Addiction Research Group, Department of Psychiatry, University of Wuerzburg,
1 Department of Psychiatry, University of Vienna, Austria and
2 Bayer Vital, Leverkusen, Germany
Received 27 March 2000; in revised form 9 January 2001; accepted 6 February 2001
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ABSTRACT |
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INTRODUCTION |
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Flupenthixol, an established antipsychotic drug, is known for its mild antidepressant and anxiolytic activity, as well as for its minimal sedative effects at low doses (Budde, 1992). Flupenthixol antagonizes dopamine binding at a number of receptor subtypes, primarily at D1, D2, D3 and with less affinity at D4 receptors, and also affects serotonin binding at 5-HT2A and 5-HT2C receptors as well as noradrenaline binding at
1-adrenergic receptors (Glaser et al., 1998
). With this non-selective, but rather broad, binding profile, flupenthixol seems to interact with a variety of important receptors which are involved in the neurobiology of craving and alcohol dependence (Robinson and Berridge, 1993
; Erickson, 1996
; De Witte, 1996
; Noble, 1996
). The drug's balanced interaction with both D1 and D2 receptors seems to be tailor-made for binding sites believed to be crucial to the biology of alcohol reinforcement (Noble et al., 1991
; McBride et al., 1993
; Hietela et al., 1994
; Lewis, 1996
; Glaser et al., 1998
; McBride and Li, 1998
).
However, only a few and contradictory reports from both animal and human studies have been done on the usefulness of flupenthixol in treating drug and alcohol abuse or dependence (Schilkrut et al., 1988; Duvauchelle et al., 1992
; King et al., 1994
; Mansbach et al., 1994
; Richardson et al., 1994
; Soyka and Sand, 1995
; Negus et al., 1996
). In an animal model using rats specially bred for voluntary high alcohol consumption, flupenthixol at low dosages (0.11 mg/kg) reduced alcohol-intake in a dose-dependent manner (Sinclair et al., 1989
). However, this effect appeared to be non-specific since food and water consumption decreased as well (Soyka and De Vry, 1998
).
More data on flupenthixol in humans come from cocaine users. In an open study with ten crack cocaine smokers, an average 72% reduction of craving and a prolonged retention in an out-patient treatment programme were reported on 1020 mg flupenthixol decanoate every 14 days (Gawin et al., 1989). Using a placebo-controlled double-blind design, Khalsa et al. (1994) reported a significant reduction of both craving and drug consumption, as well as a much better participation in psychotherapeutic treatment groups in cocaine users. Interestingly, a mean dose of 12 mg was well tolerated by patients who remained abstinent, whereas severe extrapyramidal symptoms occurred in others after smoking cocaine again (Gawin et al., 1996
). Preliminary results were also reported regarding the successful use of flupenthixol in schizophrenic cocaine users (Levin et al., 1998
). However, studies were small and some were negative.
Based on the somewhat encouraging findings in cocaine users, our clinical study was initiated to elucidate the effectiveness of flupenthixol in alcohol dependence. Our hypothesis was that flupenthixol would be more effective than placebo in preventing relapse in abstinent alcoholics.
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SUBJECTS AND METHODS |
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Study design
This study was conducted between June 1994 and March 1998. It was designed as a prospective, randomized, double-blind, placebo-controlled, bi-national multi-centre trial. A difference in relapse rates between 70% in the placebo group and 50% in the flupenthixol group was regarded as clinically relevant. To confirm this difference with a type I error of alpha = 0.05 and a type II error of beta = 0.10, a total number of at least 268 patients (134 patients in each treatment group) was projected as estimated from a priori sample size calculations. Thirteen alcohol treatment centres in Austria and Germany participated. Each centre's ethics committee approved the protocol and consent procedures of the study which was conducted in accordance with the European Good Clinical Practice Guidelines and the current version of the Declaration of Helsinki.
Procedures
Patients were randomly assigned to either 10 mg flupenthixol decanoate or placebo, both applied every second week in identical forms as an i.m. injection, over a period of 6 months (treatment phase), succeeded by a medication-free 6-month follow-up period. Treatment practices in all centres were similar. Patients received supportive psychotherapy through either individual and/or group therapy, as appropiate to clinical need. Participation in self-help support groups, such as Alcoholics Anonymous, was recommended. The patients were seen by their investigator every second week during the first 6 months. Every 4 weeks a physical examination, venepuncture (for liver function tests, red and white blood cell counts, and prothrombin time) and extensive ratings were performed. During the medication-free second part of the trial (6-month follow-up period), visits took place every eighth week. When patients missed a visit or dropped out, they or their family were contacted to obtain reasons for absence. They were deemed to have relapsed for the missed visit (the worst-case scenario presumed for missing data).
Outcome measures related to efficacy and safety
Outcome variables were based on absolute abstinence, which was defined as no alcohol consumption. To be considered abstinent, the patient's self-report had to be in accordance with the investigator's clinical assessment and the result of a breath analyser. Additionally, relapse was recorded in spite of a patient's self-reported abstinence if his liver enzyme parameters increased over baseline [40% increase in
-glutamyltransferase (GGT) or
60% increase in alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) values over baseline] according to the method of Irwin et al. (1988). Relapse did not necessarily lead to exclusion from the study unless it occurred as heavy drinking [i.e. the patient was not able to attend his scheduled follow-up appointment due to intoxication or if he revealed a breath alcohol concentration of
1
(100 mg/dl)] at a visit. The severity of relapses was rated by a physician as with or without loss of control.
The number of patients relapsed (i.e. consumed any alcohol) after 6 months of treatment was the primary parameter of efficacy. Secondary criteria were as follows: time to first relapse; relapse rate after 12 months; cumulative abstinence duration; changes in craving as assessed by a 100-mm visual analogue scale (VAS) that ranged from no desire (0) to an uncontrol- lable desire (100); changes in social functioning assessed by the Social Functioning Questionnaire (SFQ; Tyrer, 1990). All adverse events (AE) were categorized and documented according to the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) Guidelines for Clinical Safety Data Managements.
Statistical analysis
This trial was designed as a prospective study with a confirmatory statistical evaluation. The main analysis used was an intention-to-treat (ITT), procedure including any randomized patients who received at least one injection of the trial medication (Lehert, 1993). A per-protocol analysis was also performed including all patients without any major protocol violation. Missing data on abstinence were interpreted as relapse (worst-case scenario). The main comparisons of efficacy were between the flupenthixol and the placebo groups. Cross-tabulations of drinking behaviour (abstinence/relapse) were tested by Fisher's exact test. Time-to-first drink (relapse) was analysed by the life-table method of Kaplan-Meier (survival analysis), censoring missing data (log rank test; Lee, 1980). All results were interpreted at the two-tailed 5% significance level.
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RESULTS |
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Other outcome measures
Craving (VAS scores) decreased over time in placebo-treated patients independently of whether they relapsed or not, but craving scores increased in those flupenthixol-treated subjects who relapsed. Therefore, data on craving were subjected to an ANOVA repeated measure model with group (flupenthixol/placebo), outcome (relapse/no relapse) and time (at baseline/last value before relapse or premature termination or after 6 months) as factors. This ANOVA revealed significant effects for group (df = 1; F = 4.56; P = 0.035) and time (df = 1; F = 3.95; P = 0.049). The interaction for group x outcome x time revealed a tendency but failed statistical significance (df = 1; F = 3.43; P = 0.067).
The same ANOVA procedure for the analysis of SFQ-scores revealed a significant main effect only for time (df = 1; F = 9.67; P = 0.002): scores decreased between first and last rating (i.e. improvement of social functioning).
Logistic regression analysis
A logistic regression analysis was performed to calculate the effect of every main baseline feature (Table 1) on the primary parameter of efficacy (i.e. relapse rate after 6 months in a worst-case analysis). The model identified one variable, that is GGT, as having a statistically significant effect (P = 0.02) on outcome. To further check the relevance of this finding, we calculated an ANOVA with treatment (flupenthixol vs placebo) and GGT (dichotomized at the median) as factors and with relapse rate being the dependent variable. This yielded a highly significant main effect for treatment group (P < 0.001) but no significant main effect for GGT or for the interaction treatment x GGT.
Adverse events
The total number of adverse events was less on flupenthixol (n = 211) than on placebo (n = 268). At least one adverse event was reported by 59 (41.5%) flupenthixol-treated patients and by 69 (49.6%) placebo-treated patients (2 = 1.85; df = 1; P = 0.19). The most common adverse events were incidents of intercurrent diseases of minor severity or of non-specific complaints. Adverse events were rated according to their severity: serious adverse events occurred in only four (2.8%) patients on flupenthixol (renal colic, suicide, abortion during the 12th week of unknown pregnancy, fracture of lower leg due to accident), but in six (4.3%) patients on placebo (suspected breast cancer, adrenal cyst, attempted suicide, psychotic episode, removal of stent due to oesophageal stenosis, blood loss). One patient in the flupenthixol group committed suicide during the 6-month medication-free follow-up period. None of these serious events was assessed as causally related to the study drug. Adverse events as a reason for premature termination were reported in only three (2.1%) patients on flupenthixol and in two (1.4%) patients on placebo (Table 2
).
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DISCUSSION |
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The results of this trial did not support our originally formulated hypothesis. Since flupenthixol-medicated patients and placebo-treated patients were well matched in age, sex, alcohol consumption and severity of dependence, our data suggest that flupenthixol is able to significantly reduce an alcoholic's chance of remaining abstinent. Additionally, flupenthixol-treated patients revealed a cumulative abstinence duration less than that of placebo-treated subjects, indicating that this medication does increase not only the number, but also the duration, of relapses, compared to placebo. Additional support for this interpretation is provided by the design of the study. Multi-centre trials like ours usually decrease the risk of bias in the selection of patients. Although such a biasing influence cannot be completely excluded, a tendency that favoured flupenthixol was observed in only one out of 13 centres. In other words, the negative effect of flupenthixol on abstinence maintenance did not depend on a few outliers, but was reflected by the data of almost every centre. However, in the two major centres with a combined total of 119 patients, the difference in the relapse rates between the treatment groups was pronounced, thus contributing substantially to the overall result.
For the sake of internal consistency, we checked the influence of every main baseline characteristic on outcome, finding that GGT was the only parameter revealing a significant effect on relapse. Since GGT levels were higher (but not significantly) in the flupenthixol group, this may possibly indicate a tendency for alcoholism to be more severe in flupenthixol-treated patients, which might cause their worse outcome. However, this speculation was not supported by an ANOVA which revealed no effect of GGT on relapse independently of the treatment groups.
Flupenthixol decanoate given in a dosage of 10 mg every second week was well tolerated and safe. Both numbers and severity ratings of adverse events were higher, though not significantly, in the placebo-treated group; thus making it unlikely that flupenthixol-treated patients drank alcohol to cope with medication-related adverse effects. This is in accordance with the report of Gawin et al. (1989), who came to a similar conclusion regarding cocaine users.
Craving decreased over time in placebo-treated patients, independently of whether they relapsed or not, but craving scores increased in those flupenthixol-treated subjects who relapsed. Therefore, it seems justified to ask whether flupenthixol might be able to induce craving for alcohol a speculation totally in contrast to our original hypothesis. The analysis of variance calculated to test this possibility revealed a tendency which did not statistically (P < 0.10) confirm this supposition. Nevertheless, it is well known that patients' characteristics may influence the outcome of pharmacological alcohol relapse prevention studies. It might be that certain types of alcohol dependence (see Lesch and Walter, 1996) are more susceptible to the apparent adverse effects of flupenthixol that we have demonstrated.
The results of the present trial are generally in line with those recently reported with other dopaminergic substances such as lisuride or bromocriptine (Naranjo et al., 1997; Schmidt et al., 1997
). Thus, it seems that a modulation of dopaminergic pathways by dopamine D1 and/or D2 receptor agonists or antagonists has no beneficial effect on relapse prevention in alcohol dependence.
Results from an animal study, which were not available at the beginning of this trial, agree with our findings. Wolffgramm and Heyne (1995) developed a behaviour-dependent animal model for drug and alcohol addiction, in which the oral administration of flupenthixol (1 mg/kg/day) significantly increased voluntary alcohol intake in alcohol-dependent rats (J. Wolffgramm and A. Heyne, personal communication).
In conclusion, our trial demonstrated that abstinence in alcohol-dependent patients can be adversely affected by a pharmacological intervention, flupenthixol.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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Participating centres and investigators: Austria: Wien, Anton-Proksch-Institut, Kalksburg: O. Lesch, M. Saletu, A. Nimmerrichter, H. Walter, G. Zyhlarz, N. Benda, A. Leitner, B. Subasi; Germany: Angermuende, Krankenhaus, Abteilung für Psychiatrie: G. Richter, P. Rybarczyk, N. Morkel, I. Basler; Augsburg, Bezirkskrankenhaus, Klinik für Psychiatrie und Psychotherapie: M. Schmauss, M. Niederecker, M. Banszerus, L. Teufel; Bayreuth, Bezirkskrankenhaus, Klinik für Psychiatrie und Psychotherapie: C. Mattern, G. Rauch; Darmstadt, Elisabethenstift: U. Vorbach, W. Beck, T. Bracher; Ingolstadt, Psychiatrische Klinik: M. Lemke, A. Kagerbauer; Lohr, Krankenhaus für Psychiatrie und Neurologie des Bezirks Unterfranken: G. Jungkunz, H. Eckrich, M. Frey, P. Grampp, H. Münzel, K. Reitzle; Muenchen, Psychiatrische Universitätsklinik: M. Soyka, C. Aichmüller, G. Kotter, H. Rothenhäusler, C. Schütz; Offenbach, Praxis Dr Klinger: P. Klinger, A. Sapok; Regensburg, Bezirksklinikum Regensburg, Psychiatrische Universitätsklinik: H. Fleischmann, C. Wenig, C. Schäfer, A. Kirschteuer; Stuttgart, Bürgerhospital: K.-L. Täschner, J. Fischer, A. Menges; Werneck, Krankenhaus für Psychiatrie und Psychotherapie des Bezirks Unterfranken: H. Jansen, G. Zöller; Wuerzburg, Psychiatrische Universitätsklinik: J. Boening, N. Wodarz, C. Mauerer, M. Oelschläger, T. Kraus, G. A. Wiesbeck.
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