Alcoholism Research Program, Servicios de Salud Mental, Retiro, Madrid, Spain and 1 Unidad de Conductas Adictivas (UCA), Servicio de Psiquiatría, Hospital Universitario 12 de Octubre, Madrid, Spain
* Author to whom correspondence should be addressed at: Alcoholism Research Program, "Retiro" Mental Health Centre, Doctor Castelo, 60, 28009 Madrid, Spain. E-mail: garuva{at}inicia.es
(Received 6 September 2004; first review notified 8 October 2004; in revised form 12 January 2005; accepted 7 March 2005; Advance Access publication 29 March 2005)
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ABSTRACT |
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INTRODUCTION |
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NTX is an opioid-receptor antagonist which is believed to act in alcoholism by blocking the putative effects of endogenous opioids release after alcohol consumption, and thus blocking the pleasurable effects or "high" of alcohol (Volpicelli et al., 1995a; O'Malley et al., 1996
; Na and Lee, 2002
). Using this effect, naltrexone might reduce the quantity and frequency of drinking among alcoholics who relapse (O'Malley et al., 1992
; Volpicelli et al., 1992
, Jimenez-Arriero et al., 1998
). However, its effectiveness varies among patients, and not everyone who drinks alcohol shows evidence of a "high" or an increase in endogenous opioids (Gianoulakis et al., 1989
). This has led to a research aimed at identifying the alcoholic subtype that most benefits from treatment with it. Given the heterogeneity of alcohol dependence, it has been of interest to investigate the potential predictors of response. The post-hoc analysis of the original sample in which Volpicelli et al. (1992)
studied the efficacy of naltrexone concluded that the drug may be useful for subjects presenting high levels of craving and somatic symptoms (Volpicelli et al., 1995a
). In another study, the same research group found that patients with high levels of alcohol craving or a substantial family history of alcoholism were more likely to benefit from naltrexone treatment (Monterosso et al., 2001
). Kranzler et al. (2003)
have recently reported the efficacy of naltrexone in the treatment of early problem drinkers.
Alcoholism is a multifactorial disorder involving biological and psychosocial interactions, and with substantial heritability (Goodwin, 1985). Some clinical traits, used for classifying alcoholic subsets, have been proposed as clinical markers of potential special biological vulnerability (Cloninger et al., 1988
; Babor et al., 1992
). The purpose of our current study was to determine whether family history of alcoholism (FHA+) was related to a satisfactory outcome in our clinic's alcoholic patients treated with naltrexone, and also to examine the predictive power of other clinical variables.
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SUBJECTS AND METHODS |
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Subjects
Once subjects had completed the detoxification period, either in the hospital or as an outpatient, they were informed about the therapeutic options (with and without naltrexone), but told that the treatment (drug/no drug) they would receive would be chosen at random. They were informed that neither a relapse nor failing to follow the prescribed treatment would lead them to be asked to leave the trial. However, they would be taken out of the trial if they failed to make contact with the psychiatrists in a period of over 15 days (i.e. two consecutive visits). They were also informed that they could drop out of the study at any time. After receiving full information about the study they were asked for their consent to take part.
Of the 407 alcoholic patients approached, 52 were excluded because of medical problems that contraindicated the use of naltrexone (e.g. AST and ALT >3 times normal values), and 19 later refused to participate because of problems related to reporting with the frequency required by the study. Thus, 336 subjects participated. Participants were alcohol-dependent males, aged between 18 and 65 years, who had requested detoxification in the Addictive Behaviour Unit of the Doce de Octubre hospital (Madrid). At intake, the patients met the DSM-IV criteria for alcohol dependence (APA, 1994). In addition, we applied the following exclusion criteria: (i) opiate use during the year before inclusion in the trial; (ii) presence of another psychiatric disorder diagnosed by the DSM-IV (SCID) at baseline evaluation (Firsts et al., 1995
); and (iii) a medical condition that could contraindicate the use of naltrexone.
Of the 336 participating subjects, 268 were detoxified with diazepam over a period of 510 days (138 in the NTX-group and 130 in the non-NTX group). They had been abstinent for a mean of 14.5 days (SD 7.2), before starting the medication.
Treatments offered
Patients in the naltrexone group were prescribed 50 mg/day. (No placebo was used in this study). Supportive group therapy was offered to all patients, once a week, throughout the entire study period. Therapy was less structured than in classical relapse prevention programmes. Basic relapse prevention techniques were used (for dealing with situations of risk, craving and negative emotional states). Abstinence was positively reinforced. When the psychiatrist found that the patient, in either of the groups, met the clinical criteria for depressive or anxiety disorder, sertraline (100200 mg/day) was added. Insomnia was treated with hydroxyzine, an H1 receptor antagonist, for insomnia (50100 mg/day h.s.). In cases of alcohol intake or of high level of subjective craving, or when both clinician and patient considered it appropriate, disulfiram was added to the treatment.
Assessments
Alcohol dependence level was defined according to DSM-IV criteria (SCID-IP, Firsts et al., 1995); the Addiction Severity Index (ASI) (McLellan et al., 1980
) and the Severity of Alcohol Dependence Scale (SADS) (Stockwell et al., 1979
; Rubio et al., 1998
). Craving was evaluated with three analogue scales (frequency, duration and intensity) (Miller, 1996
). During follow-up assessments, participants were evaluated each week on the basis of the participant's self data on alcohol intake and consumption pattern (Miller, 1996
). In addition, the following biological parameters of alcohol use were used: serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), and carbohydrate-deficient transferrin (CDT). Other substance-use disorders were defined according to the DSM-IV criteria (SCID-IP, Firsts et al., 1995
)
Family history of alcoholism was assessed by interviewing first-degree relatives (parents, siblings, offspring). Subjects were classified as family history positive (FHA+) if they had a first-degree relative with a history of alcohol dependence. Where necessary, the diagnosis was made by applying the Research Diagnostic Criteria-Family History (RDC-FH) (Bueno et al., 1989).
The following outcome variables were computed: number of drinking days, number of heavy drinking days (defined as the consumption of >5 drinks or 40 g ethanol/day), abandonment of treatment, days of continued abstinence and final abstinence defined as absolute and continuous abstinence in the final 28 days of the follow-up period.
Patients visited their psychiatrists every week (±3 days) until the end of the study. In the event of relapse, frequency of visits was increased in order to help curtail the relapse and to offer the patient assistance, if required. At each visit, entries in the diary of alcohol consumption they had been asked to complete at home were checked, along with craving, and compliance with the treatment. Consumption and compliance data were compared with the information given by the family. Where there was a clear contradiction, we opted to use the information suggesting the most consumption. Biological parameters were not used for determining the amount of consumption or relapse, as it may be that occasional consumption of alcohol fails to have an influence on plasma levels of AST, ALT, GGT and CDT.
Blind assessors
Outcome data were collected by assessors who saw patients once a week, after the weekly group therapy session. Attempts were made to keep them blinded to the drug taken by the patients. They used the following sources of data: (i) the patient's self-assessment (patients were asked not to talk about the pharmacological treatment); (ii) the psychiatrist assigned to the case, who provided any data required from the clinical records and results of biochemical analyses (but did not disclose the treatment prescribed); and (iii) the patient's family, who provided information about drinking and any attempts by the patient to cease the pharmacological treatment.
Statistical analysis
Comparison of qualitative and quantitative variables was made using chi-squared test with the Yates continuity correction and analysis of variance (ANOVA), respectively. The sample was divided according to the selected variables associated with final abstinence, and the logistic regression model was used to determine the influence of treatment with naltrexone on the final state for each subgroup. Present age was used as a covariate for analysis. We also included the rest of the predictors in this model. Finally, we used the chi-squared tendency model to determine the influence of number of predictors on outcome among those treated with and without naltrexone. The statistical package used was SPSS 9.0. A P-value < 0.05 was considered significant.
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RESULTS |
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Predictor variables for continuous abstinence in the final 28 days of follow-up
The following variables were entered into the analysis: treatment with naltrexone, craving, in- or out-patient detoxification, medical pathology associated with alcohol consumption, age at onset of drinking problems, age at onset of alcohol dependence syndrome, physical dependence, present age, family history of alcoholism, family psychiatric history, personal psychiatric history, other drug abuse/dependence, and severity of dependence. Four out of thirteen of these traits were associated with continuous abstinence in the final 28 days of follow-up: treatment with naltrexone, age at beginning of alcohol abuse (before age 25), family history of alcoholism and antecedents of abuse/dependence with other substances. We subsequently performed an analyses using the present age as a covariate, since age was associated independently with age at onset of abuse and presence of other substance use. Our analysis showed an association between naltrexone treatment and final abstinence in patients with one or more of the following traits: alcohol abuse before age 25 (2 = 4.836; P = 0.028), comorbid abuse of/dependence on other substances (
2 = 12.835; P < 0.001), or presence of FHA+ (
2 = 5.714; P = 0.017) (Table 3).
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DISCUSSION |
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The limitations of our study derive mainly from the fact that its method is not double-blind. The need to include a sample of patients similar to the subjects normally treated in our clinical settings (who tend to be more severe cases than those usually included in double-blind studies) made it advisable to maintain continuous control of the treatment by the therapists, which in turn made it difficult to carry out a double-blind study. The professionals treating these patients tend to have a positive experience with respect to the effectiveness of NTX, and this may have influenced the expectations of the patients they treated. In order to avoid the bias of these psychiatrists in the evaluation of effectiveness, "blind" interviewers were included, and attempts were made to control their "blindness" by various methods.
Our results coincide with studies finding that family antecedents of alcoholism are a marker of better response to treatment with NTX (King et al., 1997; Monterosso et al., 2001
).
The predictor variables for response to naltrexone found in this study are usually included among the traits of type 2 (Cloninger et al., 1988) and type B alcoholics (Babor et al., 1992
; Volpicelli et al., 1995b
). It has been hypothesized that such patients present dysfunctions of the dopaminergic and opioid systems (Gianoulakis et al., 1989
, 1992
; Blum et al., 1990
; Noble, 2000
). The consumption of alcohol may produce a greater release of endogenous opioids in the offsprings of alcoholics (Gianoulakis et al., 1989
). It has been pointed out that some patients with phobic features may be particularly sensitive to experiencing craving in situations of anxiety, and that such craving could be related to opioid hyperstimulation induced by stress (Volpicelli et al., 1986
, 1995b
). In these patients, naltrexone may also help to prevent relapse. The blocking of opioid hyperactivation as a result of alcohol consumption would also block the dopaminergic hyperactivation responsible for the phenomena of reinforcement and priming (Di Chiara and Imperato, 1988
; Koob and Bloom, 1988
; Benjamin et al., 1993
; Di Chiara et al., 1996
). These data led us to hypothesize that the better response to NTX achieved in these individuals may be explained by their capacity for blocking the effects of alcohol on a dysfunctional opioid and/or dopaminergic system. A functional polymorphism of the mu-opioid receptor gene has recently been associated with NTX response in alcoholic patients (Oslin et al., 2003
).
Our result may be helpful for understanding some inconsistencies found in published articles on the effectiveness of naltrexone (Gastpar et al., 2002). The under- or over-representation of patients with the characteristics found in our study may explain the global effectiveness results (Rubio et al., 2002
). That is, in samples with low prevalence of comorbidity with other substance-use disorders (Gastpar et al., 2002
) and low proportions of FHA+, the effectiveness of naltrexone will probably be quite similar to that of placebo. The negative result of Krystal et al. (2001)
goes against our hypothesis in that the prevalence of FHA+ in our study was lower than in their study. However, other suggestions have been offered (Rubio et al., 2002
) to explain the lack of naltrexone effectiveness in the study of Krystal et al.
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CONCLUSIONS |
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