ACUTE EFFECTS OF LORATADINE, DIPHENHYDRAMINE AND PLACEBO, ALONE AND WITH ALCOHOL, ON SKILLS PERFORMANCE

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1 ACUTE EFFECTS OF LORATADINE, DIPHENHYDRAMINE AND PLACEBO, ALONE AND WITH ALCOHOL, ON SKILLS PERFORMANCE C. Jeavons Wilkinson and Herbert Moskowitz University of California at Los Angeles (UCLA) and Southern California Research Institute, Los Angeles, California, U.S.A. Summary. In a double-blind, 2 x 3 mixed factorial-design experiment, 42 healthy men were assigned to receive either alcohol (n=21) or placebo (n=21) in combination with 10 mg loratadine, 50 mg diphenhydramine, and placebo at three separate treatment sessions. Driving-related skills, including divided attention, vigilance, and critical tracking, were measured. Diphenhydramine impaired performance and increased self-reported sedation relative to placebo or loratadine which did not differ from each other. Alcohol impaired performance; and no alcohol-drug interactions were found. Results of this acute study suggest the new antihistamine, loratadine, does not impair drivingrelated skills performance. INTRODUCTION Epidemiological studies suggest a positive correlation between increased risk of traffic accidents and drivers' blood alcohol concentrations (BACs) (e.g., Hurst, 1973). Laboratory studies have demonstrated impairment of drivingrelated skills performance can occur at BACs as low as 0.02% (Moskowitz & Robinson, 1987). Starmer (1985) reviewed evidence suggesting antihistamines also may increase accident rates. Given the widespread use of antihistamines, more studies are needed to clarify their effects, both alone and in combination with alcohol use, in terms of traffic safety. Laboratory performance tests are relevant for predicting potential risk of impairment to drivers who use antihistamines. In fact, possibly due to the greater task complexity, such laboratory tests have been found to be more discriminative of diphenhydramine's impairing effects than 'off road' driving tests (Posner et al., 1985). While sedation and impaired performance are likely to occur with the classical antihistamines, several new antihistamines appear to have no such effects (e.g., Bradley & Nicholson, 1987; Moskowitz & Burns, 1988; Woodward, 1988). The present study examined the acute effects of one new antihistamine, loratadine (SCH 29851), in comparison to diphenhy-dramine and placebo. A 2 (alcohol and placebo groups) x 3 (drug treatments) mixed factorial design was used to examine drug treatment effects alone and in combination with a moderate dose of alcohol (i.e., peak BAC of 0.07%). The study used a behavioral test battery which measures performance skills important in driving and operating machinery. This computerized test battery yields reliable and sensitive measures for detecting impairment by alcohol and other drugs such as diphenhydramine (e.g., Burns & Moskowitz, 1980; Wilkinson & Burns, 1989). 476

2 METHOD Following screening interviews and full medical evaluations to rule out subjects with any medical, emotional, or substance abuse disorders, 42 healthy men between the ages of 21 and 40 were enrolled in the study. Written informed consent was obtained from each subject prior to participation. All subjects completed two training days to establish stable performance on the laboratory test battery prior to beginning treatment. The study used a double-blind, 2 x 3 mixed factorial design to compare the acute effects of 10 mg loratadine, 50 mg diphenhydramine, and placebo (within subjects) with either 0.68 g alcohol/kg bodyweight or placebo (between groups). Subjects were assigned randomly to either alcohol (n=21) or placebo (n=21) groups. All subjects received the three drug treatments in a balanced, randomized order at separate weekly sessions. At each testing session, subjects were administered a drug 30 minutes prior to receiving the alcohol or placebo beverage. The drinks were consumed over a paced 30 minute period. Following completion of the drink, and a 30-minute absorption period, the performance test battery was administered at 90 and 230 minutes postdrug; (i.e., 30 and 170 minutes post drink completion). Each test battery lasted approximately 90 minutes and included divided attention, vigilance and critical tracking tasks which measure skills important for safe man-machine interactions. In addition, measures of subjective effects included the Profile of Mood States scales (POMS; Lorr et al., 1982) and a selfevaluation of performance scale. A detailed description of the behavioral test battery and the specific response measures is reported elsewhere (Moskowitz & Burns, 1986). Briefly, the Critical Tracking Test (CTT) measures the subject's ability to concentrate attention and to integrate visual input with motor skills. The subject attempts to keep a moving bar centered on a video monitor against a computergenerated disturbing force which increases in difficulty causing the subject to lose control of the bar within 60 seconds of trial initiation. Twenty-five trials are given and the CTT response measure, lambda, represents the subject's average difficulty level achieved before losing control. The high-demand, 12-minute duration Divided Attention task utilizes a display of five video monitors to assess the subject's ability to perform two tasks simultaneously: visual search and compensatory tracking. Response measures include response time (RT) to detect the target (number "2") presented on any of the four peripheral monitors which display arrays of randomly changing numbers; response errors include misses, false alarms and incorrect responses. On the center monitor, the subject attempts to keep an indicator centered on the screen against a disturbing force. The tracking error is the subject's average absolute deviation of the indicator. Overall performance of Divided Attention is reflected in a composite T-score (average RT and tracking error). The low-demand Vigilance task presents an indicator stepping around a clock face of small squares on a video monitor. This task assesses the subject's ability to sustain attention to the random occurrence of infrequent signals (i.e., the indicator skips a position 8 times every 10 minutes) during a 40- minute monotonous display of visual "noise". Response measures include: RT 477

3 with Maximum Allowable RT (MART) which includes time lost due to missed signals, RT (without MART) to detected signals, and response errors (misses, false alarms). RESULTS The mean BACs for the subjects in the alcohol group did not differ across the three treatment sessions; the average peak BACs were 0.07%, and 0.03%, at the start of the first, and second, test batteries respectively. A summary of the performance measures, as a function of alcohol, drug treatment, and test battery run, is presented in Tables 1 and 2. Analyses of variance (ANOVAs) were conducted on the performance and subjective measures to test for significant treatment effects of drug (within subjects) and alcohol (between groups). Subsequent paired comparisons (t-tests) determined the direction of the significant (2 < 0.05) treatment effects. The ANOVA results revealed consistent and independent main effects of the alcohol and drug treatments; these are summarized in Table 3. In general, the significant drug effects indicated impaired performance after the diphenhydramine treatment, relative to either loratadine or placebo which did not differ significantly. These effects were most pronounced during the first test battery. The diphenhydramine-induced deficits on some of the Vigilance and Divided Attention measures were less pronounced during the second battery, but they still showed impairment relative to loratadine or placebo. As expected, on all of the performance measures except Vigilance RT without MART, the concomitant administration of alcohol caused impairment at all three drug treatment sessions. However, no evidence of any alcohol-drug interactions was found; that is, the alcohol-induced performance decrements were additive to any performance change due to the drug treatments. Subjective measures of mood and treatment effects indicated subjects felt significantly more tired and impaired only after the diphenhydramine or alcohol treatment. DISCUSSION Results demonstrate that the test battery's measures are sensitive to the impairment induced by alcohol and a known impairing antihistamine, diphenhydramine. Loratadine, however, did not produce impairment on any of the performance measures at any time, under the study conditions tested. Moreover, the subjective measures showed the alcohol or diphenhydramine treatments increased drowsiness and impairment; in contrast, loratadine and placebo showed no such subjective effects. These findings support other recent reports that 10 mg loratadine does not cause drowsiness or impair skills performance. Of note, there is one report of significant impairment of certain performance skills by loratadine (Bradley & Nicholson, 1987); however, this occurred only after an acute 40 mg dose. Thus, while chronic dosing remains to be studied, results of the present study indicate that a single dose of 10 mg loratadine is unlikely to impair driving or other skilled activities requiring safe performance. 478

4 REFERENCES Burns, M. & Moskowitz, H. (1980). Effects of diphenhydramine and alcohol on skills performance. European Journal of Clinical Pharmacology. 17, Hurst, P. M. (1973). Epidemiological aspects of alcohol in driver crashes and citations. Journal of Safety Research. 5, Lorr, M., McNair, D. M., & Fisher, S. (1982). Evidence for bi-polar mood states. Journal of Personality Assessment. 46, Moskowitz, H. & Burns, M. (1986). Cognitive performance in geriatric subjects after acute treatment with antidepressants. Neuropsvchobiology. 15; (suppl. 1), Moskowitz, H. & Burns, M. (1988). Effects of terfenadine, diphen-hydramine, and placebo on skills performance. Cutis. 42, Moskowitz, H. & Robinson, C. D. (1987). Effects of low doses of alcohol on driving-related skills: A review of the evidence. U.S. Dept, of Transportation (NHTSA Report No. DOT HS ). Springfield, Virginia: National Technical Information Service. Posner, J., Ashby, L., Cohen A. F., & Warwick, S. (1985). Methods of assessing potential risk of sedative drugs to drivers. British Journal of Clinical Pharmacology. 19, 127P-128P. Starmer, G. (1985). Antihistamines and highway safety. Accident Analysis and Prevention. 17, Wilkinson, C. J. & Burns, M. (1989). Validation of behavioral tests of alcoholinduced impairment in humans. Alcoholism: Clinical and Experimental Research. 13, 340. Woodward, J. K. (1988). Pharmacology and toxicology of nonclassical antihistamines. Cutis, 42,

5 TABLE 1 Acute Effects of Loratadine, Diphenhydramine and Placebo, Alone and with Alcohol, on Skills Performance Summary, Performance Test Measures Means (and Standard Deviations), ALCOHOL Group, 21 Subjects T R E A T M E N T TASK MEASURES: Loratsdise Diphenhydramine Placebo CTT: Lambda (0.85)(1. 07) (1.21)(1.31) (0.86) (1.10) DIVIDED ATTENTION: Tracking Error (0.15)(0. 21) (0.24 )(0.23 ) (0.21)(0.17) Response Time (0.93) (0. 75) (1.67)(1.12) (0.89)(1.33) Total Errors (3.8) (3. 0) (12.7) (4.9) (4.3) (7.5) VIGILANCE: RT without MART (0.28)(0. 30) (0.32)(0.33) (0.37 )(0.25) RT with MART (1.17)(1. 09) (1.44)(1.13) (1.33)(1.17) Total Errors (10.9)(11.4) (14.7)(11.8) (12.3)(14.1) Note: Higher scores = poorer performance except on CTT Lambda; RT = Response Time; MART = Maximum Allowable RT 480

6 TABLE 2 Acute Effects of Loratadine, Diphenhydramine and Placebo, Alone and with Alcohol, on Skills Performance Summary, Performance Test Measures Means (and Standard Deviations), PLACEBO Group, 21 Subjects T R E A M E N T TASK MEASURES: Loratadine Diphenhydramine Placebo CTT: Lambda (1.08) (1.07) (1.06)(1.15) (0.98)(1.05) DIVIDED ATTENTION: Tracking Error (0.13)(0.19) (0.17)(0.22) (0.20)(0.18) Response Time (0.78)(0.77) ( )( ) (0.82)(0.86) Total Errors (1.3) (1.6) ( 2. 0 ) ( 2. 0 ) (1.7) (2.0) VIGILANCE: RT without MART (0. 32)(0. 27) (0.40) (0.30) (0.23)(0.20) RT with MART (0. 80)(0. 95) (1. 08)(1.01) (0.68) (0.67) Total Errors (7.0) (7.7) (11.1) (9.4) (6.0) (4.7) Note: Higher scores = poorer performance except on CTT Lambda; RT = Response Time; MART = Maximum Allowable RT 481

7 TABLE 3 Acute Effects of Loratadine, Diphenhydramine and Placebo, Alone and with Alcohol, on Skills Performance Summary, ANALYSES OF VARIANCE of Performance Test Measures F and p values for Alcohol and Drug Effects ALCOHOL EFFECTS DRUG EFFECTS TASK MEASURES: F P F P CTT: Lambda ,.021 ** < *** DIVIDED ATTENTION: Tracking Error ,.054 * < *** Response Time ** <0.001 *** T Scores (Trk & RT) ** <0,.001 *** Total Errors ** ** VIGILANCE: RT without MART ,.050 * RT with MART * < *** Total Errors ** < *** * p < 0.10 Note: RT = Response Time ** p < 0.05 MART = Maximum Allowable RT *** p < Trk = Tracking Error df = F(1,40) ALCOHOL; F(2,80) DRUG 482