Get Well Clinic and Nursing Home, 33rd Road, Off Linking Road, Bandra, Mumbai-400050, India
* Author to whom correspondence should be addressed: Dr Avinash De Sousa. E-mail: avides999{at}rediffmail.com. Tel: 91 22 26460785; Fax: 91 22 26462672
(Received 18 August 2003; first review notified 23 September 2003; in revised form 23 August 2004; accepted 23 August 2004)
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ABSTRACT |
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INTRODUCTION |
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Naltrexone is an opioid receptor antagonist with a proven history in reducing euphoria, alcohol intake and reducing the risk of relapse in alcoholic patients (Kranzler and Van Kirk, 2001; Streeton and Whelan, 2001
). This action is thought to be due to the blockade of mu-opioid receptors. This antagonism prevents the release of endogenous opioids that would, on consumption of alcohol, produce a dopamine surge in the reward centre of the nucleus accumbens of the medulla (Benjamin et al., 1993
; Catafau et al., 1999
). Naltrexone's efficacy has seldom been evaluated in a 12-month study to date. One such was a multicentre study where 675 patients were recruited and 209 were offered treatment with naltrexone for a 12-month period. However, the study did not support the efficacy of naltrexone (Krystal et al., 2001
). Naltrexone has been compared with acamprosate (calcium acetylhomotaurinate), another anti-craving agent, in a one-year study, which showed that naltrexone was superior to the latter in preventing a relapse (Rubio et al., 2001
).
Disulfiram inhibits acetaldehyde dehydrogenase, by blocking the further metabolism of acetaldehyde, which is an intermediate metabolic product of alcohol in the body. The resulting increased acetaldehyde levels in the body lead to the characteristic disulfiramethanol reaction (DER) that includes a sense of uneasiness, flushing and a feeling of nausea and vomiting (Savas and Gullu, 1997).
The only published study that compared the efficacy of naltrexone with disulfiram was a pilot study in patients with both alcohol and cocaine dependence, in which disulfiram had a superior effect (Carroll et al., 1993). The aim of the present study was to compare their efficacy in the treatment of pure alcohol dependence. A double-blind design was not chosen because there would have been excessive resistance to treatment compliance in a long blinded trial. Moreover, the patient's awareness that he is under disulfiram treatment is an important factor towards its efficacy.
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SUBJECTS AND METHODS |
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Inclusion criteria
The inclusion criteria were as follows: (1) age between 18 and 65 years; (2) DSM-IV criteria for alcohol dependence and (3) patients were required to have a stable family environment so that the family could ensure treatment compliance and provide information on regular follow-up.
Exclusion criteria
The exclusion criteria were: (1) other substance use and dependence excluding nicotine dependence; (2) any comorbid psychiatric disorder that met DSM-IV criteria excluding nicotine dependence; (3) any medical condition that would interfere with treatment compliance is a contraindication for the drugs used in the study; (4) liver function tests elevated above three times the normal value and (5) previous treatment with naltrexone and/or disulfiram.
After the completion of detoxification treatment either in the hospital setting or on an out-patient basis, the subjects were informed about the objectives of the study. They were informed about the duration of the study and the nature of the two drugs to be used in the study (naltrexone and disulfiram), their mechanisms of action, their side-effects profile and the importance of maintaining proper compliance. They were also informed that the drug given to them would be chosen at random but that they would know about the drug that they were receiving. They were told that a relapse or non-compliance would lead to their exclusion from the trial. They were also told that they would be dropped from the trial in the absence of a regular follow-up with a family member. They were given the freedom to choose to leave the study at any time.
Procedure and assessments
After signing the informed consent declaration, the subjects completed questionnaires that pertained to: (1) the Addiction Severity Index (McLellan et al., 1980); (2) severity of Alcohol Dependence Scale (Stockwell et al., 1983
); (3) a scale to measure the three parameters of craving i.e. frequency, duration and intensity (Anton et al., 1995
); (4) a calendar to record any alcohol consumption during the follow-up and (5) a baseline investigation in all patients to evaluate serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and bilirubin.
After randomization, the patients received either 50 mg of naltrexone or 250 mg of disulfiram daily. Both the drugs were given as a single daily dose in the morning after breakfast. Compliance was enhanced by asking the family members to observe the patient when he takes the medication. (Only the non-dispersible form of disulfiram is available in India.)
They were followed up weekly for the first three months and then fortnightly till the end of the trial. They were assessed at each follow-up for craving and adverse effects along with compliance and alcohol consumption, which was checked against the reports made by family members. All the patients were offered supportive group psychotherapy once a week during the trial on a weekly basis and this was less structured than would be in a classical deaddiction programme. Abstinence was positively reinforced. The patients also received symptomatic treatment, for depression (sertraline 50100 mg/day) or insomnia (zolpidem 510 mg at night) when required. Benzodiazepines were not permitted.
Outcome measures
The following outcome measures were assessed:
Accumulated days of abstinence; days until the first relapse (relapse was defined as the consumption of >5 alcohol drinks in 24 h i.e. 40 g of alcohol); number of drinks consumed per typical week; number of drinks consumed at a typical drinking occasion; craving measures; serum GGT measured once in three months; discontinuation of pharmacological treatment; and drop out from the study.
To improve the consistency and independence of the ratings, the final outcomes were rated by a psychologist independent of the study. However, because she was on the staff of the clinic, she was not necessarily blinded to the treatment group in all cases.
Statistical analysis
Chi-squared test and the Student's t-test were used in the statistical analysis. All outcome analyses were conducted under the principle of intention to treat drop-outs were considered as those who relapsed. The analysis of number of drinks consumed per week, number of drinks consumed at a time and the serum GGT were analysed by analysis of covariance (ANCOVA).
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RESULTS |
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There were no significant differences between the treatment groups in terms of sociodemographic or clinical variables that were measured at baseline (Table 1).
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Sertraline was prescribed to three patients because depressive episodes emerged. Zolpidem was prescribed to 23 patients because they complained of insomnia. Side-effects were more common in the naltrexone group than in the disulfiram group, in the form of nausea (33 and 5%, respectively), drowsiness (12 and 1%, respectively), abdominal pain (10 and 1%, respectively) and diarrhoea (8 and 1%, respectively). All these side-effects disappeared within 15 days of the start of the study.
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DISCUSSION |
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In about 7580 cases the patient's spouse monitored the treatment whereas in the rest either the parents (mother or father) or a brother/sister monitored the same. In India there are more joint families than nuclear and hence there is usually more than one member of the family willing to monitor the supervised medication, therefore we assigned one member to take the responsibility and the same member was advised to be with the patient at the time of follow-up.
Limitations of the study
This was an open study and the investigators were not blinded. At the start of the study the investigator was not aware as to the type of treatment that would be more effective. But as the study progressed, there was a better outcome noted with disulfiram that may have resulted in the investigators making more efforts to ensure better compliance in that group. This could have, hypothetically, introduced a bias. However, there was also greater improvement seen in the disulfiram group in terms of the levels of serum GGT; this provides an objective corroboration of the self-report made by the patient and investigator-rated measures. The assessment for compliance was obtained from the report made by a family member. It would have been more accurate if a laboratory marker was in use to determine this measure. In this study, all the cases had very good primary support groups that may have led to better compliance and fewer drop-outs than seen in other published works. From this study we conclude that disulfiram has superiority over naltrexone in preventing a relapse in alcohol dependence, but further investigation in different types of alcoholics and various treatment settings is warranted.
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REFERENCES |
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