at 9:30 A.M., diphenhydramine produced decrements in digit symbol substitution (F = 2.96; df = 3,45;p < 0.05), whereas both loratadine doses had no effects. The afternoon performance battery (1:30 P.M.) demonstrated no effects of the treatments. DISCUSSION These data clearly demonstrate that diphenhydramine, but not loratadine at 10 and, produced sleepiness compared to placebo. The sleepiness produced by diphenhydramine cannot be attributed to the dosing regimen. This is evident in that the drug effects were present throughout the day and not only at 9 A.M. after the first dose (immediate peak) or at 5 P.M. after the last dose (potential accumulation). The increased sleepiness with diphenhydramine became most dramatic at midday, which is the usual nadir in alertness. In other words, diphenhydramine exacerbated the usual midday increases in sleepiness relative to both placebo and active drug. This suggests that other variables compromising alertoess would have a similar interactive effect with sedating antihistamines; for example, shift workers or jet travelers are known to be sleepier than usual for 1 or 2 days after shifting their sleep times."' '^ It also suggests that those various subpopulations in society that are sleepier than the normal may be at risk for a sedative antihistamine effect. Elderly people and young adults in general are somewhat sleepier than others, and their ability to function may be compromised with sedating antihistamines.'' Finally, these data raise an important methodological issue. It is interesting to note that the MSLT results appear to be so much more sensitive than the traditional methods of assessing sedation (i.e., performance testing). Changes in the psychomotor tests were small and of borderline statistical significance. By contrast, the changes in sleep latency were quite robust and also very consistent. This suggests the importance of the use of a direct objective measure of sedation, which the MSLT has proven to be in a variety of clinical and experimental conditions.

$JULY 1987 In summary, these data demcmstrate that traditional antihistamines, such as di{4^]hydibmine, produce increased daytime sleepiness and disnq)t some measures of performance.$

5 98 Roth et al. J. ALLERGY CLIN. IMMUNOL. JULY 1987 In summary, these data demcmstrate that traditional antihistamines, such as di{4^]hydibmine, produce increased daytime sleepiness and disnq)t some measures of performance. The increased sleepiness is most clearly apparent at the usual circadian nadir in alertness. By contrast, these data demonstrate that loratadine in doses of 10 and were not associated with excessive sleepiness and impaired performance. REFEREfiK^ES 1. Schwartz JC, Barbin G, Duchemin AM, Garbarg M, Llorens C, Pollard H, Quach TT, Rose C. Histamine receptors in the brain and their possible functions. In: Ganellin CR, Parsons ME, eds. Pharmacolf^y of histamine receptors. Boston: Wright Co., 1982: Wada H, Watanabe T, Yamatodani A, Maeyama K, Itoi N, Cacabelos R, Seo M, Kiyono S, Nagai K, Nakagawa H. Physiological functions of histamine in the brain. In: Ganellin CR, Schwartz JC, eds. Frontiers in histamine research. New York: Pergamon Press, 1985: Carskadon M, Dement W. The multiple sleep latency test: what does it measure? Sleep 1982;5: Richardson G, Carskadon M, Orav E, Dement W. Circadian variation of sleep tendency in elderly suid young adult subjects. Sleep 1982;5:S82, 5. Carskadon M, Dement W. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48: Zorick F, Roehrs T, Kostorefc G, Sicklesteel J, Hartse K, Wittig R, Roth T. Psttetm of sleef»ttess in various disorders of excessive somnolence. Sleep 1982;5:S Lumley M, Roehrs T, Zorick F, Lamphere J, Roth T. The alerting effects of naps in steep-deprived subjects. Psychophysiol(^ 1986;23: Roehrs T, Tietz E, Zorick F, Roth T. Daytime sleepiness and antihistamines. Sleep 1984;7: Bamett A, lorio LC, Kreudwr W, Tozzi S, Ahn HS, Gulbenkian A. Evaluation of the CNS pt«perties of SCH 29851, a potential nonsedating antihistamine. Agents Actions 1984; 14: Rechtshaffen A, Kales A. A manual of standardized terminology, techniques, and scoring system for sleep stages of human subjects. Bethesda, Md.: National Institutes of Health. 1968; publication No Verhaegen P, Maasen A, Meers A. Health problems in shiftworkers. In: Johnson L, Tepas E, Colquhoun W, CoUigan M, eds. Proceedings of National Institute for Occupational Safety and Health, the twenty-four hour workday. Washington, D. C: U.S. Department of Public Health, 1981: Seidel W, Roth T, Roehrs T, Zorick F, Dement W. Treatment ofa 12-hr shift in sleep schedule with benzodiazepines. Science 1984;224: Dement W, Carskadon M. An essay on sleepiness. In; Actualities en Medicine Experimentale. Montpdlier, France: Ewo Med Press 1981:47.

Daytime Sleepiness and Antihistamines

Sleep, 7(2): 137-141 1984 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