Vol. 15. No. 6 Novernber/Decernber I99 I
0145-6008/91/1506-0970$3.00/0 ALCOHOLISM: CLINICAL A N D EXPERIMENTAL RESEARCH
Bromocriptine in the Treatment of Alcohol Dependence Maurice Dongier, Luc Vachon, and George Schwartz
A double-blind controlled study of the effects of bromocriptine on drinking behavior and associated symptoms in ambulatory alcoholics showed a marked improvement in both treatment and control groups. However, significant differences in favor of the medication were observed in psychopathologicalmeasures, and trends in the same direction in most of the other efficacy parameters. Key Words: Alcoholism, Treatment, Bromocriptine, Psychopharmacology.
S THE LONG-TERM effects of alcohol on the brain A are better understood, in particular on neurotransmission, it is logical to turn to pharmacological agents to attempt to correct the abnormalities induced by alcohol, and thereby to provide biological adjuvants to the psychological and social approaches. The aims are to reduce the craving for alcohol, and to improve psychopathological symptoms such as depression, anxiety, and other disorders related to the neurochemical abnormalities correlative of alcohol dependence. The development of such psychopharmacological approaches has been recently the object of several comprehensive reviews.’-3 They include for instance inhibitors of serotonin r e - ~ p t a k egamma-ami,~ nobutyric acid (GABA) agoni~ts,~ and dopamine (DA) agonists.6-8However, all of these attempts are for the time being at the experimental stage, and there is little place for pharmacotherapy in the rehabilitation of alcoholic patients, either as an adjunct or as a primary modality. There is no evidence that the long-term course of alcohol dependence is influenced by any pharmacotherapy, and meager evidence that various psychological and social approaches are much more successful. Noteworthy is the fact that between 28% and 80% of alcoholics drop out of treatment within the first month, and attempts to reduce the drop out rate have been largely unsuccessfu1.9 Among its many effects on neurotransmitters, alcohol shows a diphasic action on the dopaminergic system: a small acute dose of ethanol enhances the activity of the system, whereas chronic administration decreases it and desensitizesdopaminergic receptors.” (For a review of the animal evidence which provided a rationale for human trials, see Hoffman and Tabakoff ’I). Studies in man have given some support to connections between alcohol deFrom Douglas Hospital Research Centre, Alcohol Research Program, and McGill University Montreal, Canada. Received for publicarion February 12, 1991; acceppled July 17, 1991 This research was supported by the Douglas Hospital Research Centre and Sandoz Canada. Reprint requests: Maurice Dongier, M.D., Douglas Hospital Research Centre, 6875 LaSaNe Boulevard, Verdun. Quebec H4H 1R3, Canada. Copyright 0 1991 by The Research Society on Alcoholism. 970
pendence and central nervous system dopamine function. Low levels of DA have been reported in the caudate nucleus and hypothalamus. ’* Bromocriptine, (2-bromo-alpha-ergocryptine mesylate) is a synthetic ergot alkaloid which has the property of activating postsynaptic dopaminergic receptors, hence its use in Parkinson’s disease. Bromocriptine is not the only dopamine agonist to have been proposed in the treatment of alcoholism: apomorphine has been used for more than 50 years13essentially as an emetic agent in order to create a conditioned reflex of aversion for alcohol. It has been used in uncontrolled studies in several thousands of alcoholics and some consider that independently of conditioning, its central action in the brain reduces dependence and contributes to decrease anxiety.l4$I5 Bromocriptine, in addition to its effects on dopamine receptors, increases the hypothalamic turnover of noradrenaline, possibly through an antagonistic action at the noradrenergic receptors, and may contribute to alleviate symptoms of the decreased noradrenergic activity in alcoholics. l 6 Borg’s group first used bromocriptine to alleviate withdrawal symptoms,6 and then camed out a double-blind study in 50 chronic alcoholic^.^ Significant improvement was observed in alcohol consumption, in various associated psychiatric symptoms, and in different criteria of social adaptation. The duration of treatment was 6 months and no follow-up at the end of the treatment was mentioned. Morgan et al.,” Morgan,’* and Anokhinalg also published favorable but uncontrolled data. The present study was undertaken in an attempt to confirm and further extend the findings of Bog7 on the effects of bromocriptine on alcohol consumption and alcohol-related problems. METHOD This was a prospective, double-blind study comparing bromocriptine and a placebo in two parallel groups of alcoholic subjects. The study comprised a treatment phase, which included a 9 d a y titration and a 7week maintenance period, with biweekly evaluations, and a follow-up phase, with monthly evaluations without treatment. Subjects were randomized to receive either bromocriptine or placebo during the treatment phase. In an attempt to balance the two group populations with respect to the seventy of their condition and some factors possibly influencing outcome, they were randomly assigned by a blinded member of the staff not involved in any of the assessments, stratified according to gender, severity of alcoholism, and family history of alcoholism. All subjects signed an informed consent form. The daily dosage of medication was increased over a 9day titration phase, if tolerated, from I .25 mg every day to 2.5 mg 3 times a day and maintained for the remainder of the treatment phase. Placebo was dosed Alcohol Clin Exp Res. Vol 15, No 6 , 1991: pp 970-977
97 1
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
in the same manner, and given in an identical appearing form. During the maintenance period (weeks 2 to 8), the mean daily dose among active treatment completers was 6.7 and 6.9 0.2 mg (mean + SEM) for the placebo and the bromocriptine group, respectively. The individual dosage varied between 2.5 and 7.5 mg in subjects receiving the placebo, and between 4.6 and 7 mg in those treated with bromocriptine. No significant difference between the two groups was observed in the final number of capsules per day. At the end of week 8, the treatment was discontinued abruptly. The subjects then remained without medication for the duration of the follow-up phase. Subjects of both sexes with age limits of I8 and 65 years were recruited either through advertisement in local newspapers and radio stations, or referrals to the clinic. The subjects had to be of at least a normal intellectual level judged by clinical assessment and on sociodemographic data and meet the DSM111 criteria for alcohol abuse or dependence based on clinical assessment. Not included were subjects who, at entry, reported abstinence for more than 15 days, or who presented intermittent alcoholism, defined as more than two interruptions of alcohol abuse over the previous 3 years, each interruption being of more than a 2-month duration. Intermittent alcoholics were excluded because of the short time frame of the clinical trial, to reduce the chance of‘kpontaneous” fluctuations in drinking behavior. Also excluded were subjects reporting concurrent drug addiction or presenting secondary alcoholism, i.e., pre-existing psychopathology such as schizophrenia, major affective disorders, antisocial or borderline personality disorders, major organic syndromes (e.g., Korsakoff ’s syndrome), liver failure, or severe physical consequences of alcohol abuse. DSM-111 criteria were used during the clinical assessment to rule out both substance abuse and mental disorders. The use of sedative, anxiolytic, antidepressant o r neuroleptic drugs had to be discontinued for at least 2 weeks prior to the beginning of the study and was not allowed during the study. Concomitant use of other medications was checked at every visit. Compliance check was performed by pill-count at each visit. In addition, a daily record of the medication taken was completed by the subjects. Noncompliance was arbitrarily defined as the omission of study medication for either 4 or more consecutive days, or for a total of 7 days or more during the 8-week treatment period. The initial assessment included: ( I ) a physical examination, (2) a routine laboratory evaluation, (3) the DSM-111 criteria for alcohol abuse or dependence, (4) the severity of alcoholism, measured by the scores on Alcohol Dependence Scale (ADS),20and Michigan Alcoholism Screening Test (MAST)2’(initially described as a screening instrument, the MAST has been later used as a reliable measure of the degree of problem ( 5 ) the evaluation of alcoholism according to the criteria of se~erity),~~‘~‘ the National Council on Alcoholi~m,~’ (6) the subjects’ family history of alcoholism (pedigree using Research Diagnostic Criteria),26(7) the history of alcohol consumption (years of drinking), (8) the present alcohol consumption: number of standard drinks per day over the past week (standard drink: 12 ounces (341 ml) of beer 5%, 5 ounces (142 ml) of wine, 3.5 ounces (99 ml) of fortified wine, 1.5 ounces (43 ml) of spirits, adjusted for the subject’s weight); number of drinking days per month, (9) the Drinking Behavior Interview (DBI),27and (10) Edwards’ Troubles Scale (ETS)28and Hardship Sale (EHS).28The DBI consists of 3 I scorable items in a structured interview questionnaire (e.g., effects on family and social life: number of quarrels, drink-provoked, during the past 2 months. . . ). The ETS and the EHS are alcohol-related symptoms checklists, the first one by self-evaluation, the second one by next-of-kin evaluation, each providing a score from 0 to 10. Evaluations to assess efficacy were conducted at baseline (week 0), at 2-week intervals during the treatment phase (weeks 2, 4, 6, 8), and at Imonth intervals during the follow-up phase (weeks 12, 16). The efficacy assessments included the following: alcohol consumption (expressed as number of standard drinks per day related to body weight), number of drinking days per week, craving (five-point scale), gamma-glutamyltransferase (GGT) activity (assessed only at weeks 0 and 8), Hamilton Rating
+
Scale for D e p r e ~ s i o nHamilton ,~~ Anxiety Scale,3oand Hopkins Symptom Checklist (SCL-90-R).3’.32 Vital signs and routine laboratory evaluations were carried out at weeks 0 and 8. Possible side effects were monitored at each visit during the treatment phase. A comparison of background information data between the placebo and the treatment groups was carried out for the following three subject populations: ( 1 ) all subjects enrolled in the study (hereafter referred to as the total subject population), (2) subjects who were evaluable for the assessments of efficacy at the end of the treatment phase (week 8) (hereafter referred to as treatment completers), and (3) subjects who were evaluable for the assessment of efficacy at the end of the follow-up phase (week 16) (hereafter referred to as follow-up completers). The statistical analysis of the efficacy data of both the treatment (weeks 0, 2, 4, 6, 8) and follow-up (weeks 8, 12, 16) phases was carried out using a two-way analysis of covariance for repeated measurements, covarying for week 0 value in order to take into account differences between the two groups at baseline. For all efficacy parameters, an estimation of the values was performed if data from a given subject was missing for either week 2,4, or 6 during the treatment phase. Due to statistical constraints, subjects for whom data were missing for more than one visit during the treatment phase, or for week 12 during the follow-up phase, were excluded from the efficacy analysis.
RESULTS
Subjects Population A total of 84 subjects were enrolled in the study, of whom 38 (placebo: N=20, bromocriptine: N= 18) were evaluated in the analysis of efficacy following the treatment phase, and 20 (placebo: N=9, bromocriptine: N= 1 1) were included in the efficacy analysis of the follow-up phase. Seventy-eight subjects were recruited through advertisement, six through referrals to the research clinic. None of the subjects received any alcohol abuse treatment or psychiatric treatment in addition to their visits for study purposes. In Table 1, severe/very severe alcoholism is defined by a score above 30 on the Alcohol Dependence Scale. The two treatment groups were comparable at entry, with respect to their demographic data, except for age and the score of the Edwards’ Hardship scale, which were significantly lower ( p < 0.05) in the bromocriptine group. Trends for similar differences were also observed in the treatment completers. All subjects showed evidence of severe alcoholism in terms of consumption, number of drinking days, years of abuse, and all scales of drinking behaviour. No statistically significant differences between the two treatment groups were found at baseline with regard to the parameters related to alcoholism. However, a trend for a higher number of drinking days per month was observed in the bromocriptine group, as compared with the placebo group, in the total subject population, as well as in both the treatment and follow-up completers. Additional drugs used by “completers” in the treatment group were: diazepam 5 mg, one tablet on day 35 and one on day 37 in one patient; penicillin for 10 days for bronchitis in another one; vitamins ( B I , Biz, c, E) in four subjects; dicyclomine (antispasmodic) in one subject; ox-
DONGIER ET AL.
912
Table 1. Subjects Characteristics at Baselinet Active treatment completers
Total population
Sex Female Male Age (years’) [min.-med.-max.] Severity of alcoholism Mild/moderate Severelvery severe NCA criteria Steady Questionable Family history NOfM Moderate Severe Years of drinking [min.-med-max.] Alcohol consumption (units per day) (min.-med.-max.] Drinking days/month [min.med.-max] MAST (score) [min.-med-max.] ADS (score) [min.-med.-max] DBI (score) [min.-med.-max.] ETS (score) [min.med.-max.] EHS (score) [min.med.-max.]
Placebo ( N = 41)
Bromocriptine (N = 43)
Placebo (N = 20)
Bromocriptine (N = 18)
8 (20%) 33 (80%) 43.6 f 1.8 [21-45-541
10 (23%) 33 (77%) 38.8 f 1.2 (2537-581
NSS
4 (20%) 16 (SOYO) 45.3 f 2.4 [23-48-651
5 (28%) 13 (72%) 40.0 f 1.8 I294 1-54]
0 (0%) 41 (100%)
2 (5%) 41 (95%)
NS
0 (0%) 20 (100%)
1 (6%) 17 (94%)
40 (98%) 1 (2%)
43 (100%) 0 (0%)
NS
20 (100%) 0 (0%)
18 (100%) 0 (0%)
13 (32%) 9 (22%) 19 (46%) 9.4 f 1.o [ 1-8-25] 14.1 f 1.4 [0-14-4 1]
13 (30%) 9 (21Yo) 21 (49%) 10.9 f 8.85 [2-10-251 15.4 f 1.4 (4-12-361
6 (30%) 5 (25%) 9 (45%) 10.4 f 1.4 [3-70-251 13.9 f 1.9 [4-14-47]
7 (39%) 2(11%) 9 (50%) 10.8 f 1.1 [2-70-201 1 1 . 7 f 1.4 (5-11-29]
24.4 f 1.2 [5-26-31] 28.5 f 1.7 (9-37 -491 17.3 f 1.0 [6-77-30] 52.1 f 3.4 [8-55-59] 4.1 f 0.3 [ 14-91 5.1 f 0.4 [0-5-91
26.8 f 1.2 [6-37-31] 27.9 f 1.4 [5-26-51] 18.3 f 0.9 [8-7 7-29] 57.1 f 2.9 [26-56-94] 4.6 f 0.3 11-4-91 3.8 f 0.5 [ 14-91
25.5 f 1.7 [8-31-31] 27.8 f 2.3 [ 12-27-49] 17.7 f 1.1 [8-17-27] 49.4 f 4.3 [8-52-77] 3.8 f 0.3 [24-61 4.7 f 0.5 [ 1-54]
30.0 f 0.6 [203 1-31] 25.5 f 2.2 [ 5-25-42] 17.3 f 1.4 [&17-271 51.9 f 4.6 [27-42-901 4.4 f 0.4 [1-5-71 3.8 f 0.7 [ 1-5-91
NS NS NS
NS ( p = 0.069) NS NS NS NS
Follow-up completers Placebo (N = 9)
Bromocriptine (N = 11)
4 (44%) 5 (56Or’o) 44.7 f 4.5 [23-50-571
3 (27%) 8 (73%) 42.3 f 2.1 [3042-54]
NS
NS
0 (0%) 9 (100%)
0 (0%) 11 (100%)
NS
NS
9 (100%) 0 (0%)
11 (100%) 0 (070)
2 (22%) 3 (33%) 4 (44%) 11.3 f 2.7 (3-8-251 12.5 f 2.0 [4-14-23]
4 (36%) 1 (9%) 6 (54%) 11.2f 1.8 [2-10-201 11.5 2.0 15-1 1-29]
25.7 f 2.6 [12-31-31] 24.6 f 3.5 [ 12-20421 17.8 2.8 [ 10-76-261 44.1 f 8.7 [8-52-71] 3.7 f 0.5 [2-3-61 5.1 f 0.9 [143-81
29.4 f 1.1 [20-31-31] 28.4 f 2.2 [la-26-42] 17.8 i 1.a (8-19-27] 52.4 5.0 [35-43-88] 4.4 f 0.4 [2-4-61 4.4 f 0.4 [1-5-91
NS NS ( p = 0.067)
NS NS NS
NS ( p = 0.070) NS NS NS NS NS
*
*
NS
NS NS NS
NS NS NS NS NS NS
t Data expressed as number of subjects or mean f SEM. $ NS, not significant. = 42 (missing data in one subject). ‘ p 4 0.05.
5N
Table 2. Premature Discontinuations and Exclusions during Active Treatment azepam 10 mg at bedtime for 4 days in another one; Placebo BromocriDtine diphenhydramine (antihistaminic) 25 mg twice daily for Enrolled 41 (100%) 43 (100%) 5 days in one patient; oral antidiabetic (sulfonylureas) in Discontinuations one. Side effects 3 (7%) 5 (12%) In the psychopathological parameters, there were no Lack of efficacy 1 (2%) 1 (2%) Loss of follow-up 10 (24%) 9 (21%) statistically significant differences between the two treat27 (66’/0) 28 (65%) Completed ment groups at baseline, besides a trend close to signifiExclusions cance (p = 0.051) for a higher score on the “Anxiety” 9 (12%) Noncompliance 5 (12%) Missing data 1 (2%) 2 (5%) dimension of the SCL-90-R evaluation in the bromocrip€valuable cases 20 (49%) 18 (42%) tine group. However, since for several parameters the seventy at baseline appeared higher in the active treatment than in the placebo group, the statistical comparisons Table 3 shows the individual treatment duration, as well between the two groups were carried out taking into as the nature and severity of events encountered in subjects account the individual baseline values and changes ob- who prematurely discontinued the treatment due to side served during the treatment period, as already mentioned. effects. Among these subjects, side effects rated as severe were observed in one case in each treatment group. Treatment Phase Table 4 shows the results of the efficacy assessments at Table 2 shows the reasons for premature discontinua- the beginning and the end of the treatment phase, as well tions of the treatment as well as the reasons for exclusion as the number of subjects who improved, did not change of subjects from the analysis of efficacy during the treat- or deteriorated with regards to these assessments during this period. men t phase. A statistically significant improvement (p < 0.001) was The rate at which subjects prematurely discontinued the treatment or were excluded for noncompliance during observed in all efficacy parameters in both groups during the treatment phase was similar in both treatment groups. the treatment phase. This finding was also reflected on an
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
91 3
Table 3. Premature Discontinuations Due to Side Effects Placebo Number of subjects
Treatment duration (weeks)
1
4
1
3
1
1
Bromocriptine
Side effects Headaches’ Drowsiness’ Headachest Dizzinesst Headachest Dizziness$ Nausee Pyrosist
Number of subjects
Treatment duration (weeks)
Side effects
2
1,7
Dyspepsia‘
1
4
Nausea’
1
6
Dizziness’
1
1
Nausea$ Vergitot
* Mild.
t Moderate. $ Severe.
individual basis, as more than 70% of the subjects in both groups improved with regards to all efficacy parameters (Table 4-individual changes during treatment). No statistically significant differences were found between the two groups with regard to consumption, the number of drinking days per week, craving, the GGT activity, or the Hamilton Depression and Anxiety Scales. The number of subjects who reported complete abstinence during the entire duration of the treatment phase did not significantly differ between the two groups either (p = 0.16, Chi-square), although it appeared higher in subjects on placebo (placebo: N = 10, 50%;bromocriptine: N = 5, 28%).On the other hand, a retrospective analysis of the number of subjects in whom a decrease of at least 50% in the GGT activity was observed at the end of the treatment phase revealed a statistically significant difference in favour of bromocriptine (p < 0.05, Chi-square): such a decrease was indeed observed in two ( 17%)out of 19 cases in the placebo group, as compared with eight (47%)out of 17 in the bromocriptine group. Similar results were obtained when this analysis was restricted only to the subjects who were presenting GGT values above the normal upper limit (55 units/liter) at baseline (placebo: N = 1/6 [17%];bromocriptine: 7/9 [78%], p < 0.02, Chisquare). Statistically significant differences (p < 0.05 or p < 0.02), in favor of bromocriptine, were observed in the following variables of the SCL90-R evaluation: “Global Severity Index,” “Positive Symptom Total Score,” “Positive Symptom Distress Index,” “Interpersonal Sensitivity,” and “Anger/Hostility.” In addition, trends (p < 0.10) in favor of bromocriptine were found for the SCL-90-R dimensions “Somatization,” “Depression,” and “Paranoid Ideation.” No statistically significant treatment by variable interactions was observed using the following variables as covariates in the efficacy analysis: age, sex, severity of alcoholism, family history of alcoholism, or number of drinking days per month. Fig. 1 summarizes the extent of the improvement observed in the efficacy parameters in both treatment groups
during the treatment phase. The most pronounced improvement was found in the consumption of alcohol, which, according to self-report, decreased by approximately 90% in both groups. Other parameters improved by 25%to 70%in the placebo group, and by 43%to 85% in the bromocriptine group. Besides differences for which statistical significance was found in favor of bromocrip tine, an overall trend in the same direction emerged for most variables. Thus, the extent of the improvement observed in the active treatment group was higher than in the placebo group by 14% for the number of drinking days per week, 28%for craving, 78% for the GGT activity, 20% for the Hamilton Depression Scale, 16% for the Hamilton Anxiety Scale, and in the range of 10%-37% for the SCL-90-R evaluation. A retrospective evaluation of the analysis performed on the efficacy parameters revealed that the statistical power varied between 7% and 60%,depending on the variables analyzed.
Follow-up Phase As shown in Table 5, 10 (48%)and 13 (72%)of the subjects who completed the treatment phase in the placebo and the bromocriptine group, respectively, also completed the follow-up phase. Among these, three (placebo: N = 1; bromocriptine: N = 2) had to be excluded from the efficacy analysis because of missing data, resulting in nine and eleven evaluable cases in the placebo and the bromocrip tine groups, respectively. These numbers correspond, respectively, to 22% and 26% of the subjects who were initially enrolled in the study in each group. Due to the small number of evaluable cases remaining in the study at the end of the follow-up phase, the results pertaining to this period are presented in a descriptive fashion only. For the same reason, only the global scores of the SCL-90-R evaluation, namely, the “Global Severity Index,” the “Positive Symptom Total Score,” and the “Positive Symptom Distress Index,” are shown. Table 6 summarizes the mean values observed in the efficacy assessments in both groups at the beginning (week 8) and the end (week 16) of the follow-up phase. In the follow-up completers, the alcohol consumption and number of drinking days per week observed at the beginning of the follow-up phase were higher in the bromocriptine than the placebo group by 59% and 62%, respectively. These results are in contrast with those observed at the time of the study in the treatment completers, in whom this difference, if any, was in the opposite direction. On the other hand, slight differences (10%-32%)in favor of bromocriptine were found at week 8 in the followup completers with regards to the other efficacy parameters. At the end of the follow-up-phase, the severity of the efficacy assessment was higher in the bromocriptine than the placebo group in most of the variables, namely consumption (65%),the number of drinking days per week
DONGIER ET AL.
914 Table 4. Efficacy Assessments-Active Treatmentt
Individual changes during treatment$ Parameter
Group
N
Week 0
week 86
Consumption (no. drinks/day) Number of drinking days per week Craving (we) GGT activity (unitspiter) Hamilton Depression Scale (score) Hamilton Anxiety Scale (swre) SCL-90-R evaluation (scores) Global Severity Index Positive symptom total score
Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine
20 18 20 18 20 18 19 17 20 18 20 18
13.9 f 1.9 11.5f1.6 5.9 f 0.4 6.8 f 0.1 3.45 f 0.17 3.17 f 0.23 69 f 20 103 f 29 20.3 f 1.9 20.6 f 1.9 17.0f 1.6 20.7 f 1.9
1.72 f 0.74 1.26 f 0.43 2.0 f 0.6 1.7 f 0.5 1.55 f 0.30 0.94 f 0.23 45 f 12 41 f 8 9.30 f 1.47 7.22 f 1.51 6.30 f 1.15 5.56 f 1.12
Placebo Bromocriptine Placebo Bromouiptine Placebo Bromocriptine Placebo Bromwiptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromouiptine Placebo Bromocriptine
20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17
1.05 f 0.08 1.36 f 0.19 49.1 f 4.6 58.4 f 4.9 1.81 f 0.11 1.99 f 0.13 0.85 f 0.14 1.28 f 0.22 1.37 f 0.18 1.54 f 0.20 1.13 f 0.19 1.45 f 0.24 1.28 f 0.1 1 1.68 f 0.24 0.98 f 0.19 1.51 f 0.23 0.89 f 0.14 1.16 f 0.19 0.55 f 0.12 1.16 f 0.20 1.05 f 0.21 1.35 f 0.23 0.80f 0.12 0.92 f 0.19
Positive Symptom Distress Index Somatization Obsessive/compulsive
Interpersonal sensitivity Depression Anxiety Anger/hostiligy Phobic anxiety Paranoid ideation Psychotism
NS NS NS
NS NS NS
NS NS NS NS NS NS NS NS ( p = 0.051) NS NS NS NS
0.40 f 0.08 0.33 f 0.08 26.8 f 4.2 24.2 f 5.7 1.23 f 0.07 1.16 f 0.11 0.28 f 0.06 0.34f 0.09 0.51 f 0.11 0.41 f 0.12 0.46 f 0.12 0.31 f 0.11 0.53 f 0.12 0.40 f 0.09 0.32 f 0.10 0.38 f 0.11 0.32 f 0.07 0.18 f 0.09 0.16 f 0.07 0.14 f 0.08 0.46 f 0.13 0.31 f 0.09 0.31 f 0.08 0.25 f 0.06
NS NS
NS NS NS NS
NS
( p = 0.071) NS
NS ( p = 0.071) NS 0.
NS
I
N
D
20 18 18 17 16 15 17 16 18 18 19 18
0
0
0
0
2 1 4 3 0 0 0 0 1 0
0 0
20 17 18 17 19 16 17 17 20 16 19 17 17 17 16 17 17 17 14 13 15
0 0 0 0 0 0 1 0 0
( p = 0.059) NS
16 16
0 0 2 1 2 0 0
0 0 0 2 0 1 1 2
0
0
0 0 1
0
0
0 0 3 0 3
3 0 1 0 0
0
0
5 4 3 0 3 0
1 0 2 0 1 1
1
t Data expressed as number of subjects or mean f SEM. $ I, Improvement; N, no change; D, deterioration. f, Statistical analysis between groups: covariance analysis for repeated measurements on weeks 0, 2, 4, 6, 8, with adjustment for baseline values. 1 NS. not significant. ‘ p < 0.05; “ p < 0.02.
siness, and nausea with statistically significant higher incidence in the bromocriptine than in the placebo group (p < 0.001). However, the incidence of these side effects decreased throughout the treatment period. Tables 2 and 3 already summarized the various side effects and their relationship to discontinuation. Following the treatment period, a trend for a decrease in systolic blood pressure was observed in the placebo group (p = 0.084), while a statistically significant decrease (p < 0.001) was found in the bromocriptine group. Diastolic blood pressure did not significantly change in either group. Other isolated side effects occumng in one to three instances in the placebo group were confusion, visual problems, tremor, and cramps. In the bromocriptine Side Eflects group, illusions, euphoria, confusion, dificulty in concenThe most frequent side effects experienced in both tration, cramps, tension, hyperactivity, vertigo, visual groups during the treatment phase were dizziness, drow- problems, palpitations, and anorexia occurred. Alcohol
(89%),craving (65%), and the Hamilton Depression score (4196). Table 6 also shows the number of subjects who improved, did not change, or deteriorated during the followup phase, with regard to the efficacy assessments. Although no clear pattern emerged from this comparison, a trend for a higher proportion of subjects deteriorating was observed in the bromocriptine group on the Hamilton Anxiety Scale and the “Global Severity Index” and “Positive Symptom Total Score” variables of the SCL-90-R evaluation. In addition, three subjects (33%) who had received placebo and two (1 8%) who had been treated with bromocriptine reported complete abstinence during the entire eight-week follow-up period ( p = 0.40, Chi-square).
915
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
ological rating scales. This major effect makes it all the more difficult to identify an additional efficacy of any pharmacological treatment of alcoholism, especially in the early period of intervention. A marked improvement in all efficacy parameters was observed in both groups at the end of the treatment phase. Although such a nonpharmacological effect is usually expected in this type of population, the extent of the improvement that was observed is indicative of a remarkable effect of the study per se. On the other hand, this reduction in alcohol consumption was paralleled by a substantial decrease of the mean GGT activity, as well as by a marked amelioration in the subjects' psychopathological state known to be associated with alcohol abuse and dependence, such as symptoms of depression and anxiety, thus indicating that a general improvement in the subjects' condition did occur during the treatment period, at least from a qualitative standpoint. More than 50% of the subjects enrolled in both treatment groups prematurely discontinued treatment, and were lost to follow-up or non-compliant. These findings are in contrast with those reported by B ~ r gwho , ~ showed a remarkably small attrition over a 6-month period. This can only be due to an exceptional patients' selection, not reported in the paper and/or an exceptional quality of I 0-pv relationship between investigators and subjects and/or unique (and not reported) follow-up procedures. ComFig. 1. Improvement dunng active treatment in dnnking behavior measures, in pared with the literature on ambulatory treatment of Hamilton scales, and in the Symptom Check hSt (SCLSOR) alcoh~lism,~ attrition in the present study is average, and Table 5. Premature Discontinuations and Exclusions during Followup in Borg's study much below average. Additional aspects Placebo Bromocnptine of Borg's paper are noteworthy: during months 4 to 6 of Enrolled 21 (loo%p 1 8 (1 00%) the study, the dosage was increased for from 2.5 to 5 mg Dimtinuations 3 times a day, without apparent improvement. Based on Lack of e f f i c y t 5 (24%) 4 (22%) LOSS of follow-up 6 (28Yo) 1 (6%) this, he concludes that a daily dose of 7.5 mg is adequate. Completed 10 (48%) 13 (72%) The improvement in the bromocriptine compared to the Exclusions placebo patients kept increasing during months 4 to 6 on Missing data 1 (5%) 2(11%) Evaluabk?cases 9 (43%) 1 1 (61%) most dependent variables. This observation should en* The total includes one subject excluded from the effcacy analysis of the active courage an extended treatment period (e.g., 6 months) in treatment phase because of missing data t Lack of efficacy return to dnnking reported as the reason for discontinuing future studies. In addition to the nonpharmacological improvement the study that was observed in the efficacy parameters, the present withdrawal symptoms are of course mixed with bromo- study shows that subjects on the active treatment further criptine side effects. Alcohol-bromocriptine interactions improved as compared with those on placebo. From a are anecdotally reported in the literature but were not strict statistical standpoint, this difference appears to be found significant during the present trial: no correlation restricted to the psychopathological symptomatology of was observed between quantity of alcohol consumption the subjects, as assessed by the SCL-90-R evaluation and and presence or intensity of adverse effects. to the individual decreases in the GGT activity. Taking into account the above discussion on the results and the low statistical power of the present study, the DISCUSSION present findings seem on the whole, at least from a qualiOffering chronic alcoholics a pharmacological adjuvant tative standpoint, in line with that of Borg7 which, to our to help them reduce or stop their alcohol intake has a knowledge, is the only published report on the subchronic spectacular effect, even when the adjuvant is a placebo. effect of bromocriptine in an alcoholic population. That The reduction or interruption of alcohol consumption is study indeed showed differences in favor of the active accompanied by a marked improvement in problems re- treatment with regards to alcohol consumption, craving, lated to the abuse of alcohol, as measured by psychopath- the subjects' psychic status, depressive reactions, and the
IMPROVEMENT (9%)
0
20
40
60
80
I00
916
DONGIER ET AL. Table 6. Efficacy Assessments-Follow-up’
Individual Changest Parameter Consumption (no. drinks/day) Number of drinking days per week Craving (saxe) Hamilton Depression
sca!.e (score) Hamilton hxiety Scale (score) SCL-90-R evaluation (scores) Global Severity In&x Positive symptom total saxe Positive Symptom Distress Index Somatization Obsessive/compulsive Interpersonal sensitivity DepreSSion
Anxiety Anger/hostility Phobic anxiety Paranoidideation Psychotism
Week 16
I
N
D
0.63 f 0.56 1.OO f 0.40 0.8 f 0.6 1.3 f 0.5 1.22 f 0.40 1.OO f 0.33 7.00 f 3.70 5.29 f 1.15 3.60 f 2.16 2.71 f 1.13
1.04 f 0.51 1.72 f 0.27 0.9 f 0.4 1.7 f 0.8 0.77 f 0.32 1.27 f 0.49 5.40 f 2.66 5.14 f 1.64 2.80 f 1.46 3.86 f 1.03
3 3 2 2 4 1 3 3 3 1
3 4 4 5 4 8 0 2 1 1
3 4 3 4 1 2 2 2 1 5
5 7 5
0.38 f 0.19 0.26 f 0.12 23.2 f 9.0
0.30 f 0.15 0.30 f 0.15 19.2 f 9.7
4 2 5
0 0 0
1 5 0
Bromocriptine Placebo
7 5
20.9 f 9.5 1.27 f 0.17
23.7 f 11.6 1.24i0.10
2 1
0 2
5 2
Bromocriptine Placebo Bromocriptine Placebo Brmocriptine Placebo Bromocriptine Placebo Brmocriptine Placebo Bromoaiptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo BromoaiDti
7 5 7 5 7 5 7 5 7 5 7 5 7 5 7 5 7 5 7
0.92 f 0.16 0.41 f 0.15 0.21 f 0.14 0.38 f 0.17 0.36 f 0.18 0.27 f 0.19 0.29 f 0.17 0.68 f 0.33 0.34 f 0.14 0.32 f 0.23 0.27 f 0.16 0.23 f 0.12 0.14 f 0.08 0.23 f 0.22 0.02 f 0.02 0.07 f 0.04 0.24 f 0.15 0.26 f 0.13 0.23 f 0.09
1.06 f 0.36 0.35 f 0.20 0.18 f 0.12 0.28 f 0.15 0.40 f 0.20 0.29 f 0.18 0.30 f 0.18 0.37 f 0.19 0.47 f 0.20 0.40 f 0.26 0.27 f 0.18 0.43 f 0.26 0.26 f 0.14 0.26 f 0.16 0.06 f 0.04 0.03 f 0.03 0.38 f 0.17 0.10 f 0.06 0.26 f 0.13
2 2 3 3 2 2 2 3 1
2 1 2 2 3 2 3 2 2 2
3 2 2
Group
N
Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine
9 11 9 11 9 11 5 7 5 7
Placebo Bromocriptine Placebo
Week 8
1
1 3 3 5
2 1 2 0 4 2 1 2 3 1 2
4
0
5 2 4
2 0 2
2 2 1 1 0 1
4
0 3 1
0
* Data expressed as number of subjects or mean f SEM.
I, Improvement; N. no change; D, deterioration.
overall assessment of the use of alcohol as per the “Total Drug Taking Evaluation Scale.” In our study, only a few subjects remained as evaluable cases at the end of the follow-up phase, hence precluding a formal statistical comparison between the two groups. A clear difference was observed between the two treatment groups with regard to the tolerability assessments, in which the incidence of side effects usually encountered when initiating treatment with bromocriptine was found higher in the active treatment group. The side effects, however, tended to decrease in incidence with time, as normally observed with bromocriptine and ultimately led to a similar proportion of premature discontinuations in both groups. No clear differences emerged between the two treatment groups with respect to the safety assessments, apart from a larger decrease in the systolic blood pressure in the bromocriptine group. Although this effect could have been related to the well-known potential hypotensive action shared by ergot derivatives, it is not known to what extent changes in alcohol consumption may have also accounted for this effect.
Various studies have attributed beneficial effects to bromocriptine in the treatment of depression (for a review, see Sitland-Marken et al.33).The possibility that such an action may have accounted, at least in part, for the pharmacological effects observed in the present study cannot be ruled out. However, taking into account, on the one hand, the fact that subjects with a diagnosis of primary depression were excluded, and, on the other, the fact that trends in favor of bromocriptine were observed in variables other than the depressive symptoms, it seems unlikely that this property of bromocriptine is the sole and primary mechanism involved. Additional studies will nevertheless be necessary in order to further investigate this possibility. In conclusion, the present study shows that bromocriptine may exert beneficial actions in alcoholic subjects, as an adjunct to an ambulatory rehabilitation program, in addition to well-expected nonpharmacological study effects. However, further studies with greater patient numbers and an extended treatment period will be required in order to confirm these findings and to determine whether the pharmacological actions of bromocriptine would last
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
911
15. Feldmann HS: Apomorphine in the treatment of alcohol addicover long-term treatment, and therefore be clinically sigtion: Neurophysiological and therapeutic aspects. Psychiatr J Univ Ott nificant. 30-37, 1983
ACKNOWLEDGMENTS The excellent assistance of Denise Eliveau, R.N., for patients' evaluation and monitoring, of Jennifer Murphy, B.Sc., Sheila Kealey, B.Sc., and Lucie Legault, B.Sc.for data management, of Yves blonde, M.Sc. and Louise Fortier, M.Sc. for statistical analysis, and of Francine Bourcier for secretarial services is gratefully acknowledged.
REFERENCES 1. Liskow BI, Goodwin DW: Pharmacological treatment of alcohol intoxication, withdrawal and dependence: A critical review. J Stud Alcohol 48:356-370, 1987 2. Sinclair JD: The feasibility of effective psychopharmacological treatments for alcoholism. Br J Addict 82:1213-1223, 1987 3. Meyer RE: Prospects for a rational pharmacotherapy of alcoholism. J Clin Psychiatry 50:403-4 12, 1989 4. Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, Sykora K: The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 41:266-274, 1987 5. Lhuintre JP, Daoust M, Moore ND, Chktien P, Saligaut C, Tran G, Boismare E, Hillemand B: Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet 1:10 141016, 1985 6. Borg V, Weinholdt T: Bromocriptine in the treatment of the alcohol withdrawal syndrome. Acta Psychiatr S a n d 65:101-111, 1982 7. Borg V: Bromocriptine in the prevention of alcohol abuse. Acta Psychiatr S a n d 68:lOO-110, 1983 8. Dongier M, Vachon L, Schwartz G: Bromocriptine as an adjunct to the treatment of alcohol dependence. Alcohol Clin Exp Res 14:283, 1990 (abstr) 9. Rees DW: Changing patients' health beliefs to improve compliance with alcoholism treatment: A controlled trial. J Stud Alcohol 47:436-439, 1986 10. Hunt WA, Majchrowicz E: Studies of neurotransmitters interactions after acute and chronic ethanol administration. Pharmacol Biochem Behav 18:371-374, 1983 1 1. Hoffman PL, Tabakoff B: Ethanol's action on brain biochemistry, in Tarter RT, Van Thiel DH (eds): Alcohol and the Brain. Chronic Effects. New York, Plenum Medical Book Co. 1985, pp 19-68 12. Carlsson A, Adolfsson R, Aquilonius SM, Gottfries CG, Oreland L, Svennerholm L, Winblad B: Biogenic amines in human brain in normal aging, senile dementia and chronic alcoholism. New York, presented at the International Symposium on Ergot Alkaloids in Neurologic, Neuropsychiatric and Endocrine Disorders, I979 13. Dent JY: Apomorphine treatment of addiction. Some recent developments. Br J Addict 46: 1- 15, 1949 14. Feldmann HS: Le traitement de I'alcoolisme chronique par I'apomorphine. Etude de 500 cas.Sem Hopde Paris 29:1481-1491,1953
16. Fuxe K,bgren SO, Agnati LF, Andersson K,Hall H, Kohler C, Fredholm B: Central monoamine synapses as sites of action for ergot drugs, in Goldstein M, Calne DB, Lieberman A, Thorner MO (eds): Ergot Compounds and Brain Function (Neuroendocrine and Neuropsychiatric Aspects (Series Advances in Biochemical Psychopharmacology). New York, Raven Press, 1980, pp 41-62 17. Morgan MY, Jakobovits AW, James IM, Sherlock S: Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology 78:663-670, 1980 18. Morgan M Y Bromocriptine in the treatment of chronic encephalopathy and its effects on the handling of alcohol by control subjects and alcoholics. Res Clin Forums 3:39-47, 1981 19. Anokhina IP: Dopamine receptor agonists in the treatment of alcoholism, in Edwards G, Littleton J (eds):Pharmacological Treatments for Alcoholism. New York, Methuen, 1984 20. Skinner HA, Allen BA: Alcohol dependence syndrome: Measurement and validation. J Abnorm Psychol 9 1 :199-209, 1982 2 1. Selzer ML: The Michigan Alcoholism Screening Test: The quest for a new diagnostic instrument. Am J Psychiatry 127:1653-1658, 1971 22. Skinner HA: A multivariate evaluation of the MAST. J Stud Alcohol 40~831-844, 1979 23. Skinner HA: Benefits of sequential assessment. Social Work Research and Abstracts 17:21-28, 1981 24. Skinner HA: Primary syndromes of alcohol abuse: Their measurement and correlates. Br J Addict 76:63-76, 1981 25. National Council on Alcoholism Criteria Committee: Criteria for the diagnosis of alcoholism. Am J Psychiatry 129:127-135, 1972 26. Thompson WD, Orvaschel H, Prusoff BA, Kidd KK: An evaluation of the family history method for ascertaining psychiatric disorders. Arch Gen Psychiatry 39:53-58, 1982 27. Shelton J, Hollister LE, Gocka E T The Drinking Behavior Interview (an attempt to quantify alcoholic impairment). Dis Nerv Syst 30:464-467, 1969 28. Edwards G , Orford J, Egert S, Guthrie S, Hawker A, Hensman C, Mitcheson M, Oppenheimer E, Taylor C: Alcoholism: A controlled trial of"treatment" and "advice." J Stud Alcohol 38:1004-1031, 1977 29. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Psychol 6:278-296, I967 30. Hamilton M: Diagnosis and rating of anxiety, in Lader MH (ed): Studies of Anxiety. Journal of Psychiatry Special Publication 3, 1969, pp 76-79 31. Derogatis LR, Lipman RS, Covi L: SCL-90 An outpatient psychiatric rating scale-Preliminary report. Psychopharmacol Bull 9: 1328, 1973 32. Derogatis LR, Rickels K, Rock A: The SCL-90 and the MMPI: A step in the validation of a new self-report scale. Br J Psychiatry 128:280-289, 1976 33. Sitland-Marken PA, Wells BG, Froemming JH, Chu C-C, Brown CS: Psychiatric applications of bromocriptine therapy. J Clin Psychiatry 5 1 :68-82, 1990
0145-6008/91/1506-0970$3.00/0 ALCOHOLISM: CLINICAL A N D EXPERIMENTAL RESEARCH
Bromocriptine in the Treatment of Alcohol Dependence Maurice Dongier, Luc Vachon, and George Schwartz
A double-blind controlled study of the effects of bromocriptine on drinking behavior and associated symptoms in ambulatory alcoholics showed a marked improvement in both treatment and control groups. However, significant differences in favor of the medication were observed in psychopathologicalmeasures, and trends in the same direction in most of the other efficacy parameters. Key Words: Alcoholism, Treatment, Bromocriptine, Psychopharmacology.
S THE LONG-TERM effects of alcohol on the brain A are better understood, in particular on neurotransmission, it is logical to turn to pharmacological agents to attempt to correct the abnormalities induced by alcohol, and thereby to provide biological adjuvants to the psychological and social approaches. The aims are to reduce the craving for alcohol, and to improve psychopathological symptoms such as depression, anxiety, and other disorders related to the neurochemical abnormalities correlative of alcohol dependence. The development of such psychopharmacological approaches has been recently the object of several comprehensive reviews.’-3 They include for instance inhibitors of serotonin r e - ~ p t a k egamma-ami,~ nobutyric acid (GABA) agoni~ts,~ and dopamine (DA) agonists.6-8However, all of these attempts are for the time being at the experimental stage, and there is little place for pharmacotherapy in the rehabilitation of alcoholic patients, either as an adjunct or as a primary modality. There is no evidence that the long-term course of alcohol dependence is influenced by any pharmacotherapy, and meager evidence that various psychological and social approaches are much more successful. Noteworthy is the fact that between 28% and 80% of alcoholics drop out of treatment within the first month, and attempts to reduce the drop out rate have been largely unsuccessfu1.9 Among its many effects on neurotransmitters, alcohol shows a diphasic action on the dopaminergic system: a small acute dose of ethanol enhances the activity of the system, whereas chronic administration decreases it and desensitizesdopaminergic receptors.” (For a review of the animal evidence which provided a rationale for human trials, see Hoffman and Tabakoff ’I). Studies in man have given some support to connections between alcohol deFrom Douglas Hospital Research Centre, Alcohol Research Program, and McGill University Montreal, Canada. Received for publicarion February 12, 1991; acceppled July 17, 1991 This research was supported by the Douglas Hospital Research Centre and Sandoz Canada. Reprint requests: Maurice Dongier, M.D., Douglas Hospital Research Centre, 6875 LaSaNe Boulevard, Verdun. Quebec H4H 1R3, Canada. Copyright 0 1991 by The Research Society on Alcoholism. 970
pendence and central nervous system dopamine function. Low levels of DA have been reported in the caudate nucleus and hypothalamus. ’* Bromocriptine, (2-bromo-alpha-ergocryptine mesylate) is a synthetic ergot alkaloid which has the property of activating postsynaptic dopaminergic receptors, hence its use in Parkinson’s disease. Bromocriptine is not the only dopamine agonist to have been proposed in the treatment of alcoholism: apomorphine has been used for more than 50 years13essentially as an emetic agent in order to create a conditioned reflex of aversion for alcohol. It has been used in uncontrolled studies in several thousands of alcoholics and some consider that independently of conditioning, its central action in the brain reduces dependence and contributes to decrease anxiety.l4$I5 Bromocriptine, in addition to its effects on dopamine receptors, increases the hypothalamic turnover of noradrenaline, possibly through an antagonistic action at the noradrenergic receptors, and may contribute to alleviate symptoms of the decreased noradrenergic activity in alcoholics. l 6 Borg’s group first used bromocriptine to alleviate withdrawal symptoms,6 and then camed out a double-blind study in 50 chronic alcoholic^.^ Significant improvement was observed in alcohol consumption, in various associated psychiatric symptoms, and in different criteria of social adaptation. The duration of treatment was 6 months and no follow-up at the end of the treatment was mentioned. Morgan et al.,” Morgan,’* and Anokhinalg also published favorable but uncontrolled data. The present study was undertaken in an attempt to confirm and further extend the findings of Bog7 on the effects of bromocriptine on alcohol consumption and alcohol-related problems. METHOD This was a prospective, double-blind study comparing bromocriptine and a placebo in two parallel groups of alcoholic subjects. The study comprised a treatment phase, which included a 9 d a y titration and a 7week maintenance period, with biweekly evaluations, and a follow-up phase, with monthly evaluations without treatment. Subjects were randomized to receive either bromocriptine or placebo during the treatment phase. In an attempt to balance the two group populations with respect to the seventy of their condition and some factors possibly influencing outcome, they were randomly assigned by a blinded member of the staff not involved in any of the assessments, stratified according to gender, severity of alcoholism, and family history of alcoholism. All subjects signed an informed consent form. The daily dosage of medication was increased over a 9day titration phase, if tolerated, from I .25 mg every day to 2.5 mg 3 times a day and maintained for the remainder of the treatment phase. Placebo was dosed Alcohol Clin Exp Res. Vol 15, No 6 , 1991: pp 970-977
97 1
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
in the same manner, and given in an identical appearing form. During the maintenance period (weeks 2 to 8), the mean daily dose among active treatment completers was 6.7 and 6.9 0.2 mg (mean + SEM) for the placebo and the bromocriptine group, respectively. The individual dosage varied between 2.5 and 7.5 mg in subjects receiving the placebo, and between 4.6 and 7 mg in those treated with bromocriptine. No significant difference between the two groups was observed in the final number of capsules per day. At the end of week 8, the treatment was discontinued abruptly. The subjects then remained without medication for the duration of the follow-up phase. Subjects of both sexes with age limits of I8 and 65 years were recruited either through advertisement in local newspapers and radio stations, or referrals to the clinic. The subjects had to be of at least a normal intellectual level judged by clinical assessment and on sociodemographic data and meet the DSM111 criteria for alcohol abuse or dependence based on clinical assessment. Not included were subjects who, at entry, reported abstinence for more than 15 days, or who presented intermittent alcoholism, defined as more than two interruptions of alcohol abuse over the previous 3 years, each interruption being of more than a 2-month duration. Intermittent alcoholics were excluded because of the short time frame of the clinical trial, to reduce the chance of‘kpontaneous” fluctuations in drinking behavior. Also excluded were subjects reporting concurrent drug addiction or presenting secondary alcoholism, i.e., pre-existing psychopathology such as schizophrenia, major affective disorders, antisocial or borderline personality disorders, major organic syndromes (e.g., Korsakoff ’s syndrome), liver failure, or severe physical consequences of alcohol abuse. DSM-111 criteria were used during the clinical assessment to rule out both substance abuse and mental disorders. The use of sedative, anxiolytic, antidepressant o r neuroleptic drugs had to be discontinued for at least 2 weeks prior to the beginning of the study and was not allowed during the study. Concomitant use of other medications was checked at every visit. Compliance check was performed by pill-count at each visit. In addition, a daily record of the medication taken was completed by the subjects. Noncompliance was arbitrarily defined as the omission of study medication for either 4 or more consecutive days, or for a total of 7 days or more during the 8-week treatment period. The initial assessment included: ( I ) a physical examination, (2) a routine laboratory evaluation, (3) the DSM-111 criteria for alcohol abuse or dependence, (4) the severity of alcoholism, measured by the scores on Alcohol Dependence Scale (ADS),20and Michigan Alcoholism Screening Test (MAST)2’(initially described as a screening instrument, the MAST has been later used as a reliable measure of the degree of problem ( 5 ) the evaluation of alcoholism according to the criteria of se~erity),~~‘~‘ the National Council on Alcoholi~m,~’ (6) the subjects’ family history of alcoholism (pedigree using Research Diagnostic Criteria),26(7) the history of alcohol consumption (years of drinking), (8) the present alcohol consumption: number of standard drinks per day over the past week (standard drink: 12 ounces (341 ml) of beer 5%, 5 ounces (142 ml) of wine, 3.5 ounces (99 ml) of fortified wine, 1.5 ounces (43 ml) of spirits, adjusted for the subject’s weight); number of drinking days per month, (9) the Drinking Behavior Interview (DBI),27and (10) Edwards’ Troubles Scale (ETS)28and Hardship Sale (EHS).28The DBI consists of 3 I scorable items in a structured interview questionnaire (e.g., effects on family and social life: number of quarrels, drink-provoked, during the past 2 months. . . ). The ETS and the EHS are alcohol-related symptoms checklists, the first one by self-evaluation, the second one by next-of-kin evaluation, each providing a score from 0 to 10. Evaluations to assess efficacy were conducted at baseline (week 0), at 2-week intervals during the treatment phase (weeks 2, 4, 6, 8), and at Imonth intervals during the follow-up phase (weeks 12, 16). The efficacy assessments included the following: alcohol consumption (expressed as number of standard drinks per day related to body weight), number of drinking days per week, craving (five-point scale), gamma-glutamyltransferase (GGT) activity (assessed only at weeks 0 and 8), Hamilton Rating
+
Scale for D e p r e ~ s i o nHamilton ,~~ Anxiety Scale,3oand Hopkins Symptom Checklist (SCL-90-R).3’.32 Vital signs and routine laboratory evaluations were carried out at weeks 0 and 8. Possible side effects were monitored at each visit during the treatment phase. A comparison of background information data between the placebo and the treatment groups was carried out for the following three subject populations: ( 1 ) all subjects enrolled in the study (hereafter referred to as the total subject population), (2) subjects who were evaluable for the assessments of efficacy at the end of the treatment phase (week 8) (hereafter referred to as treatment completers), and (3) subjects who were evaluable for the assessment of efficacy at the end of the follow-up phase (week 16) (hereafter referred to as follow-up completers). The statistical analysis of the efficacy data of both the treatment (weeks 0, 2, 4, 6, 8) and follow-up (weeks 8, 12, 16) phases was carried out using a two-way analysis of covariance for repeated measurements, covarying for week 0 value in order to take into account differences between the two groups at baseline. For all efficacy parameters, an estimation of the values was performed if data from a given subject was missing for either week 2,4, or 6 during the treatment phase. Due to statistical constraints, subjects for whom data were missing for more than one visit during the treatment phase, or for week 12 during the follow-up phase, were excluded from the efficacy analysis.
RESULTS
Subjects Population A total of 84 subjects were enrolled in the study, of whom 38 (placebo: N=20, bromocriptine: N= 18) were evaluated in the analysis of efficacy following the treatment phase, and 20 (placebo: N=9, bromocriptine: N= 1 1) were included in the efficacy analysis of the follow-up phase. Seventy-eight subjects were recruited through advertisement, six through referrals to the research clinic. None of the subjects received any alcohol abuse treatment or psychiatric treatment in addition to their visits for study purposes. In Table 1, severe/very severe alcoholism is defined by a score above 30 on the Alcohol Dependence Scale. The two treatment groups were comparable at entry, with respect to their demographic data, except for age and the score of the Edwards’ Hardship scale, which were significantly lower ( p < 0.05) in the bromocriptine group. Trends for similar differences were also observed in the treatment completers. All subjects showed evidence of severe alcoholism in terms of consumption, number of drinking days, years of abuse, and all scales of drinking behaviour. No statistically significant differences between the two treatment groups were found at baseline with regard to the parameters related to alcoholism. However, a trend for a higher number of drinking days per month was observed in the bromocriptine group, as compared with the placebo group, in the total subject population, as well as in both the treatment and follow-up completers. Additional drugs used by “completers” in the treatment group were: diazepam 5 mg, one tablet on day 35 and one on day 37 in one patient; penicillin for 10 days for bronchitis in another one; vitamins ( B I , Biz, c, E) in four subjects; dicyclomine (antispasmodic) in one subject; ox-
DONGIER ET AL.
912
Table 1. Subjects Characteristics at Baselinet Active treatment completers
Total population
Sex Female Male Age (years’) [min.-med.-max.] Severity of alcoholism Mild/moderate Severelvery severe NCA criteria Steady Questionable Family history NOfM Moderate Severe Years of drinking [min.-med-max.] Alcohol consumption (units per day) (min.-med.-max.] Drinking days/month [min.med.-max] MAST (score) [min.-med-max.] ADS (score) [min.-med.-max] DBI (score) [min.-med.-max.] ETS (score) [min.med.-max.] EHS (score) [min.med.-max.]
Placebo ( N = 41)
Bromocriptine (N = 43)
Placebo (N = 20)
Bromocriptine (N = 18)
8 (20%) 33 (80%) 43.6 f 1.8 [21-45-541
10 (23%) 33 (77%) 38.8 f 1.2 (2537-581
NSS
4 (20%) 16 (SOYO) 45.3 f 2.4 [23-48-651
5 (28%) 13 (72%) 40.0 f 1.8 I294 1-54]
0 (0%) 41 (100%)
2 (5%) 41 (95%)
NS
0 (0%) 20 (100%)
1 (6%) 17 (94%)
40 (98%) 1 (2%)
43 (100%) 0 (0%)
NS
20 (100%) 0 (0%)
18 (100%) 0 (0%)
13 (32%) 9 (22%) 19 (46%) 9.4 f 1.o [ 1-8-25] 14.1 f 1.4 [0-14-4 1]
13 (30%) 9 (21Yo) 21 (49%) 10.9 f 8.85 [2-10-251 15.4 f 1.4 (4-12-361
6 (30%) 5 (25%) 9 (45%) 10.4 f 1.4 [3-70-251 13.9 f 1.9 [4-14-47]
7 (39%) 2(11%) 9 (50%) 10.8 f 1.1 [2-70-201 1 1 . 7 f 1.4 (5-11-29]
24.4 f 1.2 [5-26-31] 28.5 f 1.7 (9-37 -491 17.3 f 1.0 [6-77-30] 52.1 f 3.4 [8-55-59] 4.1 f 0.3 [ 14-91 5.1 f 0.4 [0-5-91
26.8 f 1.2 [6-37-31] 27.9 f 1.4 [5-26-51] 18.3 f 0.9 [8-7 7-29] 57.1 f 2.9 [26-56-94] 4.6 f 0.3 11-4-91 3.8 f 0.5 [ 14-91
25.5 f 1.7 [8-31-31] 27.8 f 2.3 [ 12-27-49] 17.7 f 1.1 [8-17-27] 49.4 f 4.3 [8-52-77] 3.8 f 0.3 [24-61 4.7 f 0.5 [ 1-54]
30.0 f 0.6 [203 1-31] 25.5 f 2.2 [ 5-25-42] 17.3 f 1.4 [&17-271 51.9 f 4.6 [27-42-901 4.4 f 0.4 [1-5-71 3.8 f 0.7 [ 1-5-91
NS NS NS
NS ( p = 0.069) NS NS NS NS
Follow-up completers Placebo (N = 9)
Bromocriptine (N = 11)
4 (44%) 5 (56Or’o) 44.7 f 4.5 [23-50-571
3 (27%) 8 (73%) 42.3 f 2.1 [3042-54]
NS
NS
0 (0%) 9 (100%)
0 (0%) 11 (100%)
NS
NS
9 (100%) 0 (0%)
11 (100%) 0 (070)
2 (22%) 3 (33%) 4 (44%) 11.3 f 2.7 (3-8-251 12.5 f 2.0 [4-14-23]
4 (36%) 1 (9%) 6 (54%) 11.2f 1.8 [2-10-201 11.5 2.0 15-1 1-29]
25.7 f 2.6 [12-31-31] 24.6 f 3.5 [ 12-20421 17.8 2.8 [ 10-76-261 44.1 f 8.7 [8-52-71] 3.7 f 0.5 [2-3-61 5.1 f 0.9 [143-81
29.4 f 1.1 [20-31-31] 28.4 f 2.2 [la-26-42] 17.8 i 1.a (8-19-27] 52.4 5.0 [35-43-88] 4.4 f 0.4 [2-4-61 4.4 f 0.4 [1-5-91
NS NS ( p = 0.067)
NS NS NS
NS ( p = 0.070) NS NS NS NS NS
*
*
NS
NS NS NS
NS NS NS NS NS NS
t Data expressed as number of subjects or mean f SEM. $ NS, not significant. = 42 (missing data in one subject). ‘ p 4 0.05.
5N
Table 2. Premature Discontinuations and Exclusions during Active Treatment azepam 10 mg at bedtime for 4 days in another one; Placebo BromocriDtine diphenhydramine (antihistaminic) 25 mg twice daily for Enrolled 41 (100%) 43 (100%) 5 days in one patient; oral antidiabetic (sulfonylureas) in Discontinuations one. Side effects 3 (7%) 5 (12%) In the psychopathological parameters, there were no Lack of efficacy 1 (2%) 1 (2%) Loss of follow-up 10 (24%) 9 (21%) statistically significant differences between the two treat27 (66’/0) 28 (65%) Completed ment groups at baseline, besides a trend close to signifiExclusions cance (p = 0.051) for a higher score on the “Anxiety” 9 (12%) Noncompliance 5 (12%) Missing data 1 (2%) 2 (5%) dimension of the SCL-90-R evaluation in the bromocrip€valuable cases 20 (49%) 18 (42%) tine group. However, since for several parameters the seventy at baseline appeared higher in the active treatment than in the placebo group, the statistical comparisons Table 3 shows the individual treatment duration, as well between the two groups were carried out taking into as the nature and severity of events encountered in subjects account the individual baseline values and changes ob- who prematurely discontinued the treatment due to side served during the treatment period, as already mentioned. effects. Among these subjects, side effects rated as severe were observed in one case in each treatment group. Treatment Phase Table 4 shows the results of the efficacy assessments at Table 2 shows the reasons for premature discontinua- the beginning and the end of the treatment phase, as well tions of the treatment as well as the reasons for exclusion as the number of subjects who improved, did not change of subjects from the analysis of efficacy during the treat- or deteriorated with regards to these assessments during this period. men t phase. A statistically significant improvement (p < 0.001) was The rate at which subjects prematurely discontinued the treatment or were excluded for noncompliance during observed in all efficacy parameters in both groups during the treatment phase was similar in both treatment groups. the treatment phase. This finding was also reflected on an
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
91 3
Table 3. Premature Discontinuations Due to Side Effects Placebo Number of subjects
Treatment duration (weeks)
1
4
1
3
1
1
Bromocriptine
Side effects Headaches’ Drowsiness’ Headachest Dizzinesst Headachest Dizziness$ Nausee Pyrosist
Number of subjects
Treatment duration (weeks)
Side effects
2
1,7
Dyspepsia‘
1
4
Nausea’
1
6
Dizziness’
1
1
Nausea$ Vergitot
* Mild.
t Moderate. $ Severe.
individual basis, as more than 70% of the subjects in both groups improved with regards to all efficacy parameters (Table 4-individual changes during treatment). No statistically significant differences were found between the two groups with regard to consumption, the number of drinking days per week, craving, the GGT activity, or the Hamilton Depression and Anxiety Scales. The number of subjects who reported complete abstinence during the entire duration of the treatment phase did not significantly differ between the two groups either (p = 0.16, Chi-square), although it appeared higher in subjects on placebo (placebo: N = 10, 50%;bromocriptine: N = 5, 28%).On the other hand, a retrospective analysis of the number of subjects in whom a decrease of at least 50% in the GGT activity was observed at the end of the treatment phase revealed a statistically significant difference in favour of bromocriptine (p < 0.05, Chi-square): such a decrease was indeed observed in two ( 17%)out of 19 cases in the placebo group, as compared with eight (47%)out of 17 in the bromocriptine group. Similar results were obtained when this analysis was restricted only to the subjects who were presenting GGT values above the normal upper limit (55 units/liter) at baseline (placebo: N = 1/6 [17%];bromocriptine: 7/9 [78%], p < 0.02, Chisquare). Statistically significant differences (p < 0.05 or p < 0.02), in favor of bromocriptine, were observed in the following variables of the SCL90-R evaluation: “Global Severity Index,” “Positive Symptom Total Score,” “Positive Symptom Distress Index,” “Interpersonal Sensitivity,” and “Anger/Hostility.” In addition, trends (p < 0.10) in favor of bromocriptine were found for the SCL-90-R dimensions “Somatization,” “Depression,” and “Paranoid Ideation.” No statistically significant treatment by variable interactions was observed using the following variables as covariates in the efficacy analysis: age, sex, severity of alcoholism, family history of alcoholism, or number of drinking days per month. Fig. 1 summarizes the extent of the improvement observed in the efficacy parameters in both treatment groups
during the treatment phase. The most pronounced improvement was found in the consumption of alcohol, which, according to self-report, decreased by approximately 90% in both groups. Other parameters improved by 25%to 70%in the placebo group, and by 43%to 85% in the bromocriptine group. Besides differences for which statistical significance was found in favor of bromocrip tine, an overall trend in the same direction emerged for most variables. Thus, the extent of the improvement observed in the active treatment group was higher than in the placebo group by 14% for the number of drinking days per week, 28%for craving, 78% for the GGT activity, 20% for the Hamilton Depression Scale, 16% for the Hamilton Anxiety Scale, and in the range of 10%-37% for the SCL-90-R evaluation. A retrospective evaluation of the analysis performed on the efficacy parameters revealed that the statistical power varied between 7% and 60%,depending on the variables analyzed.
Follow-up Phase As shown in Table 5, 10 (48%)and 13 (72%)of the subjects who completed the treatment phase in the placebo and the bromocriptine group, respectively, also completed the follow-up phase. Among these, three (placebo: N = 1; bromocriptine: N = 2) had to be excluded from the efficacy analysis because of missing data, resulting in nine and eleven evaluable cases in the placebo and the bromocrip tine groups, respectively. These numbers correspond, respectively, to 22% and 26% of the subjects who were initially enrolled in the study in each group. Due to the small number of evaluable cases remaining in the study at the end of the follow-up phase, the results pertaining to this period are presented in a descriptive fashion only. For the same reason, only the global scores of the SCL-90-R evaluation, namely, the “Global Severity Index,” the “Positive Symptom Total Score,” and the “Positive Symptom Distress Index,” are shown. Table 6 summarizes the mean values observed in the efficacy assessments in both groups at the beginning (week 8) and the end (week 16) of the follow-up phase. In the follow-up completers, the alcohol consumption and number of drinking days per week observed at the beginning of the follow-up phase were higher in the bromocriptine than the placebo group by 59% and 62%, respectively. These results are in contrast with those observed at the time of the study in the treatment completers, in whom this difference, if any, was in the opposite direction. On the other hand, slight differences (10%-32%)in favor of bromocriptine were found at week 8 in the followup completers with regards to the other efficacy parameters. At the end of the follow-up-phase, the severity of the efficacy assessment was higher in the bromocriptine than the placebo group in most of the variables, namely consumption (65%),the number of drinking days per week
DONGIER ET AL.
914 Table 4. Efficacy Assessments-Active Treatmentt
Individual changes during treatment$ Parameter
Group
N
Week 0
week 86
Consumption (no. drinks/day) Number of drinking days per week Craving (we) GGT activity (unitspiter) Hamilton Depression Scale (score) Hamilton Anxiety Scale (swre) SCL-90-R evaluation (scores) Global Severity Index Positive symptom total score
Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine
20 18 20 18 20 18 19 17 20 18 20 18
13.9 f 1.9 11.5f1.6 5.9 f 0.4 6.8 f 0.1 3.45 f 0.17 3.17 f 0.23 69 f 20 103 f 29 20.3 f 1.9 20.6 f 1.9 17.0f 1.6 20.7 f 1.9
1.72 f 0.74 1.26 f 0.43 2.0 f 0.6 1.7 f 0.5 1.55 f 0.30 0.94 f 0.23 45 f 12 41 f 8 9.30 f 1.47 7.22 f 1.51 6.30 f 1.15 5.56 f 1.12
Placebo Bromocriptine Placebo Bromouiptine Placebo Bromocriptine Placebo Bromwiptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromouiptine Placebo Bromocriptine
20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17 20 17
1.05 f 0.08 1.36 f 0.19 49.1 f 4.6 58.4 f 4.9 1.81 f 0.11 1.99 f 0.13 0.85 f 0.14 1.28 f 0.22 1.37 f 0.18 1.54 f 0.20 1.13 f 0.19 1.45 f 0.24 1.28 f 0.1 1 1.68 f 0.24 0.98 f 0.19 1.51 f 0.23 0.89 f 0.14 1.16 f 0.19 0.55 f 0.12 1.16 f 0.20 1.05 f 0.21 1.35 f 0.23 0.80f 0.12 0.92 f 0.19
Positive Symptom Distress Index Somatization Obsessive/compulsive
Interpersonal sensitivity Depression Anxiety Anger/hostiligy Phobic anxiety Paranoid ideation Psychotism
NS NS NS
NS NS NS
NS NS NS NS NS NS NS NS ( p = 0.051) NS NS NS NS
0.40 f 0.08 0.33 f 0.08 26.8 f 4.2 24.2 f 5.7 1.23 f 0.07 1.16 f 0.11 0.28 f 0.06 0.34f 0.09 0.51 f 0.11 0.41 f 0.12 0.46 f 0.12 0.31 f 0.11 0.53 f 0.12 0.40 f 0.09 0.32 f 0.10 0.38 f 0.11 0.32 f 0.07 0.18 f 0.09 0.16 f 0.07 0.14 f 0.08 0.46 f 0.13 0.31 f 0.09 0.31 f 0.08 0.25 f 0.06
NS NS
NS NS NS NS
NS
( p = 0.071) NS
NS ( p = 0.071) NS 0.
NS
I
N
D
20 18 18 17 16 15 17 16 18 18 19 18
0
0
0
0
2 1 4 3 0 0 0 0 1 0
0 0
20 17 18 17 19 16 17 17 20 16 19 17 17 17 16 17 17 17 14 13 15
0 0 0 0 0 0 1 0 0
( p = 0.059) NS
16 16
0 0 2 1 2 0 0
0 0 0 2 0 1 1 2
0
0
0 0 1
0
0
0 0 3 0 3
3 0 1 0 0
0
0
5 4 3 0 3 0
1 0 2 0 1 1
1
t Data expressed as number of subjects or mean f SEM. $ I, Improvement; N, no change; D, deterioration. f, Statistical analysis between groups: covariance analysis for repeated measurements on weeks 0, 2, 4, 6, 8, with adjustment for baseline values. 1 NS. not significant. ‘ p < 0.05; “ p < 0.02.
siness, and nausea with statistically significant higher incidence in the bromocriptine than in the placebo group (p < 0.001). However, the incidence of these side effects decreased throughout the treatment period. Tables 2 and 3 already summarized the various side effects and their relationship to discontinuation. Following the treatment period, a trend for a decrease in systolic blood pressure was observed in the placebo group (p = 0.084), while a statistically significant decrease (p < 0.001) was found in the bromocriptine group. Diastolic blood pressure did not significantly change in either group. Other isolated side effects occumng in one to three instances in the placebo group were confusion, visual problems, tremor, and cramps. In the bromocriptine Side Eflects group, illusions, euphoria, confusion, dificulty in concenThe most frequent side effects experienced in both tration, cramps, tension, hyperactivity, vertigo, visual groups during the treatment phase were dizziness, drow- problems, palpitations, and anorexia occurred. Alcohol
(89%),craving (65%), and the Hamilton Depression score (4196). Table 6 also shows the number of subjects who improved, did not change, or deteriorated during the followup phase, with regard to the efficacy assessments. Although no clear pattern emerged from this comparison, a trend for a higher proportion of subjects deteriorating was observed in the bromocriptine group on the Hamilton Anxiety Scale and the “Global Severity Index” and “Positive Symptom Total Score” variables of the SCL-90-R evaluation. In addition, three subjects (33%) who had received placebo and two (1 8%) who had been treated with bromocriptine reported complete abstinence during the entire eight-week follow-up period ( p = 0.40, Chi-square).
915
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
ological rating scales. This major effect makes it all the more difficult to identify an additional efficacy of any pharmacological treatment of alcoholism, especially in the early period of intervention. A marked improvement in all efficacy parameters was observed in both groups at the end of the treatment phase. Although such a nonpharmacological effect is usually expected in this type of population, the extent of the improvement that was observed is indicative of a remarkable effect of the study per se. On the other hand, this reduction in alcohol consumption was paralleled by a substantial decrease of the mean GGT activity, as well as by a marked amelioration in the subjects' psychopathological state known to be associated with alcohol abuse and dependence, such as symptoms of depression and anxiety, thus indicating that a general improvement in the subjects' condition did occur during the treatment period, at least from a qualitative standpoint. More than 50% of the subjects enrolled in both treatment groups prematurely discontinued treatment, and were lost to follow-up or non-compliant. These findings are in contrast with those reported by B ~ r gwho , ~ showed a remarkably small attrition over a 6-month period. This can only be due to an exceptional patients' selection, not reported in the paper and/or an exceptional quality of I 0-pv relationship between investigators and subjects and/or unique (and not reported) follow-up procedures. ComFig. 1. Improvement dunng active treatment in dnnking behavior measures, in pared with the literature on ambulatory treatment of Hamilton scales, and in the Symptom Check hSt (SCLSOR) alcoh~lism,~ attrition in the present study is average, and Table 5. Premature Discontinuations and Exclusions during Followup in Borg's study much below average. Additional aspects Placebo Bromocnptine of Borg's paper are noteworthy: during months 4 to 6 of Enrolled 21 (loo%p 1 8 (1 00%) the study, the dosage was increased for from 2.5 to 5 mg Dimtinuations 3 times a day, without apparent improvement. Based on Lack of e f f i c y t 5 (24%) 4 (22%) LOSS of follow-up 6 (28Yo) 1 (6%) this, he concludes that a daily dose of 7.5 mg is adequate. Completed 10 (48%) 13 (72%) The improvement in the bromocriptine compared to the Exclusions placebo patients kept increasing during months 4 to 6 on Missing data 1 (5%) 2(11%) Evaluabk?cases 9 (43%) 1 1 (61%) most dependent variables. This observation should en* The total includes one subject excluded from the effcacy analysis of the active courage an extended treatment period (e.g., 6 months) in treatment phase because of missing data t Lack of efficacy return to dnnking reported as the reason for discontinuing future studies. In addition to the nonpharmacological improvement the study that was observed in the efficacy parameters, the present withdrawal symptoms are of course mixed with bromo- study shows that subjects on the active treatment further criptine side effects. Alcohol-bromocriptine interactions improved as compared with those on placebo. From a are anecdotally reported in the literature but were not strict statistical standpoint, this difference appears to be found significant during the present trial: no correlation restricted to the psychopathological symptomatology of was observed between quantity of alcohol consumption the subjects, as assessed by the SCL-90-R evaluation and and presence or intensity of adverse effects. to the individual decreases in the GGT activity. Taking into account the above discussion on the results and the low statistical power of the present study, the DISCUSSION present findings seem on the whole, at least from a qualiOffering chronic alcoholics a pharmacological adjuvant tative standpoint, in line with that of Borg7 which, to our to help them reduce or stop their alcohol intake has a knowledge, is the only published report on the subchronic spectacular effect, even when the adjuvant is a placebo. effect of bromocriptine in an alcoholic population. That The reduction or interruption of alcohol consumption is study indeed showed differences in favor of the active accompanied by a marked improvement in problems re- treatment with regards to alcohol consumption, craving, lated to the abuse of alcohol, as measured by psychopath- the subjects' psychic status, depressive reactions, and the
IMPROVEMENT (9%)
0
20
40
60
80
I00
916
DONGIER ET AL. Table 6. Efficacy Assessments-Follow-up’
Individual Changest Parameter Consumption (no. drinks/day) Number of drinking days per week Craving (saxe) Hamilton Depression
sca!.e (score) Hamilton hxiety Scale (score) SCL-90-R evaluation (scores) Global Severity In&x Positive symptom total saxe Positive Symptom Distress Index Somatization Obsessive/compulsive Interpersonal sensitivity DepreSSion
Anxiety Anger/hostility Phobic anxiety Paranoidideation Psychotism
Week 16
I
N
D
0.63 f 0.56 1.OO f 0.40 0.8 f 0.6 1.3 f 0.5 1.22 f 0.40 1.OO f 0.33 7.00 f 3.70 5.29 f 1.15 3.60 f 2.16 2.71 f 1.13
1.04 f 0.51 1.72 f 0.27 0.9 f 0.4 1.7 f 0.8 0.77 f 0.32 1.27 f 0.49 5.40 f 2.66 5.14 f 1.64 2.80 f 1.46 3.86 f 1.03
3 3 2 2 4 1 3 3 3 1
3 4 4 5 4 8 0 2 1 1
3 4 3 4 1 2 2 2 1 5
5 7 5
0.38 f 0.19 0.26 f 0.12 23.2 f 9.0
0.30 f 0.15 0.30 f 0.15 19.2 f 9.7
4 2 5
0 0 0
1 5 0
Bromocriptine Placebo
7 5
20.9 f 9.5 1.27 f 0.17
23.7 f 11.6 1.24i0.10
2 1
0 2
5 2
Bromocriptine Placebo Bromocriptine Placebo Brmocriptine Placebo Bromocriptine Placebo Brmocriptine Placebo Bromoaiptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo BromoaiDti
7 5 7 5 7 5 7 5 7 5 7 5 7 5 7 5 7 5 7
0.92 f 0.16 0.41 f 0.15 0.21 f 0.14 0.38 f 0.17 0.36 f 0.18 0.27 f 0.19 0.29 f 0.17 0.68 f 0.33 0.34 f 0.14 0.32 f 0.23 0.27 f 0.16 0.23 f 0.12 0.14 f 0.08 0.23 f 0.22 0.02 f 0.02 0.07 f 0.04 0.24 f 0.15 0.26 f 0.13 0.23 f 0.09
1.06 f 0.36 0.35 f 0.20 0.18 f 0.12 0.28 f 0.15 0.40 f 0.20 0.29 f 0.18 0.30 f 0.18 0.37 f 0.19 0.47 f 0.20 0.40 f 0.26 0.27 f 0.18 0.43 f 0.26 0.26 f 0.14 0.26 f 0.16 0.06 f 0.04 0.03 f 0.03 0.38 f 0.17 0.10 f 0.06 0.26 f 0.13
2 2 3 3 2 2 2 3 1
2 1 2 2 3 2 3 2 2 2
3 2 2
Group
N
Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine Placebo Bromocriptine
9 11 9 11 9 11 5 7 5 7
Placebo Bromocriptine Placebo
Week 8
1
1 3 3 5
2 1 2 0 4 2 1 2 3 1 2
4
0
5 2 4
2 0 2
2 2 1 1 0 1
4
0 3 1
0
* Data expressed as number of subjects or mean f SEM.
I, Improvement; N. no change; D, deterioration.
overall assessment of the use of alcohol as per the “Total Drug Taking Evaluation Scale.” In our study, only a few subjects remained as evaluable cases at the end of the follow-up phase, hence precluding a formal statistical comparison between the two groups. A clear difference was observed between the two treatment groups with regard to the tolerability assessments, in which the incidence of side effects usually encountered when initiating treatment with bromocriptine was found higher in the active treatment group. The side effects, however, tended to decrease in incidence with time, as normally observed with bromocriptine and ultimately led to a similar proportion of premature discontinuations in both groups. No clear differences emerged between the two treatment groups with respect to the safety assessments, apart from a larger decrease in the systolic blood pressure in the bromocriptine group. Although this effect could have been related to the well-known potential hypotensive action shared by ergot derivatives, it is not known to what extent changes in alcohol consumption may have also accounted for this effect.
Various studies have attributed beneficial effects to bromocriptine in the treatment of depression (for a review, see Sitland-Marken et al.33).The possibility that such an action may have accounted, at least in part, for the pharmacological effects observed in the present study cannot be ruled out. However, taking into account, on the one hand, the fact that subjects with a diagnosis of primary depression were excluded, and, on the other, the fact that trends in favor of bromocriptine were observed in variables other than the depressive symptoms, it seems unlikely that this property of bromocriptine is the sole and primary mechanism involved. Additional studies will nevertheless be necessary in order to further investigate this possibility. In conclusion, the present study shows that bromocriptine may exert beneficial actions in alcoholic subjects, as an adjunct to an ambulatory rehabilitation program, in addition to well-expected nonpharmacological study effects. However, further studies with greater patient numbers and an extended treatment period will be required in order to confirm these findings and to determine whether the pharmacological actions of bromocriptine would last
BROMOCRIPTINE AND ALCOHOL DEPENDENCE
911
15. Feldmann HS: Apomorphine in the treatment of alcohol addicover long-term treatment, and therefore be clinically sigtion: Neurophysiological and therapeutic aspects. Psychiatr J Univ Ott nificant. 30-37, 1983
ACKNOWLEDGMENTS The excellent assistance of Denise Eliveau, R.N., for patients' evaluation and monitoring, of Jennifer Murphy, B.Sc., Sheila Kealey, B.Sc., and Lucie Legault, B.Sc.for data management, of Yves blonde, M.Sc. and Louise Fortier, M.Sc. for statistical analysis, and of Francine Bourcier for secretarial services is gratefully acknowledged.
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