Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study

Gerhard A. Wiesbeck*,, Heinz-Gerd Weijers, Otto M. Lesch1,, Thomas Glaser2,, Peter-Joachim Toennes2, and Jobst Boening

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


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Flupenthixol, with its broad receptor profile, interacts with a variety of dopamine and serotonin binding sites which are important in the neurobiology of alcohol dependence. Its pharmacology, together with encouraging results from both animal studies and clinical trials with cocaine users, led us to postulate that flupenthixol would significantly prevent relapse in detoxified alcohol-dependent individuals. We conducted a prospective, randomized, double-blind, placebo-controlled, multi-centre trial with two parallel groups and appropriate statistical evaluation. Subjects met criteria for moderate to severe alcohol dependence (DSM-III-R), without any concomitant psychiatric disorder. After complete detoxification, 281 women and men received either 10 mg of flupenthixol decanoate or placebo as i.m. injection every second week for 6 months on an out-patient basis, followed by 6 months of follow-up. Efficacy was based on absolute abstinence, with relapse being defined as consumption of any alcohol after inclusion in the study. In contrast to the hypothesis, flupenthixol did not reduce, but was associated with more, relapses. Though well tolerated, relapse rates after 6 months of treatment were 85.2% (flupenthixol) versus 65.5% (placebo), a highly significant difference from the medication. Flupenthixol was also inferior to placebo with regard to other secondary criteria of efficacy (cumulative abstinence duration, relapse rate after 12 months). These results indicate that a 10 mg dose of flupenthixol decanoate does not have a beneficial effect on abstinence maintenance in alcohol-dependent individuals.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Traditional alcohol treatment programmes reveal limited success. For example, Project MATCH Research Group (1997) reported abstinence rates ranging from 19% (out-patient treatment) to 35% (in-patient treatment) during a 12-month follow-up. Since relapse rates peak during the first months after cessation of drinking (Lesch et al., 1989Go; Feuerlein and Kuefner, 1989Go; Swift, 1999Go), a search has begun for pharmacological means to prevent relapse especially during this difficult period (Garbutt et al., 1999Go).

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, 1992Go). 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 {alpha}1-adrenergic receptors (Glaser et al., 1998Go). 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, 1993Go; Erickson, 1996Go; De Witte, 1996Go; Noble, 1996Go). 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., 1991Go; McBride et al., 1993Go; Hietela et al., 1994Go; Lewis, 1996Go; Glaser et al., 1998Go; McBride and Li, 1998Go).

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., 1988Go; Duvauchelle et al., 1992Go; King et al., 1994Go; Mansbach et al., 1994Go; Richardson et al., 1994Go; Soyka and Sand, 1995Go; Negus et al., 1996Go). In an animal model using rats specially bred for voluntary high alcohol consumption, flupenthixol at low dosages (0.1–1 mg/kg) reduced alcohol-intake in a dose-dependent manner (Sinclair et al., 1989Go). However, this effect appeared to be non-specific since food and water consumption decreased as well (Soyka and De Vry, 1998Go).

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 10–20 mg flupenthixol decanoate every 14 days (Gawin et al., 1989Go). 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., 1996Go). Preliminary results were also reported regarding the successful use of flupenthixol in schizophrenic cocaine users (Levin et al., 1998Go). 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.


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients
After written informed consent, 281 patients, women (n = 77; 27.4%) and men (n = 204; 72.6%) between the ages of 22 and 55 years, were enrolled through 13 alcohol treatment centres across Germany and Austria. Patients had to fulfil at least six DSM-III-R criteria (303.90) for moderate or severe alcohol dependence ascertained by clinical interview (American Psychiatric Association, 1987Go). Additionally, they had to reach a score of >=11 according to the Munich Alcoholism Test (Feuerlein et al., 1980Go). The severity of the alcohol-dependence syndrome was rated with the ‘Goettinger Dependence Scale’ (GABS; Jacobi et al., 1987), which is the German version of the ‘Severity of Alcohol Dependence Questionnaire’ (SADQ; Stockwell et al., 1979). Further requirements were complete abstinence from alcohol consumption and any pharmacotherapy (as assessed by repetitive controls of liver enzymes, breath-alcohol analyses, and urine tests) for a minimum of 14 days and a maximum of 42 days and the absence of any withdrawal symptoms verified by a weighted score of <2 on the Withdrawal Syndrome Scale for alcohol and related psychoactive drugs (Bech et al., 1989Go). Co-morbidity (depression, anxiety) at the time of inclusion was controlled for by defining cut-off scores on the Hamilton Depression Rating Scale (HAMD score >18) (Hamilton, 1960Go) and on the Hamilton Anxiety Rating Scale (HAMA score >16) (Hamilton, 1959Go) as exclusion criteria. Further conditions for participation were: a negative urine test for psychoactive drugs, the absence of severe neurological and medical disorders, no psychiatric disorder requiring psychotropic medication or hospitalization, and the intention to remain abstinent.

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 {gamma}-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{per thousand} (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, 1993Go). 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.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Characteristics of the patients
A total of 281 patients received either flupenthixol (n = 142) or placebo (n = 139). Of these 281 patients (ITT), 244 entered the per-protocol analysis. The flupenthixol and the placebo group were well matched, since they did not differ significantly in sex, age, body weight, and a variety of variables characterizing drinking behaviour and the alcohol-dependence syndrome (Table 1Go).


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Table 1. Main features of the trial sample
 
Of 281 patients enrolled, 91 (32.4%) completed the trial (6 months treatment, 6 months follow-up). One hundred and nine patients who were receiving flupenthixol (76.8%) and 81 patients being treated with placebo (50.3%) were withdrawn ({chi}2 = 19.1; df = 1; P < 0.0001). However, for seven out of eight recorded reasons for drop-out, the difference between the two treatment groups was not statistically significant (Table 2Go). ‘Relapse’ was the only reason why flupenthixol-treated patients (24.7%) and placebo-treated patients (14.4%) differed significantly.


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Table 2. Reasons for drop-out
 
Efficacy
After 6 months of treatment, more flupenthixol-medicated than placebo-treated patients had relapsed. The difference proved highly significant in both worst-case ITT analysis (i.e. cases not retrievable were counted as relapse) and ITT analysis which took only documented relapses into consideration. The difference between the two groups remained highly significant until the end of the 12-month trial (Fig. 1Go). The per-protocol (PP) analysis revealed similar results: during 6 months of treatment 97/126 (77.0%) patients in the flupenthixol group and 69/118 (58.5%) patients in the placebo group relapsed (P <= 0.002; Fisher's exact probability test). At the end of the 12 months treatment, only 34 (23.9%) flupenthixol-treated patients, compared with 58 (41.7%) placebo-treated patients, had been continuously abstinent (worst case analysis; P = 0.002). The survival curve is shown in Fig. 2Go.



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Fig. 1. Enrolment, randomization and follow-up in a controlled study of flupenthixol (F) versus placebo (P) for alcohol dependence.

 


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Fig. 2. Relapse rates (intention-to-treat analysis) after 6 and 12 months of treatment. FLX, flupenthixol; PLC, placebo.

 
During the first 6 months, the mean time to first relapse, a secondary outcome measure, was 48 ± 39 days for patients on flupenthixol and 48 ± 40 days for patients on placebo, respectively (Fig. 3Go).



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Fig. 3. Time to first relapse (Kaplan-Meier survival analysis).

 
Since the above parameters do not reflect abstinent periods after a first relapse, the total number of abstinent days was calculated as the ‘cumulative abstinence duration’ (CAD). During the first 6 months of treatment, the mean (± SD) CAD in the flupenthixol-treated group was 100 ± 62 days or 56% days abstinent. This was significantly less than 122 ± 66 days or 67% days abstinent in the placebo-treated group (P = 0.0015; Wilcoxon test). ‘Loss of control’ occurred in 33/101 (32.7%) of flupenthixol-treated patients compared to 19/75 (25.3%) of placebo-treated participants. This difference did not reach statistical significance ({chi}2 = 1.14; df = 1; P = 0.32).

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 1Go) 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 ({chi}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 2Go).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
We conducted a rigorous trial evaluating the effectiveness of a 10 mg dose of flupenthixol decanoate injection in preventing relapse in alcohol-dependent individuals. Previous studies focused on alcohol consumption in animals, on cocaine or drug dependent humans. They were retrospective, non-randomized, unblinded or just single-case reports. None of them had a prospective design. Therefore, to the best of our knowledge, there has been no study similar to ours so far.

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., 1997Go; Schmidt et al., 1997Go). 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.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study was sponsored by the Bayer Company, Leverkusen, Germany. The statistical analysis was performed by the ‘Institut für numerische Statistik’ (IFNS), Cologne, Germany. We are indebted to Claudio A. Naranjo, MD, University of Toronto, for his helpful comments in reviewing the manuscript.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* *Author to whom correspondence should be addressed at: Addiction Research Group, Psychiatric Clinic, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany. Back

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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 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
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