THE EFFECTS OF THE (SUB)CHRONIC ADMINISTRATION OF AN ANTIHISTAMINE AND MEBHYDROLIN ON REAL CAR DRIVING AND PSYCHOMOTOR PERFORMANCE OF PATIENTS AND HEALTHY VOLUNTEERS * * * * J. J. de Gier, ; J. A. M. Van Herwaarden ; * ** and F. A. Nelemans, SYNOPSIS The side effects of an antihistamine, mebhydrolin, were measured on real-driving behavior and psychomotor performance. Twenty healthy volunteers, each receiving 50 mg t.d.s. for a period of 7 days, were divided into 2 groups (I and II), each with 10 subjects. Both groups were assessed on the tests, twice, with and without treatment of the drug. Group I was medicated after a base-line measurement; the other group (II) was assessed for the first time after drug treatment, while base-line values were measured after the medication had been withdrawn for at least 7 days. A third group of subjects, 6 patients suffering from hay fever, was investigated for the first time during treatment and for the second time after medication (wash-out of at least 7 days). The results showed that a repeated dose of mebhydrolin, 50 mg t.d.s., on a chronic regimen in patients, or for 7 days in healthy volunteers, had no significant consistent effect on any of the parameters measured in the driving test and in the laboratory test. INTRODUCTION Antihistamine (Hl-receptor antagonists) are effective drugs in the treatment of hay fever, allergic rhinitis, and other allergic disorders (Avery, 1976). However, their side-effects, particularly those in relation to the central nervous system, are well-known to prescribing doctors and patients receiving chronic medication with these drugs. It is generally accepted that these side-effects can cause a detrimental effect on task performance such as in car driving (Joscelyn & Donelson, 1980). Although, laboratory experiments on psychomotor tasks related to car driving have failed to produce objective evidence for these effects, it is very difficult to extrapolate from the laboratory or simulator situation to that of "real life" car driving. * Drugs and Driving Research Group, University of Utrecht, Vondellaan 14, 3521 GE Utrecht, THE NETHERLANDS. ** Committee on Traffic Medicine, Dutch Association of Doctors Motorists (WAA), Utrecht, THE NETHERLANDS. 291
The purpose of this study was to evaluate the extent of driving impairment caused by mebhydrolin, a widely used antihistamine in the Netherlands. Laboratory experiments with mebhydrolin show no evidence of any impairment of psychomotor behavior (Hindmarch & Parrott, 1979; Jones, 1960; Miiller-Limmroth & Kruger, 1977; and Wagner, 1962). Nevertheless, it is stated that most of the commonly used laboratory tests used are short and entertaining ones and could be less sensitive to sedative effects than protracted, repetitive, and boring ones (De Gier, et al., 1980). For this reason the latter type test was used in this study. Finally, the effects of mebhydrolin on real life car driving of patients and healthy volunteers were also studied in this experiment. METHODS In order to assess the possible impairment due to mebhydrolin on real life car driving of patients, we decided to collaborate with general practitioners in the Province of Utrecht. Patients suffering from hay fever and receiving mebhydrolin medication were asked to participate in the study. Individual patients were made aware of the general protocol of the study and the aims of the investigations. Subjects were advised not to consume alcoholic beverages 24 hours prior to the test days. A driving test and a laboratory test were performed during treatment and for the second time after treatment had ceased (after a wash-out period of at least 7 days). Unfortunately, this approach yielded only 6 patients (all males) after a period of 6 weeks. Therefore, we decided to extend the total number of subjects by including healthy volunteers employing the same design as indicated for the patients. Twenty male subjects were divided into 2 groups (I and II), each of 10 subjects (Table 1). Both groups were assessed on the tests twice, that is, with and without administration of mebhydrolin 50 mg t.d.s. for a period of 7 days. For Group I the medication started after a base-line measurement; for Group II the assessments were made for the first time after drug treatment whereas base-line values were taken after the administration of the drug had been discontinued for at least 7 days. 292
Table 1 The Mean Values ( + s.d.) of Age, Weight and Driving Experience of Patients and Healthy Volunteers Group I Group II Group III (n=10) (n=10) (n=6) Age (years) 25.3 + 4.6 24.8 + 3.0 27.3 + 4.4 Weight (kg) 72.5 + 5.3 73.4 + 6.9 75.3 + 5.1 Driving experience mean length (years) 5.9 + 4.8 5.1 + 3.1 8.1 + 5.1 km x 103. yr-1 18.3 + 19.8 18.1 + 13.3 16.4 + 12.0 Driving Test During the test driving skills were rated by a trained observer in the front seat of the car (with dual controls) using a 110-item check list. The items reflect behavioral components and congnitive skills involved in driving. Items were rated on a 3-point scale as "satisfactory," "moderate," and "insufficient." A final driving ability score was assessed by calculating the total number of items scored as "insufficient" in a selection of 22 so called "important" items. The importance of an item was indexed according to the fundamental contribution of this item to traffic safety. A full description of the driving test conditions is given elsewhere [De Gier, 1979; 1980 a]. In order to decide which score on the 22 items would characterize a subject as an unsafe driver, the driving scores of 20 learner drivers were used to set this criterion. These drivers performed our driving test within 7 days after they failed the practical examination for a license of the Dutch licensing authorities. Laboratory Tests We used attention-demanding tasks that have been described in full elsewhere (De Gier & Nelemans, 1981). These tasks are based on visual vigilance and are designed 293
to be protracted and boring. A high-attention demanding task (A) and a low-attention demanding task (B) are performed for 1 hour each (without an interval) in a soundproof room. In Task A the subject has to detect randomly introduced irregularities in the sequence in which a moving dot (speed 900 msec/movement) lights up in a 10 x 10 stationary pattern of small open circles on a color CRT. A normal sequence is said to occur if the moving dot does not skip a circle or skip 3 circles of the stationary pattern. An irregularity is said to occur if the moving dot skips 1 circle. The latter if detected by the subjecjb is recorded as a "hit." Incorrect responses are recorded as "false alarms" and "misses." In Task B the subject has to keep the joystick controlled cursor within the boundaries of a slowly moving (0.5 cm/sec) CRT-displayed square (dimensions: 70/30 mm). Changes of direction of movement (horizontal movement only) are randomly introduced and the subject's performance is recorded and defined as the number of seconds that the center of the cursor is outside the boundaries of the square. RESULTS The results of the driving test show the number of items scored as insufficient out of 22 items indicated as most important regarding their fundamental contribution to unsafe driving (Table 2). Statistical evaluation revealed no significant (5% level of significance for a 2-tailed test) differences in real car driving performance within (Wilcoxon matched-pairs signed-ranks test) and between (Mann-Whitney U Test) the 3 groups of subjects. From the laboratory test we found only one significant drug effect in Group III. The patients showed significantly more (p is less than 0.05) false alarms during treatment with mebhydrolin. Again no between-group between-group differences were noticed (Figure 1). 294
Table 2 Number of Items Scored as "Insufficient" in the Driving Test Group I Group II Group III ubject no drug mebhydrolin mebhydrolin no drug mebhydrolin no dru 1 5 (1) 6 (2) 4 (0) 11 (5)* 0 (0) 0 (0) 2 1 (0) 11 (4)* 3 (2) 6 (3) 0 (0) 4 (1) 3 1 (0) 0 (0) 4 (1) 0 (0) 4 (1) 9 (3) 4 5 (2) 11 (5)* 1 (0) 3 (1) 0 (0) 4 (1) 5 1 (1) 6 (3) 2 (0) 1 (0) 3 (1) 0 (0) 6 1 (0) 0 (0) 1 (1) 1 (0) 0 (0) 2 (0) 7 1 (0) 0 (0) 0 (0) 0 (0) 8 0 (0) 0 (0) 4 (1) 4 (2) 9 0 (0) 0 (0) 0 (0) 2 (0) 10 0 (0) 1 (1) 0 (0) 5 (3) () Number of items scored as "insufficient" out of the six items reflecting "visual perception" and "anticipation of events". * Less than 4 items scored as "insufficient" constitutes unsafe driving. DISCUSSION It has been demonstrated before that the driving test used in this study is able to show differences in driving performance after the use of moderate quantities of alcohol (0.45 g/kg) and in patients receiving diazepam are compared with control subjects (De Gier, 1979; 1980 a). The results of the driving test in this study indicate that mebhydrolin, 50 mg 3 times a day, does not significantly impair car 295
driving ability as measured on items reflecting car driving behavior. The results also indicate a slight tendency for an impairment in scores on the second test day as compared to the first. They reveal no sign of any practice or session effect. Because driving performance in 2 of the 3 groups was measured on the second test day without administration of the drug, this tendency is probably due to the subjects' lack of motivation to show their best. The 3 groups did not differ significantly from each other in task performance as measured in the laboratory test. However, the patients showed significantly more false alarms during medication. Because this effect did not appear in the other 2 groups, this result is probably not due to a drug effect. A possible explanation is the increased motivation of patients receiving mebhydrolin medication. In any case the laboratory tests show no detrimental effects of mebhydrolin. In earlier studies Task B proved to be sensitive to the effects of benzodiazepines in acute (10 mg diazepam) and chronic dose regimens (De Gier et al. 1980; De Gier, 1980 b). Since the laboratory task was designed for benzodiazepines, the results with a drug of an other class of sedative drugs, such as the antihistamines, is worthwhile. CONCLUSIONS Within the limitations of the present study, mebhydrolin in a (sub)chronic administration does not significantly impair real life car driving and psychomotor performance of patients and healthly volunteers. ACKNOWLEDGEMENTS This work was supported by a grant from The Dutch Association of Doctors Motorists (WAA). REFERENCES Avery, G. S. (1976). Drug Treatment. Sydney: ADIS Press. Pp. 259-260. De Gier, J. J. (1979). A subjective measurement of the influence of ethyl alcohol in moderate levels on real driving performance. Blutalkohol, 16: 363-370. 296
De Gier, J. J., 'T Hart, B. J., Nelemans, F. A., and Bergman, H. (1980). Psychomotor performance and real driving performance of out-patients receiving diazepam medication. Psychopharmacology, 73: 340-344. De Gier, J. J. (1980 a). Evaluation of Drugs in Real Driving Situations. Doctoral Thesis, University of Utrecht. De Gier, J. J. (1980 b). Effects of diazepam on psychomotor performance. Paper presented at the First World Conference on Clinical Pharmacology and Therapeutics; 3-9 August, London. De Gier, J. J., and Nelemans, F. A. (1981). Driving performance of patients receiving diazepam medication. In Goldberg, L. (ed.), Alcohol, Drugs, and Traffic Safety, Volume III. Stockholm: Almqvist & Wiksell. Pp. 1009-1023. Hindmarch, I., and Parrott, A. C. (1978). A repeated dose comparison of the side effects of five antihistamines on objective assessments of psychomotor performance, central nervous system arousal and subjective appraisals of sleep and early morning behavior, Arzneimittel Forsch., 28: 483-486. Jones, N. (1960). Antihistamine treatment of hay fever with special reference upon reaction time. Practitioner, 185: 334-339. Joscelyn, K. B., and Donelson, A. C. (1980). Drug Research Methodology. Vol. 11: The Identification of Drugs of Interest in Highway Safety. Ann Arbor, Michigan: University of Michigan. Miiller-Limmroth, W., and Kruger, H. (1977). Study on effect of the daytime antihistaminic mebhydrolin on motor reaction time and mental processing time. Clinical Therapy, 1: 219-227. Wagner, H. J. (1962). Uberprufung des Leistungsverhaltens unter den Einwirkung Verschiedener Antihistaminica. Arzneimittel Forschung, 12: 1065-1070. 297
task A I task B mean score (I) of hits mean num ber o f false alarms mean num ber o f seconds out * p < 0.0 5 C R O U P I J C R O U P II 7 G R O U P I I I (n=6) p atients ~i -1 0 0-75 50- -50 25-2 5 no d ru g M e b h y d ro lin M e b h y d ro lin no d ru g M e b h y d ro lin no d ru g 50 mg t. d. s. 50 mg t. d. s. 50 mg t. d. s. F i g u r e 1. T h e r e s u l t s o f t h e l a b o r a t o r y t e s t. 298