A review of the effects of antihistamines on mental processes related to automobile driving

Transcription

1 A review of the effects of antihistamines on mental processes related to automobile driving F. M. Gengo, PharmD, ac and C. Manning a Buffalo, N.Y. The newer, second-generation Hi-receptor antagonists have been shown to have potent antiallergic effects without inducing sleepiness. However, because traditional antihistamines may cause functional or cognitive impairment, the clinician still must consider warning patients about activities that could be hazardous. Because the effects of drugs on driving an automobile are difficult to measure directly, studies must use surrogate activities in a laborator3' setting. Effects of antihistamines on the central nervous system are assessed with psychomotor tests, which are selected on the basis of their relativi~ to real-world activities, to develop a profile of mental processes that may be affected. This article reviews the psychomotor tests and study design used to characterize the intensi~ and duration of drug effects after single and multiple doses and in combination with other impairing agents such as ethanol. Severul studies have been published that assess the effects of cetir&ine, an Hi-receptor blocker, on mental performance. In the study discussed here, diphenhydramine hydrochloride and hvdroxvzine were used as positive controls to demonstrate that the period during which some traditional antihistamines impair performance is different than the period of reported drou'siness thev induce. The results of this series of studies show that cetirizine induced minimal changes in mental performance tests and only following the highest (2 mg) dose studied. ( J ALLERGY CLIN IMMUNOL 199;186:34-9.) With the introduction of the newer, so-called nonsedating agents, it has become more difficult to answer the question of whether patients should be cautioned against activities such as driving an automobile or operating potentially dangerous machinery. Clearly, newer antihistamines have been found to produce potent antiallergic effects without causing excessive drowsiness, but the certainty that these drugs do not impair one's ability to drive an automobile is limited by the imperfect methods for measuring impaired driving performance. 1-4 Whereas there are rigorous objective measurements, such as sleep latency studies, to measure drowsiness, it is difficult to measure directly the effects of a drug on an individual's ability to drive a car. The purpose of this article is to review the current approaches used to determine the potential for an antihistamine to impair driving abilities. Previous reviews From the Neuropharmacology Division, 9 Dent Neurologic Institute, Buffalo, N.Y., the Department of Neurology, b School of Medicine, State University of New York, Buffalo, N.Y., and the Department of Pharmacy, ~ School of Pharmacy, State University of New York at Buffalo, Buffalo, N.Y. Reprint requests: F. M. Gengo, PharmD, Dent Neurologic Institute, Dvision of Neuropharmacology, 3 Gates Circle, Buffalo, NY / Abbreviation used BAC: Blood-alcohol concentration have compiled data reporting the sedative effects of antihistamines. However, much of this literature makes no distinction between a drug's tendency to induce drowsiness and its potential to induce mental impairment. Those reports that specifically study antihistamine-induced impairment frequently select tests that are known to be sensitive to drug effects, but the tests are not selected on the basis of their relationship to a specific real-world activity. More recently approved antihistamines have been evaluated for their potential to produce sleepiness apart from their potential to impair task performance. This information is necessary to determine whether warnings must appear in the drug's prescribing information. However, to date, no specific performance tests have been shown to be most appropriate in assessing a drug's potential to impair driving. This article addresses the logic, methods, and types of data needed to provide useful information about an antihistamine's potential to interfere with a patient's ability to drive.

2 VOLUME 86 Effects of antihistamines on driving 35 NUMBER 6, PART 2 PSYCHOMOTOR PERFORMANCE ] [ Cardso~ing:Choicerea~iontime I SENSORY CENTRAL NERVOUS SYSTEM MOTOR Stimulus Perception Recognition Processing Integration Memory Learning Ballislic Gross Fine Coordination detection Auditory Letter Digit Mental Critical Digit Verbal Finger Stabilometer Hand Peg vigilance cancellation Symbol arithmetic flicker fusion span learning tapping steadiness board SENSORI-MOTOR PERFORMANCE SIMPLE REACTION TIME: PURSUIT ROTOR FIG. 1, A summary of tests of psychomotor function shown to be sensitive to a wide range of drugs (Modified from Hindmarch I. Psychomotor function and psychoactive drugs. Br J Clin Pharmacol 198;: ) To determine whether a drug impairs automobile driving requires specific assessment of the drug's potential to induce impairment of mental performance. Drug-induced impairment consists of a transient but inescapable state of deteriorated mental performance in which a patient cannot rally to overcome the impairment? The dissipation of drug-induced impairment is more a function of drug clearance from the central nervous system from a function of patient motivation. Impairment seems to be an effect distinct from drowsiness or sleepiness. In the case of alcoholinduced impairment, BACs of.7 gm/dl, although rarely causing drowsiness, produce a fourfold increase in the relative risk of a fatal traffic accident. 6 Recent studies have also reported the lack of correlation between symptoms of drowsiness and measures of antihistamine-induced mental impairment. 7-1~ These studies point out the importance of determining both the potential for impairment and the potential drowsiness associated with antihistamines to determine if patients taking the drug should be warned against driving. The ideal technique to determine whether a drug will impair the operator's ability to safely drive is to test a drug under actual driving conditions. Several European groups have devised test batteries using modified automobiles. These automobiles are equipped with sensors to detect lateral position relative to a painted road stripe. The vehicle's speed and steering wheel angle as well as the subject's EEG are also objective endpoints that are measured. Additionally, the driver and an investigator subjectively rate several aspects of the driver's performance. These vehicles are equipped with redundant driving controls for the accompanying investigator to ensure subject safety. This type of testing procedure has multiple advantages to surrogate laboratory tests including the ability to measuure the subject's sustained performance over the duration of a km course. Unlike many brief laboratory tests that have an alerting effect on subjects, sustained car driving is likely a better measure of drug effects such as lapses in attention. These real driving procedures have been shown to be very effective in measuring the effects of antihistamines on automobile driving.j1 It is unfortunate that the circumstances in the United States make such testing so difficult to conduct. LABORATORY TESTING OF DRUG-INDUCED IMPAIRMENT Laboratory tests measuring a drug's impairing effects should be the best possible approximation of the mental tasks needed to drive a car. Authors have reported12.13 previously that mental processes involved in driving include attention and scope of attention, short-term memory and recognition, sensory-motor integration, decision making, and judgment. The type of driving determines the degree to which each of these processes is important and relevant. For example, concentration has been cited as a particularly essential process for routine driving. Generally, the processes more significantly related to routine driving are perhaps best tested by monotonous and boring tasks, and antihistamines affect such tasks, j4 Unlearned processes, which test judgment and decision making, are perhaps more relevant to atypical driving situations, but they are not well represented by current performance measures Consequently, these cognitive areas are underrepresented in studies that evaluate the impairing potential of antihistamines.

3 36 Gengo J. ALLERGY CLIN, IMMUNOL. DECEMBER O 3 1,2 t'r" tx- 2i o ooo o q5 o o A Blood Alcohol Concentration (%w/v) I O. ~1 BLOOD ~CDH~ CONCENTRATION i.15 FIG. 2. The relationship between blood alcohol concentrations and driving impairment assessed by (A) traffic fatality data and (B) prolonged reaction time to an overlearned task measured using a driving simulator (Data from Mann P. Arrive alive! how to keep drunk drivers off the highway. 1st ed. New York: Woodmere Press, 1983:t6, and Gengo FM, et al. J Clin Pharmacol [in press].) An important consideration in the selection of laboratory tests is the observation that errors of attention are the most frequently cited errors leading to actual traffic accidents involving ethanol. This demonstrates the necessity of including attention tasks in a battery of tests designed to study automobile-driving impairment. To assess the potential of an antihistamine to interfere with ment~ performance, studies should incorporate several laboratory tests that assess an array of mental processes.17' 18 Neuropsychologists have determined various psychomotor tests to measure specific mental skills and processes. J9 Those used in testing impairment by drug effects are shown in Fig. 1. The Digit Symbol Substitution test, a simple penciland-paper test, is reported to measure integration, speed, and accuracy of visual and fine-motor skills. Trails B Maze Tracking, a subtest of the Wechsler Adult Intelligence scale, is reported to measure parts of memory and decision making. One of the most popular measures of sensory-motor performance is reaction time to a critical stimulus. We use a driving simulator that measures and records a complex test of choice reaction time. 5 While viewing a motion picture of traffic, the subject is unexpectedly presented with a traffic threat that starts a clock. In response to the threat, the subject must decide whether to turn right, turn left, brake, or accelerate. The device records the accuracy of the decision, the decisionmaking time, and the motor-response time. One cannot fully account for the differences between simulators and real traffic situations, such as consequences of an accident and familiarity with the task and conditions. An alternative approach to validating the usefulness of various tests to measure driving performance, specifically as it may be impaired by drug exposure, is a form of pharmacologic validation that takes advantage of the existing unique data that correlate the measured concentrations of an impairing drug, ethanol, to the risk of involvement in a fatal accident under real traffic conditions. The threshold BAC associated with that risk, or the BAC at which driving is significantly impaired, is between.5% and.7% (between.86 and 15.2 mmol/l). 6 We have recorded threshold BACs in a series of studies of normal volunteers who were given ethanol under placebocontrolled conditions and who performed various tasks on a driving simulator. During one such test in which the task was overlearned and monotonous, we found significant prolongations of reaction time when the BACs were.4% to.6% (8.68 to 13.3 mmol/l). 2~ These BACs associated with impaired performance recorded in laboratory conditions are close to those shown to be associated with increased risk of actual driving accidents (Fig. 2).

4 VOLUME 86 Effects of antihistamines on driving 37 NUMBER 6, PART " 17" ~_ 16" r,r" 15' 14. ( A o nr 15- O~ B o Time (hours) 'Time (hours) 2" 2, 19" 19 18" 17" 18 17, 16 n j..~...--~ ~ 15- n ~ (~ C 11- i 2 u 3 4 ~ 13. D Time (hours) "time (hours) FIG. 3. Changes in Stroop word-test performance after (A) placebo, (B) mg of cetirizine, and (C) 2 mg of cetirizine, and (D) hydroxyzine, 25 mg. +, Standard deviation; % mean. (From Gengo FM, et al. Clin Pharmacol Ther 1987;42: ) We have found similar threshold BACs associated with significant deterioration in Digit Symbol Substitution scores. Data are available 21' 22 that demonstrate that deterioration in information-processing rates and divided-attention scores is associated with BACs in the range of.5% to.8% (.86 to mmol/l). These data provide some validation for the usefulness of such tests in the assessment of druginduced impairment. STUDY DESIGN CONSIDERATIONS As with any study designed to measure reversible effects of a drug in healthy volunteers or nonacutely ill patients, studies to determine the effects of an antihistamine on mental performance should be double blinded and both placebo controlled and positive controlled. Placebo must be included as a negative control, but these studies also require a positive control to ensure that the tests used to measure mental performance, under the specific conditions would be capable of detecting impairment. In a study that involves only placebo and the new antihistamine, data showing no change in test scores may indicate either that the drug does not induce impairment or that the tests lacked sufficient sensitivity to detect impairment. The positive control should be an antihistamine known to be impairing, given at the lowest dose that will produce changes in test scores. The purpose of the inclusion of the positive control (the impairing antihistamine) is not to draw direct comparisons with the study drug. The study drug should be compared with placebo, and the positive control should be used only to ensure test sensitivity. Another design consideration for these studies is whether performance was influenced by test familiarity or learning. In the case of single-dose studies, subjects can be familiarized with the test procedures on a "prestudy" day, and tests can be practiced until test scores reach a plateau. 23 Studies should be crossover with a Latin-square design, so that all treatments will be influenced equally by any residual learning. 24 A predose assessment of test performance should be conducted before drug administration on each study day. This will refamiliarize subjects with the test procedures and enable measurement of any improvement of test performance as the study proceeds. In long-term treatment studies, predose evaluations are not possible. In this case study, designs incor-

5 38 Gengo J. ALLERGY CLIN. IMMUNOL. DECEMBER 199 porating multiple placebo periods in a crossover design (as used recently by Goetz et al.) provide a test design that accounts for residual learning.l~ Tolerance to antihistamine-induced impairment does not seem to occur to a significant enough degree to be a confounding issue; however, tolerance to antihistamineinduced drowsiness has been reported, m, 25 This points to the distinct difference between drowsiness and impairment. EVALUATIONS OF CETIRIZINE To date we have conducted two studies designed to determine whether cetirizine produces any significant impairment by using tests that we believe are relevant predictors of automobile driving. 26' 27 Using a 5 mg dose of diphenhydramine as a positive control and a five-way crossover design, we compared the effects of three doses of cetirizine (5,, and 2 mg) with placebo. This dose of diphenhydramine used was the lowest dose that has been shown to produce a change in performance test scores , 29 Performance was measured by the driving simulator and Digit Symbol Substitution scores. The driving simulator data show that although diphenhydramine produced significant impairment, there was no difference in performance between placebo and any of the three doses of cetirizine.26 At later times, the effects of diphenhydramine had dissipated to be no more different than placebo, as would be predicted from its phannacokinetic profile. 3~ Digit Symbol Substitution testing showed a small decrement in scores at later times following the 2 mg dose of cetirizine. In a similar study with 25 mg of hydroxyzine as a positive control and Stroop word testing as a measure of performance, no difference was seen between placebo and either a or 2 mg dose of cetirizine. 27 However, after the administration of hydroxyzine, significant deterioration occurred in test performance (Fig. 3). Again, these data suggest that whereas the tests were sensitive to the impairing effects of hydroxyzine, no effects of cetirizine greater than placebo could be detected. These studies demonstrate the lack of any measurable impairment produced by cetirizine and also show the degree to which common traditional antihistamines, such as diphenhydramine, produce impairment as measured by these tests. CONCLUSION Studies of cetirizine (in doses of 5 and rag) have demonstrated no significant impairment in drivingrelated tests. 26, 27 Moreover, it seems clear that studies of newer, nonsedating antihistamines must assess the potential to produce both drowsiness and to impairment. For physicians to have an adequate profile of a new nonsedating antihistamine about which they can properly advise patients, the following questions about that antihistamine must be addressed: 1. Does the drug impair human mental processes involved in driving? 2. Are the effects manifest at therapeutic doses? 3. Are the effects cumulative with continuous dosing? 4. Are the effects dependent on dose or concentration? 5. What are the durations of the effects? 6. Are the effects compounded by other drugs, such as ethanol? 7. Are certain populations more sensitive than others to these effects? Data are beginning to appear to suggest that single doses or short-term multiple doses of some nonsedating antihistamines do not impair mental performance. 3~ However, until all these questions are addressed in well-designed studies, patients taking even the nonsedating antihistamines should be cautious in undertaking activities such as driving. REFERENCES 1. Nicholson AN, Stone BM. Performance studies with the H~histamine receptor antagonists, astemizole and terfenadine. Br J Clin Pharmacol 1982; 13: Nicholson AN. Antihistaminic activity and central effects of terfenadine. Arzneim-Forsch Drug Res 1982;32: Kulshrestha VK, Gupta PP, Turner P, Wadsworth J. Some clinical pharmacological studies with terfeuadine, a new antihistamine drug. Br J Clin Pharmacol 1978;6: Reinberg A, Levi F, Guillet P, Burke JT, Nicolai A. Chronopharmacological study of antihistamines in man with special reference to terfenadine. Eur J Clin Pharrnacol 1978;14: Gengo FM, Gabos C. Antihistamines, drowsiness, and psychomotor impairment: CNS effect of cetirizine. Ann Allergy ;59II:53-8. Mann P. Arrive alive: how to keep drunk and pot-high drivers offthe highway. 1st ed. New York: Woodmere Press, 1983:16. Moser L, Huther KJ, Koch-Weser J, Lundt PV. Effects of terfenadine and diphenhydramine alone or in combination with diazepam or alcohol on psychomotor performance and subjective feelings. 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6 VOLUME 86 Effects of antihistamines on driving 39 NUMBER 6, PART 2 of twice daily hydroxyzine versus terfenadine. J ALLERGY CLIN 1MMONOL 1989;84: O'Hanlon JF, Brookhuis KA, Louwerens IW, Volkerts ER. Performance testing as part of drug registration. In: O'Hanlon JF and Gier 1I, eds. Drugs and driving. London: Taylor and Francis, Starmer GA, Bird KD. Investigating drug-ethanol interactions. Br 1 Clin Pharmacoi 1984;18:27S-35S. 13. Linnoila M, Mattila MI. Drug interaction on psychomotor skills related to driving: diazepam and alcohol. Eur J Clin Pharmacol 1973;5: Clarke LH, Nicholson AN. Performance studies with antihistamines. Br J Clin Pharmacol 1978;6: degier JJ. Driving tests with patients. Br J Clin Pharmacol 1984;18:3S-8S. 16. O'Hanlon JF. Driving performance under the influence of drugs: rationale for, and application of a new test. Br J Clin Pharmacot 1984;I8:121S-9S. 17. Kleinknecht RA. Psychomotor skillswsummary. Br I Clin Pharmacol 1984;18:39S-41S. 18. Broadhent DE. Performance and its measurement. Br J Clin Pharmacol 1984;18:5S-9S. 19. Hindmarch I. Psychomotor function and psychoactive drugs. Br J Clin Pharmacol 198; Gengo FM, Gabos C, Straley C, Manning C. The pharmacodynamics of ethanol: effects on performance and judgement. J Clin Pharmacol 199;3: Burns M, Moskowitz H. Effects of diphenhydramine and al- cohol on skills performance. Eur I Clin Pharmacol 198;17: Moskowitz H. Attention tasks as skills performance measures of drug effects. Br I Clin Pharmacol 1984;18:51S-61S. 23. Bornstein RA, Baker GB, Douglass AB. Short term retest reliability of the Halstead-Reitan Battery. J Nerv Ment Dis 1987;175: Woods JR, Williams JG, Tavel M. The two period cross-over design in medical research. Ann Intern Med 1989;1: Weiner M. Sedation and antihistamines. Arzneim-Forsch Drug Res 1982;32: Gengo FM, Gabos C, Mechtler L. Quantitative effects of cetirizine and diphenhydramine on mental performance using an automobile driving simulator. Ann Allergy 199;64: Gengo FM, Dabronzo J, Yurchak A, Love S, Miller JK. The relative antihistaminic and psychomotor effects of hydroxyzine and cetirizine. Clin Pharmacol Ther 1987;42: Linnoila M. Effects of antihistamines, chlormezanone, and alcohol on psychomotor skills related to driving. Eur J Clin Phannacol 1973;5: Bangh R, Calvert RT. Effect of diphenhydramine and ethanol on histamine skin response and mental performance. Eur ] Clin Pharmacol 1977;12: Gengo FM, Gabos C, Miller JK. The pharmacodynamics of diphenhydramine induced drowsiness and changes in mental performance. Clin Pharmacol Ther 1989;45: O'Hanlon JF. Antihistamines and driving safety. Curls 1988;42:-3.