Drug and Alcohol Dependence, 12 (1983) 323-332 Elsevier Scientific Publishers Ireland Ltd.

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(-)+ACETYLMETHADOL EFFECTS ON ALCOHOL AND DIAZEPAM USE, SEXUAL FUNCTION AND CARDIAC FUNCTION*

WILLIAM A. HARGREAVES**, JOAN TYLER, J. ARTHUR WEINBERG, JAMES L. SORENSEN and NEAL BENOWITZ

Departments of Psychiatry and Medicine, San Francisco General Hospital Medical Center, University of California, San Francisco, CA 94103 (U.S.A.)

(Received August 16th, 1983)

SUMMARY

Selected behavioral and physiological effects of maintenance on (-)a- acetylmethadol (LAAM) were examined for 67 men beginning LAAM maintenance. Thirty-four began LAAM maintenance after 1 month or more on methadone; 33 others were using street heroin immediately before beginning LAAM. Subjects were followed for 20 weeks on LAAM; assessment focused on changes in alcohol and diazepam use, sexual behavior and testi- cular function, and cardiovascular function.

There was a trend toward increased alcoholism-related behaviors, but not consumption of alcohol, when on LAAM. Use of diazepam remained low. Subjects reported slightly enhanced sexual activity: reported number of ejaculations tended to increase, although interest in sexual activity remained constant. Semen volume values remained in the low normal range. In contrast to an earlier published report of reduced sperm motility in methadone and heroin users, normal motility was noted in this sample. The incidence of abnormal sperm morphology decreased from baseline to the end of the study. Cardiovascular function, as assessed by response to standard exercise, was unchanged during LAAM maintenance. Electrocardiograms revealed minor abnormalities prior to beginning LAAM maintenance; but these abnormalities did not consistently change during treatment. There is little evidence that the effects of LAAM maintenance differ from the effects of methadone maintenance on these behavioral and physiological functions.

Key words: (-)a-Acetylmethadol - Heroin addiction - Maintenance treat- ment - Sexual function - Cardiac function - Alcohol use

*Supported by contract AGR NDA 44108 from the State of California and by grants DA 01696 and DA 01512 from the National Institute on Drug Abuse. **To whom reprint requests should be sent at: Room 7M3, General Hospital Medical Center, 1001 Potrero Avenue, San Francisco CA 94103, U.S.A.

0376-8716/83/$03.00 o 1983 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

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INTRODUCTION

LAAM is a long-acting synthetic opiate similar to methadone, which has been tested for a number of years as a maintenance treatment of heroin addiction [ 1 J . Although many aspects of the safety and efficacy of LAAM have been evaluated in controlled comparisons to methadone [ 2-81 adverse physiological or behavioral effects may have been overlooked.

There has been specific concern about the effects of long-acting opioids on sexual activity and testicular function [g-11]. Cicero et al. [ 121 found testicular function to be altered in a group of 29 methadone maintenance clients, compared to 43 narcotic-free controls or 16 heroin addicts. Ejaculate volume was reduced, and sperm motility was below the range of values for normal subjects. Both methadone maintenance and heroin-addicted subjects tended to report fewer ejaculations per month than drug-free subjects, some attributing this in part to their use of narcotics. To the extent that these differences result from the persistently high opiate levels in methadone maintenance clients, one would expect the same or greater effects with LAAM. Mendelson et al. [13] found that LAAM lowered plasma testosterone levels 4-25 h after oral ingestion and suggested that assessments of secondary sex organ function in males on LAAM maintenance should be carried out.

Cardiac effects occur in the chronic administration of many drugs; how- ever, none have been documented for methadone when used to treat narcotic addiction [ 111. In the large-scale studies of LAAM, no meaningful effects were seen on pulse and blood pressure [2,6,7]. Rendig et al. [14] have demonstrated that high concentrations of LAAM or methadone exert a direct myocardial depressant effects, but no published reports have addres- sed the effects of LAAM on cardiac function in narcotic addicts.

The present investigation examined possible effects of LAAM on the incidence and severity of alcohol and diazepam use, on sexual behavior and testicular function, and on cardiovascular function. Our concern was to determine whether patients showed adverse changes when moving from street heroin or from previous maintenance with methadone on to LAAM maintenance.

METHODS

Su bjec ts Male heroin addicts, who were already participating in a double-blind

study of alternate LAAM dosage strategies [8], were recruited for the additional assessment procedures of this safety study. Sixty-seven subjects participated in one or more of the assessments of alcohol and diazepam use, sexual function, and cardiac function. Mean age of the sample was 31 years; 48% were from minority ethnic groups, 68% had graduated from high school, and they had been using opiates for a mean of 11.7 years. Subjects were either just beginning LAAM maintenance following varying periods of street heroin use (N = 33) or had been on methadone maintenance for 1

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month or longer (mean = 7.5 months) and transferred to LAAM main- tenance (N = 34). Those who transferred from methadone had been receiving from 20 mg to 80 mg doses (mean = 58.7 mg). The 67 subjects began LAAM at dosages from 30 mg to 90 mg (mean = 51.5 mg).

Although patients with serious medical conditions were screened out of the study before intake, a number of the subjects in the study had health difficulties. Six reported a history of medical problems, including hyper- tension, rheumatoid arthritis, atherosclerotic vascular disease, chronic alcohol use, mitral valve disease, and syphilis. Twenty-one subjects exhibited abnormal laboratory data, including liver function tests (11 subjects), com- plete blood count values (6), urine values (5), blood sugar (3) and reactive serology (2). The study intake physical examination revealed abnormalities in 18 subjects, the most significant of which were gynecomastia (3 subjects); probable previous pancreatitis (1 subject) and a previous asthmatic condition.

Measures Alcohol use. The self-reported Michigan Alcoholism Screening Test

(MAST) [15] was administered to measure subjects’ history of alcohol use. In interviews at 0,4, 8,12,16 and 20 weeks after beginning LAAM, sub- jects were asked about their drinking behavior in the previous month and their use of beer, wine and hard liquor. A breathalyzer alcohol test was administered at each interview. . The data from periodic interviews provided two kinds of information about subjects’ drinking while on LAAM: alcoholism-related behaviors and amount of alcohol consumed. A summary score of ‘Alcoholism Behavior’ was calculated from six items in the monthly interview (Table I). The Alcoholism Behavior scale picked up episodes that generally indicate pro- blems with alcohol, e.g., arrests for drunk driving, number of times drunk. Reported alcohol consumption was measured separately from other alco- holism behavior (Table II).

Diuzepam use. To assess subjects’ use of diazepam we employed both self-report and urine testing at weeks 0, 4,8,12,16 and 20. Diazepam usage was estimated from client reports of frequency and amount of usage, using a method parallel to the one shown in Table II for alcohol consumption.

Sexual behavior and testicular function. A sexual activity and function questionnaire was administered to all subjects at weeks 0, 4 and 20. Questions included interest in sexual activity, frequency of ejaculation, incidence of five specific difficulties (impotence, premature ejaculation, delayed ejacu- lation, ejaculation failure, and painful ejaculation), and an item that asked the subject how his sexual functioning seemed to be affected by his current drug use. Based on responses to all items, subjects were rated by the interviewer as reporting their sexual functioning as impaired, unaffected, or enhanced by their current drug use. A smaller sample of subjects (20 at baseline and 12 again at 20 weeks) consented to provide semen specimens, which were analyzed for volume, motility of sperm, sperm count, and sperm morphology.

Body measurements were gathered at weeks 0,4 and 20 to detect evidence

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TABLE I

ALCOHOLISM BEHAVIOR SCORE

This summary score was calculated as the sum of the following six items, scored as shown below. The first item was read verbatim to the subject, the remainder judged by the interviewer after further questioning. A score was calculated if responses were available on at least five of the six items.

1. “How would you describe your drinking behavior at the present time-would you say no drinking at all, social drinking, heavy drinking or problem drinking?” None (0), Social (l), Heavy (Z), Problem (3)

2.

3.

Number of times drunk in past month. None (0), 1-4 (l), 5-10 (Z), > 10 (3)

Longest period between drinks in past month. 1 week or more (0), 3-4 days (l), 24 h (Z), <12 h (3)

4. Times drinking alone in past month. Never (0), Once in awhile (l), Frequently (Z), Almost always (3)

5. Days of work missed/inactivity because of drinking in past month. None (0), l-2 days(l), 3-5 (Z), >5 (3)

6. Arrested for drunk driving in past month. No (0), Yes (3)

TABLE II

ALCOHOL CONSUMPTION SCORE

A summary score of reported total alcohol intake in the past month was calculated as the sum of three products of frequency by ounces for beer, wine, and hard liquor, respectively. With the items scored as shown below, the summary score is an estimate of the total ounces of pure alcohol consumed in the past month.

1. How often did client drink any BEER? None (0), Less often than weekly (3), l-2 days a week (6), 3-4 days a week (15), Nearly every day (27), Every day (30)

2. How much BEER did client drink on a typical day when drinking? 1-3 glasses (0.96), 1-2 quarts (2.88), 3 quarts (5.76), 4 quarts (9.60), 6 quarts (11.52)

How often did client drink any WINE? (same scoring as item 1)

How much WINE did client drink on a typical day when drinking? 1 water glass or l-2 wine glasses (0.96), 2-3 water glasses or 4-6 wine glasses (2.40), fifth-wine bottle (3.07), 2 fifths (6.14), 3-4 fifths (10.75), gallon (15.36)

How often did client drink any HARD LIQUOR? (same scoring as item 1)

How much HARD LIQUOR did client drink on a typical day when drinking? 1-3 shots (0.8), 4-6 shots (2.0), 7-10 (3.2), 11-14 shots (4.8), 1 pint (6.4), 2 pints (12.8) 3 pints or 1 fifth (19.2), 4 pints (25.6)

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of breast enlargement, controlling for body weight. Body measurements included weight, circumference of chest, waist, and hips, and skin fold thickness at multiple sites.

Cardiovascular function. A 12-lead electrocardiogram was taken at weeks 0, 4 and 20. Tracings were read by a cardiologist who was blind to their order. At weeks 0,4 and 20 blood pressure and heart rate were recorded under nine conditions: in the supine position; then 1, 2 and 3 min after standing; then just prior to exercise and 0, 1, 2 and 3 min after the end of exercise. Exercise consisted of stepping up and down onto a 218-mm high platform for one minute at a rate of 36 complete steps/min.

All testing was performed during a regular clinic visit following a dose of LAAM or methadone or in the morning when the subject did not appear to be experiencing severe withdrawal symptoms. The subjects were asked to refrain from alcohol for the 24 h prior to the test, from coffee or tea on the morning of the testing, and from cigarettes 60 minutes prior to testing. A urine test for methadone, opiates, amphetamines, barbiturates, and diazepam at the time of the cardiovascular assessment provided a partial check on other drug use.

RESULTS

Alcohol use On the MAST 17 of 56 subjects (30%) scored five or above, indicative of

a history of problems with alcohol. This 30% incidence of a history of problems with alcohol is higher than that in the non-addict population but not discrepant from the prevalence in other maintenance populations.

The mean Alcoholism Behavior scores for subjects who remained in the study for 20 weeks remained close to 2.0; a subject with a score of two typi- cally described himself as a ‘social drinker’ (one point) with 3-4 days between drinks (one point), with no other storable alcoholism behavior. There was a small upward trend over time in the two groups combined (F = 5.19; df = 1, 34; P = .03); however, the actual trend is very small. Furthermore, reported alcohol consumption showed no change, fluctuating at about 15 ounces per month, or a half ounce per day (less than one beer per day). Thus, any trend toward increased alcoholism among these subjects appears only in their reports of other alcoholism behaviors, and not in the amount of alcohol consumed.

Further independent information on alcohol use was provided by an alcohol breathalyzer test administered at each test period during the client’s regular clinic visit. Nine out of 144 tests for the ‘transfer’ group were positive (6%) while 3 out of 107 tests for the ‘street’ group were positive (3%). The test results may underestimate the extent of alcohol use, because the test reflects only current levels of alcohol. Most clients who drank heavily did not appear in the clinic while intoxicated, since to do so might result in their LAAM or methadone dose being withheld. Our clinical impression, based on

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anecdotal reporting by the subjects and the frequency with which they seemed intoxicated during clinic visits, was that perhaps 9 subjects were problem drinkers during the course of the study. Of the 9 problem drinkers, 4 gave the impression of increased drinking over time, the other remained stable.

Diazepam use Diazepam use remained below a mean of 15 mg/month, except at pretest

when street subjects reported some use to treat withdrawal symptoms. Urine tests for diazepam also indicated a low incidence of use. Altogether 22 of 230 tests were positive for diazepam. Half of these positive tests were accounted for by two subjects with valid prescriptions for back pain. There- fore, diazepam use or abuse does not seem to have been prominent in this group of subjects.

Sexual behavior and testicular function The questionnaire data provided the most direct information about

sexual behavior. Differences between the two groups (Street vs. Transfer) and time trends were examined using a repeated measures analysis of variance with an orthogonal breakdown of time trends that took into account the uneven spacing of the measurement occasions. (Symmetry assumptions were tested and met.) Sex interest and ejaculation frequently did not differ signifi- cantly between groups or over weeks, although there was a suggestion of a linear increase in ejaculation frequency over time (F = 3.24; df = 1, 25; P = 0.08). In the combined street and transfer groups, subjects reported a slight but progressive decrease in overall impairment of sexual function (linear trend F = 4.67; df = 1,25; P = 0.04). The subjects who reported sexual impair- ment complained most often of decreased interest in sex, rather than of specific difficulties; however, some specific sexual problems occurred. Of the 5 symptoms, only premature ejaculation showed a significant change over time and the trend was toward decreased incidence.

The possible effect of LAAM on breast enlargement was examined by first computing the ratio of chest to waist-plus-hips measures as an index of relative breast size. Mean chest ratios for the two subject groups at the three time points were all virtually identical. There were significant changes over time in body weight (F = 96.1; df = 2, 48; P < 0.001) and skinfold thick- ness (F = 13.78, df = 2, 48; P < 0.001). Subjects in the street sample gained an average of 4.9 kg by week 20; in the methadone transfer group, many of whom had been on methadone maintenance only a month, sub- jects showed a smaller increase of 3.2 kg by week 20. Skinfold thickness also showed an increase (reflecting more subcutaneous fat), though this gain occurred more gradually over the 20-week period. Both subject groups showed an average increase of more than 2 mm, about a 25% increase over the 20 weeks.

Twenty subjects agreed to participate in the semen analysis procedure and

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provided a semen sample at week 0 and 12 of these subjects remained at week 20 and provided a second semen sample. Seven were in the street addict sample; five were transfer subjects. At week 0 the mean semen volume was 2.03 + 0.48 ml. Normal range of semen volume per ejaculate is 1.5 to 6 ml. Sperm motility and morphology did not change over time. Sperm motility one hour after sampling was reported to be low in the Cicero et al. investigation [ 121, although they measured sperm motility in only five methadone clients and two heroin users. All seven of their subjects were below the ‘normal’ range of 53-73s. Our street sample at week 0 showed 30--60-min motility values of 40-95%, averaging 62.1% in the seven subjects who gave samples at both admission and week 20. The normal values at the clinic where testing occurred is 50% or above, up to 60 min. Week 20 rates averaged 55.8%, a non-significant change. Incidence of abnormal sperm cells was higher at week 0 than at week 20: at week 0 average incidence of abnormal sperm morphology was 4%, compared with 1% at week 20.

Two of the twelve subjects showed consistently high sperm counts (over 250 M/ml), associated with low semen volumes. Four others showed values over 100 M/ml on one of the two occasions. Ten of the 12 subjects showed sperm count values that are below the usual normal range of 60 M/ml. How- ever, Cicero et al. [12] report a mean sperm count of 46.6 (range O-183) in 40 normal controls 110.2 (range 1-415) in 22 methadone patients and 75.0 (range 2-410) in 16 heroin addicts. The sperm count values we observed are therefore not lower than those reported by Cicero for normals. Increased sperm counts after 20 weeks on LAAM were as common as decreased counts, suggesting that LAAM has no consistent effect on sperm count.

Blood pressure and heart rate The average blood pressure and heart rate response of subjects to the

detailed exercise procedure is shown in Table III. On the average, supine blood pressure was 112/72 mmHg and heart rate was 71 beats/min. When subjects stood up systolic pressure decreased on the average 2 mmHg, while diastolic pressure increased the same amount, and heart rate increased 13 beats/min. Exercise increased systolic pressure 14 mmHg, decreased diastolic pressure 10 mmHg and increased heart rate 20 beats/min. By 3 min after exercise these measures returned to the pre-exercise levels.

The effects of LAAM across the three time periods, 0, 4 and 20 weeks, were tested via two-way repeated measures analyses of variance for each of the nine measures (see Table III). Within each of these analyses our primary interest was in the test of the linear trend over weeks (taking into account the uneven spacing of the assessment occasions); of secondary interest was the interaction of the time trend with group membership. In interpreting the results one must keep in mind that each analysis of variance yielded 8 significance tests and we computed 9 of these for a total of 72 tests of signi- ficance. Therefore one could expect, by chance alone, that a few would be statistically ‘significant’. Only 6 yielded P-values at or below 0.10, two at

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P = 0.05. Examining the pattern of results, there is no evidence that LAAM consistently affected blood pressure or heart rate, either while a client was at rest, upon standing, or after exercise.

Electrocardiogram A total of 120 electrocardiograms from 45 subjects were collected. Non-

specific abnormalities were observed in 19 of the 45 pre-LAAM electro- cardiograms. Twelve subjects showed non-specific T-wave abnormalities. Five showed first degree heart block, as evidenced by a P-R interval greater than 0.20 s. One patient showed left atria1 enlargement and left axis deviation and another patient showed a minor right ventricular conduction defect. Among the 12 patients with initial T-wave abnormalities, T-waves did not change in most cases, although some cases became more normal during LAAM administration. There were no changes that could be interpreted as a progression of abnormalities during LAAM.

TABLE III

CARDIOVASCULAR MEASUREMENTS 0,4 AND 20 WEEKS AFTER BEGINNING LAAM MAINTENANCE IN ‘STREET’ AND ‘TRANSFER’ SUBJECTS WHO REMAINED IN LAAM MAINTENANCE FOR 20 WEEKS

F- and P-values shown for the linear trend over time, in a groups-by-time two-way re- peated measures analyses of variance; F for other effects in these analyses were not significant except as noted.

Measurements Street (N = 14) Transfer (N = 14) - F P Week Week Week Week Week Week 0 4 20 0 4 20

Supine

Systolic BP (mmHg) 109.9 112.0 112.3 114.1 116.9 114.9 0.19 NS

Diastolic BP (mmHg) 70.0 69.0 68.1 73.9 72.6 68.7 4.87 0.04 Heart rate (bpm) 72.6 69.7 12.9 69.6 72.3 69.3 0.00 NS

After standing 1 min

Systolic BP (mmHg chng) ~- 0.57 2.14 -1.64 0.14 -5.29 --7.21 3.00’ 0.10 Diastolic BP (mmHgchng) 4.14 4.29 3.43 0.43 -1.14 2.93 0.5gb NS

Heart rate (bpm chng) 13.4 12.6 14.9 11.6 14.3 15.6 4.40 0.05

I min after exercise

Systolic BP (mmHg chng) 10.6 14.7 12.0 11.8 17.7 15.7 0.16 NS Diastolic BP (mmHgchng) --10.0 --lo.9 -5.7 -11.1 -7.8 -13.7 0.03 NS

Heart rate (bpm chng) 16.6 19.1 24.6 19.5 19.2 19.7 3.26’ 0.08

aQuadratic trend by group interaction F = 4.03, P = 0.06. bGroup F = 3.43,P = 0.08. ‘Linear trend by group interaction F = 2.83, P = 0.11.

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DISCUSSION

This study did not uncover any serious adverse effects of LAAM as a maintenance drug for opiate addicts, Some relatively minor effects were found, similar to those reported for methadone, There was a trend among subjects toward increasing their alcoholism-related behaviors while on LAAM. While the average increase was small, it may be a problem for the lo-20% of the subjects who account for this effect. Clinically, we are aware of patients on LAAM and on methadone who will, upon leaving the clinic, immediately retire to a tavern or to their house and drink moderately, with the intention of combining the opiate dose with alcohol to give what they view as a pleasurable ‘high’. It is possible that such combined use of alcohol and opiates may lead to increases in the behavioral consequences of drinking, even if total alcohol consumption does not increase. We cannot tell from this study whether increased alcoholism-related behavior is a phenomenon of maintenance treatment in general, as others have suggested [ 161, or whether the problem is specifically worse with LAAM as a maintenance drug.

Subjects did not report increased sexual dysfunction attributable to LAAM and, in fact, reported a significant reduction in sexual impairment attributed to opiates and a trend toward an increased number of ejaculations. This may have more to do with lifestyle changes than drug effects. Our results do not support the suggestion that LAAM maintenance leads to more impairment of sexual functioning than does methadone maintenance. We observed relatively low values of semen volume, consistent with the findings of Cicero et al. [ 121. While Cicero et al. reported reduced sperm motility in a small number of methadone and heroin subjects, our results showed normal sperm motility among LAAM subjects. Without a comparison group of drug-free subjects the meaningfulness of such cross-study comparison is questionable. Our results, however, suggest that LAAM is no more hazardous than methadone in adversely influencing secondary sexual characteristics or function.

Body measures were also obtained to detect possible endocrine effects of LAAM. No breast enlargement occurred, although there were statistically significant increases in body weight and subcutaneous fat. This effect has been noted in methadone maintenance and the mechanism that produces it is not understood [ 121. In the large VA LAAM trial [6], street addicts gained weight to an equal extent whether they were randomly assigned to methadone or LAAM; in the SAODAP LAAM study [ 71, patients already stabilized on methadone maintenance did not gain weight whether they stayed on methadone or were randomly assigned to transfer to LAAM. In the present study, the larger weight increase in the street sample underscores the idea that some addicts entering maintenance are below their optimal weight, and lifestyle changes may account for the weight gain seen in some patients.

The present study also did not detect adverse effects on blood pressure

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and heart rate under the stress of exercise. Cardiac function in LAAM main- tenance was previously measured by Towery and Rios (unpublished), who examined electrocardiograms for a series of LAAM patients followed for 12 weeks. They did not find any adverse effects of LAAM. Our study con- siderably extends the knowledge of cardiac function during LAAM main- tenance.

The most important cautionary note of this study is the suggestive trend for problems with alcohol to worsen in the initial weeks of LAAM main- tenance. It is reassuring that these subjects reported no difficulty with sexual functioning that they attributed to LAAM, in spite of what one would expect from the endocrine effects of opiates. Although the present study is limited by the absence of a comparison group of subjects receiving meth- adone, it adds further positive information on the safety of LAAM when chronically administered as a maintenance treatment.

ACKNOWLEDGEMENTS

The authors express their appreciation to Barbara Baker, Judi Kletter, H. Richter, M. Callas, Evelyn Le Blanc, Drew Leder, Luriko Shon, Edward Kersch, Beverly Mangus and the staff and clients of the Mission Methadone Maintenance Treatment Program, San Francisco, California.

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