THE INTERACTION OF BUSPIRONE AND DIAZEPAM WITH ALCOHOL IN HEALTHY HUMAN SUBJECTS SYNOPSIS

Transcription

1 THE INTERACTION OF BUSPIRONE AND DIAZEPAM WITH ALCOHOL IN HEALTHY HUMAN SUBJECTS k A. Smiley ; H. Moskowitz; and K. Ziedman SYNOPSIS The effects of buspirone and diazepam, both alone and combined with alcohol, on skills performance were investigated using a mixed group design. Thirty male subjects each received 3 treatments: 10 mg diazepam, 10 mg buspirone, and a drug placebo. Half of these subjects received an alcohol placebo with their drug treatment; the other half received an alcohol dose of 0.63 g/kg bodyweight. Subjects performed a test battery comprising driving simulator (half-hour drive), word frequency, handsteadiness, body sway, and visual backward masking tasks. Diazepam produced significant impairment of balance and gross body control (body sway test), eye-hand co-ordination and muscle control (hand steadiness test), information processing ability (visual backward masking test), and driving skill measured in the driving simulator. In comparison, buspirone had few significant effects on performance. The addition of alcohol to the drug treatment was associated with increased impairment, though few effects were significant for the alcohol treatment. No drug-alcohol interactions were found. INTRODUCTION Recent epidemiological research has suggested that tranquilizers may increase the probability of involvement in a traffic accident (Bo et al., 1975; Skegg et al., 1979). These results are supported by experimental studies which indicate skills performance impairment by many anxiolytic agents. Diazepam has been the most frequently examined tranquilizer. Numerous reports have suggested that it produces significant skills deficits (Kleinknecht & Donaldson, 1975; Moskowitz & Burns, 1977). In contrast, preliminary reports from animal studies suggest that buspirone hydrochloride, a newly developed anxiolytic drug, has produced little or no impairment in animal behavior analogous to aspects of human performance (Allen et al., 1974; Wu et al., 1972). * Southern California Research Institute, Los Angeles, California, USA. 1257

2 In this study we compared skills performance under diazepam and buspirone treatments, in humans, using a variety of tasks ranging from tests of simple psychophysical functions to more complex measures of behavior sensitive to alcohol and drug use; we the drugs in combination with alcohol as well as alone. Research indicates that the addition of alcohol to diazepam further impairs performance (Burford et al., 1975; Linnoila & Hakkinen, 1974; Smiley et al., 1974). In contrast, some investigators using rats and mice have reported buspirone to potentiate the effect of alcohol much less than diazepam (Allen, 1978). Therefore, the interaction of diazepam and buspirone with alcohol was studied with particular attention given to the direction of a possible interaction. Treatments examined in the current study were buspirone (10 mg) and diazepam (10 mg) alone, and in combination with alcohol at a dose level of 0.63 gm ethanol per kg bodyweight. The tasks were selected as important for driving and other situations requiring human interaction with machinery. Subjects METHOD Thirty male subjects were selected from applicants who had been driving at least 3 years, were years old, weighed kg, had 20/30 vision minimum (corrected or uncorrected), and were moderate alcohol users as defined by the scale described by Cahalan et al. (1969). The Minnesota Multiphasic Personality Inventory was used to exclude potentially unstable subjects. Medical examination, with renal and liver function tests, eliminated individuals not in good physical health. E x p e r i m e n t a l D e s i g n A 2 x 3 mixed factorial design was used with drugs as a within group variable and alcohol as a between groups variable. One group of 15 subjects received the drug treatment in combination with an alcohol dose. The other group of 15 subjects received the drug treatments in combination with a placebo alcohol treatment. Each subject was tested on 3 occasions; each time he received 1 of the 3 drug doses: placebo, 10 mg of diazepam, or 10 mg of buspirone, in combination with the appropriate alcohol treatment. The sequence of drug treatment sessions was determined by a 3 x 3 balanced Latin square design (replicated 5 times). 1258

3 The experiment was double-blind with regard to both drug treatments and alcohol treatments. The buspirone, diazepam, and placebo capsules, identical in appearance, were supplied by the Mead Johnson Pharmaceutical Division. Test Battery The test battery required approximately one hour. Each subject performed the following sequence of tests in order: driving simulator test, word frequency, body sway, hand steadiness, and visual backward masking. The tests are described below. Driving Simulator: The subject sat in car-cab and viewed a 6' x 8' (150 x 200cm) projector screen 6' (150 cm) in front of him. A graphics display of a roadway scene was picked up from a CRT by a camera and then rear-projected onto the screen using an Advent Video Beam projector. The graphics display was generated by a PDP-11/60 computer in combination with a Megatek graphics system. The subject's steering, accelerating, and braking movements resulted in appropriate changes in the image of the roadway scene. The driving tasks included: tracking and lane position maintenance while following cruves in the presence of wind gusts; keeping headway constant while following a lead car which was varying its speed, both with and without wind gusts; emergency decision making when confronted with an obstacle in the road; route following; and passing while avoiding obstacles (representing oncoming traffic) in the opposing lane (Figure 1). During the course of each run the subject was also required to perform a secondary task consisting of cancelling red and green lights to his left and right sides with 2 pedals. This task simulated occasional demands on a driver's attention due to other traffic events, for examples, parked cars, and cars approaching an intersection. (The simulator is described in detail by Michelson et al., 1978). The simulator run lasted approximately 30 minutes and was 14 miles km in length. Word Frequency Test: The word frequency test provided a measure of the speed of processing complex information. Oldfield and Wingfield (1965) showed that the time to onset of naming an object is inversely proportional to the logarithm of the frequency of appearance of this object's name in the written language. The word frequency test used pictured objects whose names ranged from being frequently to infrequently used. The test required the participant to name the pictured objects as quickly as possible; the response measure was the latency of subject's response. 1259

4 Body Sway Test: The body sway test measured balance and gross body control. The participant stood with feet together, head tipped back, and eyes closed. Sway in 2 planes was measured by the excursions of strings, attached at the back and side to a leather strap around his chest. Three 1-minute trials were run. Hand Steadiness Test: Eye-hand co-ordination and muscle control were measured by requiring the subject to hold a metal stylus within a small hole in a metal plate while avoiding contact of stylus and plate. The number of times the stylus contacted the plate and the total contact time were recorded electronically. Visual Backward Masking: This task measured information processing rate. A 3-channel tachistoscope was used to present the subject a series of 15-msec duration visual stimuli each consisting for 4 letters and each followed by a dark interstimulus interval of 50, 75, or 100 msec, followed by a masking stimulus (random bits of letters) presented for 500 msec. The response measure was the number of correctly identified letters in correct order at each interstimulus interval. (See Moskowitz & Murray, 1976, for a more detailed task description.) Training The subjects were trained on 3 days prior to the experimental treatment runs. On each training day the subject drove in the driving simulator twice, each run lasting 30 minutes. On the second and third training days the subjects practiced the visual backward masking task as well. On the third training day the subjects practiced the body sway, hand steadiness, and word frequency tasks as well as the visual backward masking and simulator tasks. Behavioral Testing Schedule After training, the subjects attended 3 treatment sessions, separated by 1-week intervals. On treatment days monetary incentives were given based on performance. The subjects were instructed to consume no food or stimulants from the evening preceeding a treatment session. They were also required to abstain from all drug use throughout the study and to abstain from alcohol use for 48 hours proceeding a session. Upon arriving at the laboratory at the scheduled time, subjects provided a urine sample for drug screening purposes and were given a breath test to ensure an initial 0% BAC (Blood Alcohol Concentration). On treatment days the 1260

5 subject then received his assigned beverage (alcoholic or placebo) administered in 3-drinks of equal volume over a 30-minute period, at the end of which a test drug was administered. The alcohol beverage consisted of equal parts 80-proof vodka and orange juice. The amount of vodka given was 2 ml/kg bodyweight (i.e., 0.63 gm/kg pure alcohol), which was expected to produce a mean peak BAC of 0.075%. Placebo drinks consisted of a teaspoon of vodka floated on top of a beverage of equal parts orange juice and water. Thirty minutes after the administration of the test drug the subject rinsed his mouth and was given a BAC test. He was then taken to the driving simulator and completed a 30-minute simulator run. The subject performed the remaining tasks in the following order: word frequency, body sway, hand steadiness, and visual backward masking. A third BAC test was given at the end of testing and every hour thereafter until the subject's BAC was below 0.03%. Analyses The driving simulator generated a number of different driving tasks, each involving several performance measures. Seventeen measures were considered to define the most essential aspects for the driving tasks and were analyzed. Of the 17 measures, 6 were measures of the variability of lane position during tasks of differing degrees of difficulty and throughout the entire run; 2 were measures of the variability of speed when a constant speed was called for; 2 were measures of variability of headway when a lead car was present driving at variable speeds; and 1 was the total number of subjects having crashes during either the passing task or the emergency stop task. The remaining 6 measures were each specific to a particular task: mean room to spare in the emergency stop task; mean number of successful passes in the passing task; number of turnoffs taken correctly and reaction time to signal the turnoff in the route sign following tasks; and, finally, the number of peripheral lights detected during the entire run and the mean reaction time to these lights. All measures collected in the word frequency, body sway, hand steadiness, and visual backward masking tasks were used in the analysis and are enumerated in the description of the test battery. The data were analyzed using the UCLA Biomedical Computer Package (BMCP Version) of statistical programs. Each measure was examined for outliers which were then excluded from the analysis. Almost all outliers were contributed by 2 subjects, both under the alcohol and diazepam treatment conditions. 1261

6 Before analyzing the simulator results, w examined the data from the last of 6 training runs to ensure that the active alcohol and the placebo alcohol treatment groups were comparable. A non-significant but nevertheless strong trend towards a difference between the groups was noted for some variables. Therefore, an analysis of covariance was used in order to take into account this difference. Each variable in the last training run was used as a covariate for the same variable in the treatment runs. (The use of a covariate in the analysis of variance increases the power for testing the statistical significance of the alcohol effect [the between-group variable] but has no effect on the testing of the drug effect [a within-group variable].) The number of subjects having crashes was analyzed using a chi-sguared test (McCall, 1975). The number of subjects having crashes and the total number of subjects in the sample are small. Consequently only one chi-squared analysis was performed where data for both alcohol groups was combined. For the tasks other than the simulator no comparable last training run was made which could be used as a covariate, therefore analyses of variance were performed. Comparison between placebo and diazepam conditions and between placebo and buspirone conditions were then made using t-tests. RESULTS Subjects in the alcohol treatment group attained an average BAC of 0.077% (standard deviation of 0.01%) at the BAC test given just prior to the experimental testing. The average BAC at the end of the testing was 0.05% (standard deviation of 0.02%). Alcohol Effects Because alcohol was a between-group variable in this experiment, the test of its effect was not as strong as the test of the drug effect, a within-group variable. The result of this was that there were fewer significant differences due to alcohol than might have been expected. Simulator: Adding alcohol to each of the 3 drug treatments caused performance to deteriorate as measured by the majority of simulator measures (see Table 1 and Figures 2, 3, 4 and 5). However, few differences were statistically significant. Difficulties in car control were indicated by a significant increase in lane position variability in the curve following task (p less than 0.05; see Figure 2). There was a trend towards reduced headway variability for the combined lead car plus wind gust task under alcohol treatment (p less than 0.10). However, this better performance probably resulted from significant reductions in 1262

7 headway under alcohol treatment (p less than 0.05, not shown in Table 1). Although the reduced headway under alcohol may have been less safe, the subjects were able to hold the headway constant more easily because they were closer to the lead car. There was a trend towards increased numbers of successful passes under the alcohol treatment (p less than 0.10). The reduction in headway and increase in numbers of passes both indicate an increase in risk-taking under the alcohol treatment. Word Frequency Task: Mean response time was longer for words of every frequency type when alcohol was added to the drug treatments. However, none of the measures showed significant alcohol treatment effects at the p 0.05 level, though they did show a trend toward poorer performance under alcohol for Type 5 words (p less than 0.10; see Figure 6 and Table 2). Body Sway and Hand Steadiness Tasks: For the body sway test there was a significant alcohol treatment effect. Both lateral and anterior/posterior excursions were significantly greater (p less than 0.05) for the placebo alcohol group (see Figure 7). This result was completely unexpected, as well as being inconsistent with the results from all the other tasks used and with results of other studies using the body sway task (Idestrom & Cadenius, 1968; Moskowitz et al., 1974). Despite best efforts to select subjects randomly, the most likely explanation of this finding is group differences. It should be emphasized that the drug effect, which was not subject to between-group differences, was consistent across groups. In the hand steadiness task the addition of alcohol to the drug treatments was associated with an increase in the number of contacts and the mean contact time. However neither of these effects was significant (see Figure 8). Visual Backward Masking Task: The addition of alcohol to the drug treatments resulted in a reduction in the number of correctly identified letters (see Figure 9). However, again the effects were not significant. It should be noted that the blood alcohol concentration had fallen to 0.05% by the end of the test battery. At this level between group comparisons using small groups seldom result in significant alcohol effects, though trends towards impairment may be evident. Alcohol Drug Interaction Effects: None of the measures from any of the task showed an alcohol-drug interaction effect at the 0.10 level or better. It is, thus, appropriate to examine the measures for the effects of the 3 drugs, regardless of the alcohol treatment, using pairwise analysis. 1263

8 I I I I I Summary of Adjusted Treatment Means and Analysis of Covariance Results for the Simulator Variables r - ro <0 Q- Q_ Q - E I I I* * * -O I IJD* O t I C\J CM 00 <4- + CU +-> oo c= - to - QJ fl3 fo Z3 to U I o c n (J c ro *4 " O ' D ' D - O O lo C lo 0) <D «- <U O +-> r 2 r X =3 CU o r I CO CT> cn o ID O o o CO CO l o CD CM cr>o t > CO X> XJ fo ro CU CU C to XJ CU 4-> <U - C 4-> to CD CO U +-> - r <U r > to o CU 4 - c X I 4 - S- S- O <U =3 V) C Q.+ J +-> S O C D + J + J + J +-> CU CU CU E E. CD-I- -r- 5-4->+-> <U <o Q-+-> E C O O From 2 x 3 analysis of covariance ***: p less than 0:001; **:p less than 0.01; *p less than 0.05; b: p less than Buspirone performance better than placebo. C C S- S- 1264

9 Summary of Treatment Means and Analyses of Variance Results for the Visual Backward Masking, Hand Steadiness, Body Sway and Word Frequency Task in c «3 - a> n +-> r Nl 03 C O <D -cr o b= o +-> o mi CD < t n h - o cn -o-o S - S- o o - 4 Cd (_) Cd O CdU Cd O Cd u C\J CO l > LO UD CO CVII-"- *=1- CO CT) CvJ c n l o id c n r - l CO CVJ c\ j c \ j r o ooo CD CD cd v) to in E E E S_ O') GO CO From 2 x 3 analysis of variance ***: p less than 0.001; **: p less than 0.01; *: p less than 0.05; b: p less than Buspirone better performance than placebo. O O *r

10 Diazepam Effects Pairwise analyses in which both alcohol treatment groups were included were used to compare the placebo and diazepam conditions. Simulator: Diazepam significantly impaired driving performance. Pairwise analyses comparing diazepam with placebo showed significant differences for 7 performance measures, and a trend toward a difference in 1 measure. Both lane position and speed control were affected. Lane position variability increased in the curve following task (p less than 0.05; see Figure 2) and over the entire run as was indicated by significant increases in the total number of lane excedances and total time spent with 1 wheel out of the lane (p 0.05). Speed variability increased significantly in the curve following task where a constant speed of 30 mph (48 kmph) was called for (p less than 0.01). When drivers made an emergency stop upon the sudden appearance of an obstacle, room to spare between the simulator and the obstacle decreased significantly under the diazepam treatment in comparison with placebo (p less than 0.01; see Figure 3). Perceptual performance was significantly impaired by the diazepam treatment in the route sign following task. In comparison with the placebo condition, fewer of the target turnoffs were taken (p less than 0.01) and reaction time to the turnoffs was slower (p less than 0.005; see Figures 4 and 5). In the peripheral light detection task there was a mean but non-significant decrease in number of lights detected and a trend towards an increase (p less than 0.10) in reaction time under the diazepam treatment. Word Frequency Test: The word frequency test measures complex information processing ability. The response measures were numbers of pictured objects labelled incorrectly, and mean response time for labelling words in 5 categories ranging from Type 1 words (most frequently used) to Type 5 words (least frequently used). Mean response times were longer for diazepam than placebo in 9 out of 10 comparisons (5 word types x 2 alcohol treatment conditions). Differences in response times were significant for Type 2 words (p less than 0.05) and close to significant for Type 3 words (p less than 0.10; see Figure 6). Body Sway and Hand Steadiness Tasks: Both the body sway and the hand steadiness tasks showed diazepam to impair performance. Diazepam was associated with significantly more posterior/anterior excursions in the body sway task, and increased contacts and contact time in the hand steadiness task (p less than 0.01); see Figures 7 and 8). 1266

11 Visual Backward Masking Task; The visual backward masking task provides a measure of information processing rate. The response measures were the number of correctly identified letters at 3 interstimulus intervals. Significantly fewer letters (p less than 0.01) were correctly identified at all 3 intervals under the diazepam treatment, indicating a reduction in information processing rate. (See Figure 9.) Buspirone Effects Simulator; Buspirone showed no evidence of impairment in the simulator measures. Pairwise analyses comparing the buspirone and placebo conditions showed only one significant difference: speed control, as measured by variability of velocity in the curve following task, improved under buspirone treatment (see Table 1). The chi-squared test comparing number of subjects having crashes during the emergency stop task and the passing task showed a trend (p less than 0.10) towards worse performance under buspirone treatment (8 subjects out of 29 vs 2 subjects out of 29). Word Frequency Test: There were no trends of significant differences between buspirone and placebo on performance of the word frequency task. Body Sway and Hand Steadiness Tasks: In the body sway task the buspirone treatment was associated with poorer performance: the number of lateral excursions was significantly greater (p less than 0.05) under the buspirone condition. No significant effects or trends due to the buspirone treatment were noted in the hand steadiness task. Visual Backward Masking Task: Buspirone appeared to improve performance with significantly more letters seen (p less than 0.05) at the 75-msec interstimulus interval. DISCUSSION Significant impairment due to diazepam was found in rate of information processing (visual backward masking and word frequency task) and in motor control (body sway and hand steadiness tasks). Deficits in these basic skills showed up as significant impairment of driving skills as measured in a number of tasks on a driving simulator: both car control and visual search skills were significantly affected by diazepam in comparison with placebo. A number of previous studies support these results. In a driving simulator study, Linnoila and Hakkinen (1974) found 10 mg of diazepam to have significant effects on driving performance: collisions and neglected 1267

12 instructions increased. Moskowitz and Burns (1977) also found effects on preformance using a low dose of diazepam (5 mg). Diazepam significantly impaired a task requiring simultaneous performance of tracking and visual search. Marginal statistical significance also was found for the tracking task performed alone. These results are similar to those of the current study which showed diazepam to impair tracking performance and to impair a visual search task (the route sign following task) performed while the subject was tracking. In noticeable contrast to the diazepam results, buspirone showed few significant effects on performance. The single measure showing significant deterioration in performance at the 0.05 level was balanced by 2 measures showing performance significantly improved. These human performance results support the animal literature showing buspirone caused minimal or no apparent functional impairment (Allen et al., 1974; Wu et al., 1972). The addition of alcohol to buspirone or diazepam was associated with a mean deterioration in performance for most measures, although few differences were significant. However, because alcohol was a between groups variable, it was less powerfully tested than drug treatment which was a within subjects variable. CONCLUSION Diazepam at a dose level of 10 mg was found to impair a wide range of skills as measured by a driving simulator and by tasks measuring complex word processing abilities, rate of information processing, hand steadiness, and body sway. In contrast, 10 mg of buspirone appeared to have little effect on prformance. The addition of 0.63 g alcohol per kg bodyweight to the drug treatment was associated with increased impairment, though few effects were significant for the alcohol treatment. The absence of significant drug x alcohol interactions indicates that the effects of buspirone and alcohol as well as diazepam and alcohol are essentially additive. ACKNOWLEDGMENTS This work was supported by the Mead Johnson Pharmaceutical Division under Protocol No Acknowledgment is given to Drs. George Casten and Roger Newton for their assistance as Contract Monitors and to Dr. Joseph Shannon for medical assistance. 1268

13 REFERENCES Allen, L. E. (1978) Interaction of Buspirone HCI and Diazepam with CNS Depressants. Department of Biological Research Report, Mead Johnson Pharmaceutical Division, ALE-KE-07391, July. Allen, L. E., Ferguson, H. C., and Cox R. H. (1974). Pharmacologic effects of MJ , a potential tranquilizing agent. Arzneimittel-Forschung, 24: 917. Bo, 0., Hafner, J., Langard, 01., Trumpy, J., Bedesen, J., and Lunde, P. (1975). Ethanol and diazepam as causative agents in road accidents. In Israelstam, S. and Lambert, S. (eds.), Alcohol, Drugs, and Traffic Safety. Toronto, Canada: Addiction Research Foundation of Ontario. Burford, R., French, I. W., and LeBlanc, A. E. (1975). The combined effects of alcohol and common psychoactive drugs: I. Studies on human pursuit tracking capability. In Israelstam, S. and Lambert, S. (eds.), Alcohol, Drugs, and Traffic Safety. Toronto, Canada: Addiction Research Foundation of Ontario. Cahalan, D., Cisin, I. H., and Crossley, H. M. (1969). American Drinking Practices, A National Study of Drinking Behavior and Attitudes. New Haven: College and University Press. Idestrom, C., and Cadenius, B. (1968). Time relations of the effects of alcohol compared to placebo. Psychopharmacologia, 13: Kleinknecht, R. A., and Donaldson, E. (1975). A review of the effects of diazepam on cognitive and psychomotor performance. Journal of Nervous and Mental Diseases, 161: Linnoila, M., and Hakkinen, S. (1974). Effects of diazepam and codeine, alone in combination with alcohol,on simulated driving. Clinical Pharmacology and Therapeutics, 14: McCall, R. B. (1975). Fundamental Statistics for Psychology. New York: Harcourt Brace Jovanovch, Inc. Michelson, S., Niemann, R. M., Smiley, A., and Zeidman, K. (1978). A driving simulator for human performance studies using all digital techniques. Internal Report: Southern California Research Institute, November. 1269

14 Moskowitz, H., and Burns, M. (1977). The effects of alcohol and valium, singly and in combination, upon driving related skills performance. In Huelke, D. (ed.), Proceedings of the 21st Conference of the American Association for Automotive Medicine. Morton Grove, Illinois: AAAM. Pp Moskowitz, H., Daily, J., and Henderson, R. (1974). Acute tolerance of behavioral impariment by alcohol in moderate and heavy drinkers. Report on Contract DOT-HS Washington, D. C.: Department of Transportation (NHTSA). Moskowitz, H., and Murray, J.T. (1976). Alcohol and backward masking of visual information. Journal of Studies on Alcohol, 37: Oldfield, R. C., and Wingfield, A. (1965). Response latencies in naming objects. Quarterly Journal of Experimental Psychology. 17: Skegg, D. C. G., Richards, S. M., and Doll, R. (1979). Minor tranquilizers and road accidents. British Medical Journal, _1. Smiley, A., LeBlanc, A. E., French, I. W., and Burford, R. (1975). The combined effects of alcohol and common psychoactive drugs: II. Field studies with an instrumented automobile. In Israelstam, S. and Lambert, S. (eds.). Alcohol, Drugs, and Traffic Safety. Toronto, Canada: Addiction Research Foundation of Ontario. Wu, Yao-Hua, Rayburn, J. W., Allen, L. E., Ferguson, H. C., and Kissel, J. W. (1972) Psychosedative agents, 2. 8-(4-substituted 1-pipazinylalkyl)-8-azaspiro (4.5) decane-7, 9-diones. Journal of Medicinal Chemistry, 15:

15 Figure 1. Roadway scenes. 1271

16 Placebo Buspirone Diazepam Placebo Buspirone Diazepam FIGURE 2: Variability of Lateral FIGURE 3: Emergency Stop Task : Position in the Curve Following Task Room to Spare _ Placebo Beverage Alcohol Beverage Figures 2-5.

17 1 Jj 1.50 Placebo Buspirone Diazepam FIGURE 6: Word Frequency Task : Mean Response Time I M Placebo Buspirone Diazepam FIGURE 7: Body Sway Task : Number of Excursions G Placebo Beverage I Alcohol Beverage Placebo Buspirone Diazepam FIGURE 8: Hand Steadiness Task : Number of Plate Contacts Placebo Buspirone Diazepam FIGURE 9: Visual Backward Masking Taak : Mean Number of Indentifled Letters (3 ISI Combined) Figures

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