Department of Psychiatry, University Hospital of Hamburg, Hamburg, Germany
* Author to whom correspondence should be addressed at: Department of Psychiatry and Psychotherapy, University Hospital of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 40 42803 5356; Fax: +49 40 42803 3417; E-mail: kiefer{at}uke.uni-hamburg.de
(Received 9 June 2004; first review notified 28 July 2004; in revised form 8 August 2004; accepted 8 August 2004)
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ABSTRACT |
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INTRODUCTION |
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RATIONALE FOR A COMBINATION THERAPY |
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One of the drivers for relapse in abstinent alcohol dependent patients is craving to drink. Different aspects of craving have been postulated (Anton et al., 1995; Verheul et al., 1999
), which reflect different aspects of the neurobiology of alcohol dependence. Widely accepted are the notions of reward (or positive) craving which arises as a conditioned cue to drink in order to experience the hedonic effects of alcohol, and relief (or negative) craving, a conditioned cue to avoid the unpleasant effects associated with the absence of alcohol (Fig. 1).
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In addition, acamprosate and naltrexone might act on different aspects of drinking behaviour. The former seems to increase the probability that currently abstinent subjects remain abstinent, without necessarily affecting the craving for alcohol, whereas the latter might reduce the quantity of alcohol ingested, by attenuating the priming effect of initial alcohol intake or alcohol-associated cues.
From a pragmatic point of view, both drugs are on the whole well tolerated and have no propensity for potentially dangerous drugdrug interactions. Meta-analyses revealed effect sizes between 0.25 and 0.30 for both compounds (Berglund et al., 2003; Mann et al., 2004
). Hence, neither treatment shows an effect size that could not be ameliorated.
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DATA FROM PRECLINICAL STUDIES |
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The differences between the results of these studies, especially regarding the efficacy of acamprosate, might be attributable to procedural differences among the experiments. Whereas the study of Heyser et al. (2003) administered acamprosate twice a day for 5 days during ethanol deprivation (25, 100 or 200 mg/kg) before giving access to alcohol using an operant lever press procedure, Stromberg et al. (2001)
exposed rats to 4 days acamprosate once a day (50 and 200 mg) without pre-testing alcohol-free days. Kim et al. (2004)
administed acamprosate for 10 days (50 and 200 mg) during which half of the daily dosage was administered 12 h before the start of the limited access session and the other half 30 min before the start of the limited access session. Thus it seems possible that procedural differences (duration of pre-treatment, deprivation phase, application procedure) might be responsible for the reduced efficacy of acamprosate in some studies and, as a consequence, a lack of clearly detectable synergistic effect in combination with naltrexone.
However, taken together, pre-clinical data do provide some evidence that the co-administration of acamprosate and naltrexone might reduce ethanol intake more effectively than either on its own.
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SAFETY OF COMBINING ACAMPROSATE AND NALTREXONE |
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It was observed that co-administration of the two drugs significantly increased the rate and extent of absorption of acamprosate and thus the extent of exposure. The area under the curve of acamprosate plasma concentration was increased by 25%. This observation is presumably explained by a decreased rate of gastric emptying produced by naltrexone. On the other hand, there was no change in the plasma concentrations of either naltrexone or its principal metabolite 6-ß-naltrexol compared to naltrexone given alone. All treatments were tolerated and there was no impact of combined treatment on a panel of tests of cognitive function.
The second study was a randomized, placebo-controlled, double-blind, cross-over study performed in 23 non-treatment-seeking, alcohol dependent patients (Johnson et al., 2003). The study examined kinetic and dynamic factors to determine the pharmacological and behavioural safety and tolerability of low versus high doses of naltrexone (50 mg/day vs 100 mg/day) and acamprosate (2 g/day vs 3 g/day), both independently and combined. A placebo washout preceded treatment with low- or high-dose naltrexone or acamprosate. Thereafter, the alternative medication type at its lower and higher doses, respectively, was administered with continuation of the first medication. Predetermined behavioural, performance and pharmacological criteria determined significant pathological change from baseline. Significant increases in symptoms from baseline with monotherapy included nervousness and fatigue with 3 g acamprosate and somnolence and headache with 50 mg and 100 mg naltrexone, respectively. Combined treatment at various doses evinced anger, depression, somnolence, nervousness, diarrhoea and headache. For all but one subject who dropped out, increased symptoms did not produce any remarkable clinical deterioration. Naltrexone administration significantly again increased plasma acamprosate levels. Naltrexone and acamprosate, both alone and in combination at the tested doses, were behaviourally and pharmacologically safe. Adverse events were infrequent, of moderate intensity, and resolved with reassurance and symptomatic treatment. More side effects were noted with the combination of medications than with either medication alone.
The third study corresponds to a preliminary safety analysis from the COMBINE study. This is a large randomized, placebo-controlled, double-blind, study in alcohol dependent patients in North America designed to assess the efficacy of different combinations of naltrexone, acamprosate and behavioural interventions in promoting abstinence. The ongoing study is planned to include 1375 patients. Analyses of the safety data from an initial sample of 108 patients have been published (COMBINE Study Group, 2003) including retention, adherence to study parameters and medication, physical complaints and physiologic toxicity. In addition to pharmacological treatment with naltrexone and/or acamprosate, individuals received Medical Management (MM) provided by a health care practitioner alone or in combination with an enhanced behavioural intervention, Combined Behavioural Intervention (CBI) delivered by a trained therapist. A final group received CBI alone without pills. All participants were treated and assessed for a maximum of 16 weeks.
The attendance at therapy and research visits, and medication adherence and tolerability were good with no statistical differences between the medication and behavioural intervention groups. Over 75% of participants completed the week 16/end-of-study assessment and the average medication adherence (percent of total pills taken) was 65%. The level and types of physical complaints were similar among the groups as was the incidence of patient-reported adverse events. An observation that during combined treatment more subjects experienced diarrhoea (75% compared with 59% in the placebo group) was statistically insignificant. Plasma concentrations of liver enzymes (AST and ALT), bilirubin and creatinine did not differ significantly between the pharmacological combination and monotherapy groups. No unexpected adverse events were reported in patients with combined acamprosate and naltrexone.
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EFFICACY OF COMBINED THERAPY |
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It was observed that mean time to first relapse into heavy drinking was significantly longer (P < 0.05) in all three active treatment groups compared to placebo. There was no significant difference between the naltrexone alone and acamprosate alone treatment groups. However, time to first relapse was longer in the combination treatment group than in the acamprosate alone group. Similar differences emerged when the time to first drink was analysed, as well as in the proportion of patients who had relapsed at the study end (placebo: 75%; acamprosate: 50%; naltrexone: 35%; combined treatment: 27%). Even though further relapse occurred during the follow-up period, the relative treatment benefits between the three active treatment groups and placebo were maintained at the end of the 3-month open label phase (placebo: 80%; acamprosate: 54%; naltrexone: 53%; combined treatment: 34%; Kiefer et al., 2003b). At this time, there was no statistically significant difference between the three active treatment groups (naltrexone alone, acamprosate alone, and combination). With respect to the emergence of adverse events, combination therapy was generally well tolerated, with no unexpected novel side-effects noted. However, the incidence of diarrhoea (13.8% per visit) and nausea (5.6% per visit) was significantly greater in the combination group than with monotherapy.
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EXPLAINING RESPONSE RATES |
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A second hypothesis for the synergistic effects of acamprosatenaltrexone co-administration would be that the combination produces a more incisive anti-craving effect in each individual patient. Such a synergy could result from the two drugs interfering with distinct biological aspects of the craving process (reward and relief craving). If this hypothesis is true, we would not expect to find distinct populations who respond preferentially to either one or other of the two drugs.
Thirdly, pharmacokinetic interaction might underly the observed treatment benefit, whereby the bioavailability of one or both drugs might be enhanced by co-administration of the other drug. The observation that plasma levels of acamprosate are increased by 33% by co-administration of naltrexone (Mason et al., 2002
; Johnson et al., 2003
) favours this hypothesis.
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CONCLUSIONS |
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Combination treatment appears to be well tolerated, with no severe adverse events reported, although they imply an increased incidence of diarrhoea and nausea, perhaps due to a pharmacokinetic interaction. It can be concluded that there is accumulating evidence that the combination of acamprosate and naltrexone is both efficacious and safe. Given the large proportion of alcohol dependent subjects responding insufficiently to monotherapy with either acamprosate or naltrexone with the consequence of early relapse after detoxification, many patients might benefit from enhancing the efficacy of relapse-prevention treatment by combining acamprosate and naltrexone.
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REFERENCES |
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