4. Disulfiram, Antabuse - the first medication to stop drinking

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright ©2005 Springer

> Table of Contents > Disulfiram (Antabuse®): the first medication to stop drinking

Disulfiram (Antabuse®): the first medication to stop drinking

Dieter Ladewig1

Ulrich von Bardeleben2

1 Department of Substance Use Disorders, Psychiatric University Hospital, Wilhelm Klein-Strasse 27, CH-4025 Basel, Switzerland

2 Psychiatrische Klinik Meiringen, CH-3860 Meiringen/BE, Switzerland

Introduction

Disulfiram (Antabuse®) is historically one of the first medications found to stop drinking. This compound inhibits acetaldehyde dehydrogenase, so that alcohol consumption leads to an accumulation of acetaldehyde. This in turn results in distressing symptoms, including flushing, syncope, a decrease in blood pressure, and vomiting as well as diarrhea. Disulfiram is available in different dosages with 200 mg/day being a standard dose. A supervised exposition to a minimal amount of the preferred alcohol beverage may help the patient to experience the possible disulfiram-alcohol reaction under a controlled treatment management.

Treatment with disulfiram arouses controversy among the alcohol treatment community. Specialists in some countries neglect this kind of approach, whereas in other countries Antabuse® is an essential part of the treatment of alcoholism. Treatment with disulfiram may be effective, if it is part of an individualized therapy program. This ex-cathedra statement is based on a long clinical experience in Switzerland and the Scandinavian countries. Denmark, for instance, has a long tradition for its use. The often quoted finding that placebo-controlled studies are rarely in favor of this medication [1, 2] is in part in contrast to clinical experiences. Table 1 gives an overview of the methodology in 24 studies of oral disulfiram administration. In recent years, several treatment modifications with disulfiram have been described that may improve outcome variables such as duration of abstinence or the amount of alcohol consumed per day in non-abstinent phases. This implies that treatment does not consist only of a medication. One simple modification of treatment with disulfiram is supervised intake [3]. Supervised disulfiram means controlled delivery of the soluble substance in an adequate setting. This means that some form of psychosocial intervention is part of the treatment. Another approach focuses on the importance of a relationship or an accompanying behavior or marital therapy [4]. Both modifications increase the effectiveness of disulfiram.

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Table 1. Methodology in 24 studies of oral disulfiram

Total number of subjects

2836.0

Mean number of subjects per study (range)

118.0

(16-605)

Number of studies using objective criteria* (%)

20.0

(83)

Number of studies of supervised disulfiram (%)

15.0

(62.5)

Number of single blind studies (%)

4.0

(17)

Number of double blind studies (%)

1.0

(4)

Number of studies with matched controls (%)

13.0

(54)

Number of randomized studies (%)

13.0

(54)

Number of studies with statistical analysis (%)

16.0

(67)

Mean follow-up in months

(a) on treatment in 23 studies (range)

12.9

(2-24)

(b) post-treatment in six studies (range)

13.7

(0.75-48)

Mean percentage lost to follow-up per study (range)

19.6

%

(0-92%)

* but not always explicit nor comprehensive;

† not always extensive.

Although, for some clinicians, disulfiram is still the first medication to stop drinking, the spectrum of pharmacological and psychotherapeutic interventions nowadays available is such that in daily practice and in research, combinations have much more a chance of success than a mono-intervention.

Randomized open efficacy study

In addition to disulfiram (Antabuse®), acamprosate (Campral®) and naltrexone (Revia/Nemexin®) have been approved as pharmacological support for maintaining alcohol abstinence. With disulfiram, the consumption of alcohol produces the typical symptoms of flushing, nausea, tachycardia, hypotension and dyspnea- aversive effects, which may prevent the patient from further drinking. Acamprosate has been found to reduce the neural hyperexcitability of the glutamatergic system, which becomes up-regulated under the chronic action of alcohol [5] (see also Chapter 19). The clinically observed and significantly higher abstinence rate under acamprosate [6, 7] is probably due to an inhibition of conditioned withdrawal phenomena, which may appear as “craving” and function as a trigger for relapse [8]. The opioid receptor antagonist naltrexone was found to reduce the activating influence of alcohol on endogenous opioid systems [8, 9] (see also Chapter by Cowen). The release of endogenous opioids, in particular of β-endorphin, in the mesolimbic reward system plays a key role in substance dependence. Several clinical trials have identified a reduction in alcohol consumption under naltrexone [10, 11 and 12]. Whereas the effect of acamprosate and naltrexone is based on biological findings, the effect of disulfiram is primarily a psychological one. In most studies on the maintenance of alcohol abstinence using the aforementioned medications, pharmacotherapy

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was combined with various types of psychotherapy. To evaluate whether there are any differences in the course of treatment by using acamprosate, naltrexone or disulfiram in combination with a standardized cognitive behavioral group therapy, we started a study with a sample of alcoholics.

The total sample included 100 patients diagnosed with alcohol dependence according to DSM-IV. 71% of the patients who came for detoxification to the University of Basel, Department of Psychiatry, were men and 29% were women. The mean age of the sample was 44.8 (±9.2) years. Patients were recruited after at least 7 days (max. 14 days) of alcohol abstinence following in-patient detoxification. They were randomly assigned to one of the three medication groups (N = 25 each) with acamprosate, naltrexone, disulfiram, or the “non-medication” group. The patients received trial medication in fixed dosages (1800 mg/d acamprosate; 50 mg/d naltrexone; 200 mg/d disulfiram) when entering the study (12 weeks) in combination with a manualized cognitive behavioral group therapy program for relapse prevention in outpatients. This modified version of Monti's [13] group therapy program was conducted by a clinical psychologist and a psychiatrist. The 12 modules of the program were highly structured in their content and form and included the following elements: 1) An introduction to coping strategies in alcohol dependence, 2) coping with alcohol craving, 3) dealing with thoughts about alcohol, 4) general problem-solving strategies, 5) the ability to refuse the offer of alcohol consumption (saying no), 6) dealing with seemingly insignificant decisions, 7) dealing with high risk and relapse situations, 8) supporting one's own needs, 9) dealing with criticism, 10) dealing with depressed mood, 11) dealing with anger, 12) relaxation techniques.

The four groups studied showed no differences in relation to the sociodemographic data determined at the beginning of the study, such as gender, age, education, income, living and family conditions. Neither were there any differences between the groups with regard to family stress, the frequency of earlier withdrawals or patients' drinking behavior in the three months prior to entering the study. The craving for alcohol was measured on a visual analogue scale (VAS) with higher values indicating greater craving. These measurements were taken weekly. Though there was a slight difference at baseline with lower values in the acamprosate group, no significant differences between groups treated with medication were found during and at the end of the treatment. But there was a significant difference in comparison with the no-drug group. Generally, all the drugs were well tolerated with the acamprosate group reporting initial diarrhea more frequently and the naltrexone group reporting sleep disturbances more frequently. These side-effects did not cause any patient to end treatment. Concerning standard laboratory parameters, which were determined at intervals of 4 weeks, no differences between groups were found for gamma-glutamyl transferase and mean erythrocyte volume. 60% of the patients completed the 12-week study. This corresponds to a dropout rate of 40%, which is fairly low for treatment studies in substance dependence. There were no significant differences between groups in this respect (see Tab. 2).

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Table 2. Participation rates in group comparison (N = 100)

No medication

Disulfiram

Acamprosate

Naltrexone

%2 or ANOVA

Regular termination of study (%)

48

52

64

68

ns

Duration of standardized observation (weeks; × ± SD)

9.2 ± 3.8

9.2 ± 3.9

9.3 ± 4.2

9.5 ± 3.3

ns

Group meetings attended (× ± SDSD)

7.5 ± 3.4

7.2 ± 3.6

7.3 ± 3.6

6.4 ± 3.3

ns

ns : not significant;

SD : standard deviation

Even in the patients who had dropped out, it was possible and on a weekly basis to assess the amount of drinking per day. The main reason for dropping out was relapse. All missing data from patients that had dropped out of the study were statistically accounted for as full relapses. In the disulfiram group, patients stopped medication before relapse. Although 52% of the patients reported having consumed alcohol at least once during the 12-week treatment, the proportion of abstinent days was 90% overall (see Tab. 3). The four groups showed no significant differences in regard to the percentage of abstinent days. There was a significant difference between the groups in relation to the time period until the first drink; the patients in the disulfiram group had a longer period of abstinence compared to patients in the acamprosate group (p < 0.05) or patients in the naltrexone group (p < 0.05). With regard to the time period until the first relapse (>40/60 g of alcohol for women/men per drinking day), there were no significant differences between the groups. The same applied for the time period until the first serious relapse (>40/60 g of alcohol for women/men per drinking day on at least 3 successive days) for the three groups on medication, whereas the group with no medication had a significantly shorter period of abstinence. When a drinking event did occur, a comparison between groups revealed the following differences in the quantity of alcohol consumed on a drinking day: the acamprosate group drank significantly lower quantities of alcohol per drinking day compared to the disulfiram group (76 ± 45 g versus 152 ± 69 g: × ± SD; p < 0.05), and the naltrexone group drank even less (57 ± 41 g; p < 0.05). Overall, patients attended, on the average, 61% of all group meetings, which corresponds to a good acceptance of the group therapy program. A semi-structured interview of the participants in this regard revealed that, according to their own estimation, 60% of them had acquired new knowledge with regard to their alcohol problem and had experienced modifications in their behavior. The relatively rigid formal structure of the group therapy was named as the main reason for the acceptance of the program by more than 55% of the participants.

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Table 3. Results of relapse prevention program in group comparison (N = 100)

No medication

Disulfiram

Acamprosate

Naltrexone

No med. vs. D

No med. vs. A

No med. vs. N

D vs. A

D vs. N

Abstinent days (%: × ± SD)

89.4 ± 18.3

90.1 ± 18.9

91.6 ± 17.2

82.3 ± 19.6

ns

ns

ns

ns

ns

Weeks until first consumption of alcohol (median)

5

12

7

8

0.04*

ns

ns

0.04*

0.04*

Weeks until first serious relapse (>60/40 g alcohol for men/women on 3 consecutive days, median)

8

12

11

11

0.04*

0.04*

0.04*

ns

ns

Alcohol quantity/drinking day (g; × ± SD)

98 ± 77

152 ± 69

76 ± 45

57 ± 41

ns

ns

0.04*

0.04*

0.02*

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In summary, the relatively high proportion of abstinent days during treatment may be due to the effects of the different medications as well as the effects of the cognitive-behavioral therapy. Concerning the results of the disulfiram group, patients were aware of the adverse effects when consuming alcohol while taking this medication. This aspect has also been discussed in other studies on disulfiram [1]. Regarding the time period to the first relapse, the three drugs produced comparable results. However, the time period to the first drink was longest in the disulfiram group. On the other hand, the amount of alcohol consumed per day during relapse was highest in the group treated with disulfiram. This is possibly due to the known abstinence-violation effect, which may be of more importance in disulfiram treatment than in treatment with the other two substances. This might also be an effect of the anti-craving properties ascribed to these substances. Yet, all these minor differences between the three medications must not be overvalued, since the group sizes were very small. Nevertheless, outpatient treatment combining psychotherapy and pharmacotherapy seems to be a promising tool in clinical practice. This is also reflected in the remarkably high acceptance rate of this program.

Finally, expectations concerning improvement are important in any treatment, especially in alcoholism treatment. Self-confidence in achieving abstinence was measured with the KAZ [14]. We found that already before the beginning of any treatment, patients with serious relapse and those without relapse (>40 g/60 g of alcohol for women/men per drinking day on at least 3 successive days) could be differentiated. This means that alcoholics with low self-confidence should be identified and treatment with any drug should then be organized with caution. This again demonstrates the importance of psychological factors.

Conclusions

Studies with disulfiram have produced mixed results. However, there are advocates of disulfiram treatment programs. Heather [15] recommended disulfiram as a way of providing some patients with a respite from ravages of heavy drinking. Chick and Brewer [2, 16, 17] warned of the under-use of disulfiram despite the fact that the studies with a sufficient methodology are rare [18]. In particular, the study of Fuller et al. [1] implies that, at least in the short run, disulfiram can reduce the number of drinking days and the amounts of consumed alcohol - a similar finding was reproduced in our study. Some aspects of treatment raise particular methodological concerns. These include patienttreatment matching, the impossibility of double blindness (will be broken by value of the disulfiram-alcohol reaction), the use of disulfiram as part of a treatment package and the problem of compliance. A great variety of patient characteristics has been suggested, which offers potential for matching with disulfiram treatment. The strongest predictor of willingness to take medication was a belief that the medication would be helpful [19], comparable to our findings

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with the KAZ-35. The list of positive and negative predictive factors is long and in parts contradictory. This means that it is impossible to put all of them in an outcome study which fulfills adequate methodological criteria. Knowing the differences between the right and the wrong patient for disulfiram would clinically be crucial but it remains a long-term objective.

We think that disulfiram may be used to promote self-help - this means that disulfiram medication might be interpreted as a help to increase self-control - and may be used as part of a treatment package knowing that this is methodologically difficult to be proven. The combination with psychotherapeutic interventions like marital therapy, behavioral therapy or social skills training [20] is most promising for establishing compliance and abstinence. The combination of several pharmacotherapies like disulfiram and acamprosate [21] or acamprosate and naltrexone [22] and comparisons with other pharmacotherapies are other fruitful approaches [23]. This established a process of learnt abstinence [24], which was very intensively taken up by Ehrenreich et al. [25].

Years back, disulfiram (Antabuse®) was historically the first medication used to stop drinking. Today, treatment is dependent on the overall treatment setting, deciding on whether treatment starts with disulfiram, acamprosate, naltrexone, or a combination of these compounds. The strategy of combining different “anticraving” substances deserves further clinical attention and there are already several ongoing studies tackling this issue.

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