Combined effects of propranolol and ethanol on human psychomotor performance

TOXICOLOGY

AND

APPLIED

67,

PHARMACOLOGY

117- 121 ( 1983)

Combined Effects of Propranolol and Ethanol on Human Psychomotor Performance’ R. LINDENSCHMIDT,*** *Department 46223;

D. BROWN,* B. CERIMELE,~ T. WALLE,Z# AND R. B. FORNEY*

of Pharmacology and Toxicology, Indiana University School of‘ Medicine, Indianapolis, Indiana fDow Chemical Company. Indianapolis, Indiana 46268; and SDepartment of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29407

Received

July 6. 1982; accepted

October

I, I982

Combined Effects of Propranolol and Ethanol on Human Psychomotor Performance. LINDENSCHMIDT,

R.,BRowN,

D.,~ERIMELE,

B., WALLE,T.,

AND FORNEY,R.

B. (1983).

Toxicol.

67, 117- 12 1. Twelve male subjects were given placebo or 160 mg propranolol, in divided doses, during a 24.hr period before drinking a beverage containing 0 or 50 ml ethanol/ 70 kg body weight. Tests designed to measure mental and motor performance were administered 75 min after the last dose of propranolol. The tests performed included the wobble board (WB), pursuit meter (PM), delayed auditory feedback (DAF), pegboard (PB), tapping, time estimation (TE), and a modified Cornell medical index (CMI). A mean blood ethanol concentration of 48.0 f 9.1 mg/dl and a mean plasma propranolol level of 33.1 k 13.1 rig/ml were achieved. Ethanol alone significantly impaired performance in 12 out of 20 tests (p i 0.05). Propranolol significantly (p < 0.05) antagonized the decrement in psychomotor performance induced by ethanol on the PM. In all other tests, there was no significant interaction between ethanol and propranolol. Propranolol alone had no significant effect on the psychomotor tests. When the drugs were combined, the subjective symptoms, as measured by the CMI, showed a trend toward being additive. This study suggests that no adverse interaction occurs between therapeutic doses of propranolol and minimum impairment doses of ethanol. Appl. Pharmacol.

The ,&adrenergic blocking drug, propranolol, was developed for the treatment of angina pectoris. During the past 20 years, numerous studies have confirmed the beneficial effects of propranol, not only in angina pectoris (Battack et al., 1969; Coltant, 197 1; Prichard et al., 1970), but also in hypertension (Pritchard and Gillman, 1964; Zacharias et al., 1972), cardiac arrhythmias (Sloman and Stannard, 1967), hyperthyroidism (Hadden et al., 1970), anxiety (Granville-Grossman and Turner, 1966), and recently in migraine headaches (Behan and Reid, 1980). In addition to the ’ This work was supported by Merrell Dow Pharmaceutical Co. Inc. Presented in part at the Annual Meeting of the Society of Toxicology, San Diego, Calif., March, 1981. ’ To whom all correspondence should be addressed. 117

fl-adrenergic blocking action, propranolol possesses membrane stabilizing properties (Langslet, 1970) as well as various central nervous system depressant properties, such as sedation and anticonvulsant activity (Leszkovszky and Tardos, 1965). Recently, because of the CNS properties, there has been increasing interest in the use of propranolol to reduce anxiety or tension during alcohol withdrawal. It is therefore important to determine if this drug could affect motor and cognitive skills alone and in combination with ethanol. Human studies which examined the effects of propranolol on behavioral changes induced by alcohol have been reported (Alkana et al., 1976; Mendelson et al., 1974). Pretreatment with propranolol prior to alcohol administra0041-008X/83/0101

17-05$03.00/O

Copyright Q 1983 by Academic Press. Inc. All rights of reproduction in any form reserved

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tion failed to block or to attenuate cognitive, perceptual, motor, or affective changes induced by alcohol intoxication (Mendelson el al., 1974). The lack of statistically significant effects on ethanol impairment may have been caused by several factors: (a) Since there was no treatment crossover, each subject did not serve as his own control; (b) the psychomotor performance tests may not have been sensitive enough; (c) the degree of ethanol intoxication may have been too great resulting in a decreased ability to detect any combined effect; (d) although no data were presented, the peak plasma concentration of propranolol may have occurred prior to the peak plasma concentration of ethanol decreasing the possibility of interaction. The purpose of this study was to evaluate the. effect of propranolol alone and in combination with ethanol on psychomotor performance in human subjects. An experiment was designed which utilized a complete crossover latin square, a lower level of ethanol intoxication, a simultaneously achieved peak blood concentration of both drugs, and a different set of measurement parameters. This design would more definitively describe the effects of propranolol on psychomotor performance and the effect of propranolol in combination with ethanol. METHODS Twelve male volunteers were selected from a group of medical and graduate students. They ranged in age from 22 to 28 years and in weight from 145 to 195 lb. Each was judged to be overtly healthy by history, physical examination, and laboratory evaluation, including electrocardiogram, blood chemistry, and complete blood count. All subjects were considered moderate users of ethanol. Participants were instructed to abstain from drugs including caffeine the evening before. and the day of the experimental sessions. Prior to beginning the experiments, each subject signed an informed consent document, as part of a protocol approved by the IRB, Indiana University School of Medicine. Drug or placebo was administered in a double-blind manner with all treatments assigned to each subject according to a latin square crossover design. Doses of 0 or 160 mg propranolol (Inderal, Ayerst) were administered by capsule, and ethanol, 0 or 50 m1/70 kg, was administered in orange juice. Previous work has shown that this

ET AL.

amount of ethanol would produce a blood ethanol concentration of approximately 60 mg/dl. The propranolol was administered as a 40-mg capsule every 6 hr for 24 hr prior to testing with the last dose being given 75 min before the test session. The ethanol was administered 60 min before the start of the psychomotor performance test session. The test procedure lasted approximately 30 min. Each subject was tested individually, at the same time of day for all four test sessions, with the sessions being separated by at least one week. All the subjects underwent four practice sessions to become familiar with the testing procedures and to reduce subsequent learning effects. Baseline measurements were obtained one day prior to the test session so that these data served as the standard non-drug performance condition to which the test data, collected 24 hr later, were compared. In addition, analysis of these baseline data would allow for the determination of any change in baseline from week to week.

TEST

BATTERY

Modified Cornell medical index (CMI). A printed list of diverse symptoms in questionnaire form was administered at the beginning of the test battery. Subjects scored each symptom on a scale of 0 to f4. The number of symptoms which any given subject experienced and the rating given to each of these symptoms were evaluated. Stability of stance. A wobble board (WB) was used to measure balance-seeking behavior (Shipley and Harley, 1970). Motor perjbrmance. Attentive motor performance was measured with a pursuit meter (PM) and the same test pattern (0.5 cps) was used in each session (Fomey et al., 1964). Manual dexterity. Three different tests on a pegboard (PB) were used to measure manual dexterity. A separate test for manual dexterity involved the number of finger taps a subject could elicit in the allotted time. Time estimation. The subjects were asked to estimate a IO-W time period while reading. Mental performance. A delayed auditory feedback (DAF) systemcapable of producing a self-induced anxiety was used to measure mental performance (Fomey and Hughes, 1961). Blood ethanol concentrations, heart rate, and blood pressure were measured at 30-min intervals throughout the test session, with blood ethanol concentrations being determined by a Breathalyzer. A blood sample was drawn at the end of each test session for the determination of serum propranolol levels.

RESULTS Heart Rate and Blood Pressure

Plasma levels of propranolol (33.1 +_ 13.1 @ml) were within the normal therapeutic

PROPRANOLOL

AND ETHANOL

INTERACTION

119

TABLE 1 EFFECT OFPROPRANOLOLANDETHANOLONPSYCHOMOTORTESTS~ No ethanol Procedure

Ethanol b Propran

Pooled SD*

9.60 14.82 29.74 9.78

7.79 10.48 5.99 11.65

20.2 30.6 29.7 32.3

Et Sbj, Et

4075

4952

3697

7,559

Eth

7.0 -2.5

25.7 -3.8

-4.5 2.1

-6.8 1.6

41.5 4.8

Et

-7.6 0.33

-7.9 -0.42

-12.1 -0.33

-9.8 1.08

12.6 1.3

Wk wk

-1.0 0.08

-0.1 -0.58

-2.9 0.75

-2.7 0.67

3.3 2.5

-1.8 0.75

-0.8 0.08

0.8 -0.67

12.3 5.3

Wk

0.7 1.1 -0.9

2.4 1.2 1.1

2.1 2.2 3.1

2.3 2.5 2.8

Et Et Et

5.6

Et

No propran

Propran’

-0.68 -7.53 -7.27 16.65

-3.96 -7.43 0.23 -20.6 1

-4226

No propran

-

Analysis of variance*

WBf I II III IV PMB DAF’: Test 1 output Errors Test 2 output Errors Test 3 output Errors Test 4 output Errors

2.3 0.17

Sbj, Wk, Et Sbj, Wk

PB’ I II III Tapping’ Time estimating VW’ CM1 (post-testy” Questions Total score

-0.5 -0.6 -0.5 0.0 -0.3 0.6 0.3

-0.2

-3.8

-4.2

0.6

1.3

1.9

1.6

Et

1.6 1.9

8.5 11.2

8.8 13.0

3.9 6.0

Et Et

’ Data expressed as the mean of the within-subject differences obtained by subtracting baseline values from treatment values. b Ethanol dose: 50 ml ethanol/70 kg body wt. ’ Propranolol dose: 40 mg every 6 hr for 24 hr. *Because the standard deviations among the four groups did not differ appreciably, variability among the observations is expressed as a single pooled estimate of the standard deviation of the differences. * Significant source of variability: intersubject-Sbj, weekly-Wk, propranolol-Prop, ethanol-Et (p < 0.05). I Wobble board-lower score indicates more stability of stance (negative sign indicating less error score than baseline). I, eyes open; II, eyes closed; III, eyes open, motor on; IV, eyes closed, motor on. gPursuit meter-lower score indicates increased attentive motor performance (negative sign indicating less error score than baseline). ’ Antagonistic effect of propranolol on the impairment caused by ethanol. i Delayed auditory feedback: 1, verbal output; 2, reverse count; 3, subtraction; 4, color chart. j Pegboard I, any color pegs; II, all white pegs; III, red, white, and blue pegs in order. k Number of taps in IO-set time interval (negative sign indicating more error score than baseline). ‘Estimation of a lO-set time interval (negative sign indicating less error score than baseline). mCornell medical index (mod&d)-number and intensity of symptoms.

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LINDENSCHMIDT

range. While there was no significant change in systolic or diastolic blood pressure after propranolol administration, there was a significant decrease in heart rate, an expected clinical result, which was not altered by the presence of ethanol. Blood Ethanol Concentration The mean blood ethanol concentration after ethanol alone was 48.0 +- 9.1 mg/dl and was not significantly different with coadministration of propranolol, 39.0 t 3.6 mg/dl. Psychomotor

Performance

Tests

The data obtained for the two drugs and their combination are summarized in Table 1. An analysis of variance for crossover design was applied to the variables adjusted for the baseline levels by differencing. Assumptions underlying the crossover analysis were validated by analysis of variance on the baseline measurements. Single degree-of-freedom contrasts were used to evaluate the individual drug effects as well as the interaction effects. A significance level of p < 0.05 was selected. An impairment in stability of stance is reflected as an increased score for the wobble board (WB) tests. Ethanol impaired stability in tests II and III. In attentive motor performance, ethanol caused a significant impairment as reflected by the increased pursuit meter (PM) score. Impairment in the delayed auditory feedback (DAF) tests is indicated by a decrease in verbal output, or as an increase in the number of errors made. Ethanol significantly impaired reading (errors) and subtracting (output) ability. Ethanol also reduced performance in all the pegboard (PB) tests (as shown by increased PB scores) and in tapping ability and time estimation (TE). Propranolol alone had no significant effect on any of these tests. In combination with ethanol, propranolol antagonized the decrement induced by ethanol in the pursuit meter test. No significant interaction in any of the other tests was seen.

ET AL.

Modijied

Cornell Medical

Index (CMI)

The subjective symptoms produced by ethanol are reflected by the significant increases in CM1 scores. The subjective responses to propranolol alone did not differ significantly from control, but there were indications of fatigue, weakness, and tingling of the extremities. Propranolol did not significantly alter the types of subjective effects caused by ethanol but did seem to be additive with those of ethanol (i.e., no changes in the number of symptoms but an increase in the intensity of symptoms). Analysis of baseline measurements in all tests demonstrated no evidence of “practice” carryover effects from week to week. DISCUSSION Propranolol alone may have a slight adverse effect on attentive motor performance as suggested by its effect on the pursuit meter (PM); but at the same time, it significantly antagonized the effect of ethanol (on the same test). The amount of ethanol administered in this study was marginal with respect to producing significant impairment in the tests utilized. The pegboard (PB), pursuit meter (PM), and the CM1 were the most sensitive measures of ethanol impairment. The results of this study tend to support earlier findings (Drew et al., 1972; Mendelson et al., 1974) that no detectable performance changes occur as a result of experimental medication with propranolol. At the doses used here, there seemed to be no major adverse interaction when propranolol was administered in conjunction with ethanol. ACKNOWLEDGMENT The authors gratefully acknowledge Betty Martin for her technical assistance.

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PROPRANOLOL

AND

ETHANOL

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COLTANT, D. J. (1971). Comparison of effects of propranolol and practolol on exercise tolerance in angina pectoris. Brit. Heart J. 33, 62-64. DREW, W. G., KIPLINGER, G. F., MILLER, L. L., AND MARX, M. (1972). Effects of propranolol on marihuana-induced cognitive dysfunctioning. Clin. Pharmacol.

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121

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