Department of Psychiatry and Psychotherapy, University of Greifswald and Hospital for Addictive Disorders, Stralsund General Hospital, Germany
Received 2 November 2001; in revised form 13 October 2002; accepted 29 October 2002
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ABSTRACT |
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INTRODUCTION |
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In alcohol withdrawal, dopamine and N-methyl-d-aspartate (NMDA) levels are increased and GABA is decreased (Glue and Nutt, 1990). Benzodiazepines act as GABAA- and clomethiazole as GABAA- and glycine agonists reducing CNS hyperexcitability (Benkert and Hippius, 1998
). Withdrawal symptomatology has also been found to be positively correlated with peripheral dopamine levels on day 1 of a detoxification treatment (Heinz et al., 1996
); the D2 antagonist tiapride reduces this possible dopamine hyperactivity. Tiapride causes neither dependence nor respiratory depression. Furthermore, no reduction of vigilance occurs during treatment (Murphy et al., 1983
; Synthélabo archive data report No. 1347F690
; Synthélabo archive data report No. 1347F694
). In all of six controlled and randomized studies available, tiapride has been found to be effective in reducing global withdrawal symptomatology (Peters and Faulds, 1994
). In these studies, tiapride was compared with the following substances: carbamazepine (Agricola et al., 1982
), chlordiazepoxide (Lepola et al., 1984
), clomethiazole and placebo (Murphy et al., 1983
), tetrabamate (Renaudin and Lemant, 1981
), diazepam (Synthélabo archive data report No. 1347F694
) and meprobamate (Synthélabo archive data report No. 1347F690
). Beside global improvement, tiapride also showed efficacy in preventing delirium in those studies documenting this symptom (comparison with carbamazepine, chlordiazepoxide and clomethiazole); however, tiapride is not effective in preventing withdrawal seizures (Peters and Faulds, 1994
). In four of six studies reviewed here, tiapride demonstrated similar or higher efficacy in reducing anxiety or depression (tiapride vs chlordiazepoxide, clomethiazole, diazepam and meprobamate). In contrast, tetrabamate (trend) and carbamazepine were more effective in reducing anxiety (Renaudin and Lemant, 1981
; Agricola et al., 1982
). Mixed results were reported also concerning reduction of sweating [similar efficacy of tiapride compared with chlordiazepoxide but less efficacy compared with tetrabamate (trend) and clomethiazole]. Tiapride showed similar effectiveness compared with chlordiazepoxide, less compared with clomethiazole or tetrabamate, but higher than diazepam in reducing tremor. Sleep disorder was treated similarly effectively in studies comparing tiapride with chlordiazepoxide and diazepam, but clomethiazole and meprobamate performed better than tiapride. A recently published retrospective as well as prospective open study showed a similar efficacy of tiapride/carbamazepine and clomethiazole in terms of psychopathological and vegetative symptoms of AWS (Franz et al., 2001
).
In a MEDLINE search, we did not find a controlled study evaluating the properties of any withdrawal medication in patients with AWS who are still intoxicated. As an alternative, gamma-hydroxybutyric acid (GHB) has been described as a substance for treatment of AWS with few side effects and effective not only in acute withdrawal, but also in mid- and long-term treatment of alcohol dependence (Gallimberti et al., 1989, 1992
; DiBello et al., 1995
; Addolorato et al., 1996
, 1999
; Maître, 1997
; Poldrugo and Addolorato, 1999
; Beghe and Carpanini, 2000
; Maremmani et al., 2001
; Nimmerrichter et al., 2002
). Hertling et al.(2001)
recommended the use of GHB up to a blood alcohol concentration of 300 mg/dl; however, a controlled study in patients receiving GHB with blood alcohol concentrations higher than 100 mg/dl as a basis for this recommendation is not cited. Furthermore, in contrast to tiapride, there are some reports about a misuse and withdrawal potential of GHB (Li et al., 1998
; Williams et al., 1998
; Boyce et al., 2000
; Miotto et al., 2001
). Because of the need for therapy recommendations for treating intoxicated patients with AWS and because of lack of controlled studies evaluating this topic, we performed this study to evaluate the efficacy of tiapride in intoxicated vs non-intoxicated patients and compared it with the standard therapies diazepam and clomethiazole. We did not use tiapride as a monotherapy, because of its lack of anticonvulsive properties, and we added carbamazepine as a co-medication. We tested the following hypotheses: (1) tiapride/carbamazepine is equally effective in the treatment of the AWS among intoxicated, compared with non-intoxicated, patients; (2) tiapride/carbamazepine is equally effective compared with clomethiazole and diazepam in non-intoxicated patients; and (3) patients in tiapride/carbamazepine groups do not show a higher incidence of seizures or delirium, but (4) higher reduction of depression symptomatology compared with clomethiazole and diazepam.
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PATIENTS AND METHODS |
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RESULTS |
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AWS symptomatology (VAS) and psychopathology (SCL-90-R)
Psychological and somatic withdrawal symptoms as well as self-rated medical efficacy were assessed with daily VAS. A difference was only observed during 7 days in scale energetic/fresh vs tired/unenthusiastic (MANOVA), whereas no differences were observed in the other scales (Fig. 1). Post hoc analyses revealed reduced scores for depression between the pooled tiapride/carbamazepine groups (A and D), compared with the clomethiazole group (B) in the course of treatment. This reduction was different on a trend level (P = 0.058), correcting the VAS with the LOCF method and replacing missing data between given values with the arithmetic mean. After excluding patients with medication change during study, the difference became significant (P = 0.037). Without correction (missing values, LOCF), P was 0.005 for the total group. By excluding patients with medication change, we found a P = 0.011 for the uncorrected group. Finally, energy scores for diazepam were significantly lower compared with clomethiazole.
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DISCUSSION |
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We finally support the finding that the Alcohol Withdrawal Scale is effective and safe for use in score-guided withdrawal therapy (Wetterling et al., 1997; these authors recommended clomethiazole rather than carbamazepine in severe withdrawal).
Because tiapride does not have anticonvulsive properties, it had to be given together with carbamazepine to prevent withdrawal seizures. Carbamazepine also reduces withdrawal symptomatology. Thus, both medications contributed to the treatment effect in the tiapride/carbamazepine groups. It has also been proposed that carbamazepine may retard a kindling-like phenomenon, in which repeated episodes of alcohol withdrawal might be associated with increasing severity of withdrawal symptoms (Ballenger and Post, 1978). Thus, adding carbamazepine might have another positive effect.
Our finding of a similar efficacy across study medications is strengthened by the results of the VAS subscale subjective medication efficacy as well as by the other withdrawal symptomatology scales rated by patients. However, these results have to be interpreted cautiously, as there was no double-blind randomized design. Side effects, such as ataxia and diplopia in the tiapride/carbamazepine groups, which disappeared after discontinuation, could possibly be reduced by giving a lower dosage of carbamazepine.
From the results of our study as well as from the literature, tiapride seems to have a favourable effect upon mood variables (Shaw et al., 1987, 1994
). However, results in the VAS energy score were not replicated in the SCL-90-R depression subscale. Different time points of assessment (VAS: days 19; SCL-90-R: admission and 2 weeks later) might be the cause. Again, interpretation of results is difficult, because of bias due to the open design. Mood and anxiety as well as tiapride efficacy in alcohol withdrawal treatment might be genetically co-determined by a variant of the dopamine-2-receptor-gene (DRD2 exon 8) (Lucht et al., 2001
).
Our results have to be discussed in the light of reports showing decreased or even counter-productive effectiveness of D1 and D2 antagonists in alcoholism treatment, especially in relapse prevention (Walter et al., 2001). Dopaminergic hypofunction, as indicated by blunted apomorphine response (Heinz et al., 1996
) or SPECT (Guardia et al., 2000
), has been found to increase relapse. Treatment with flupenthixol (D1, D2, D3 antagonist) showed mixed results with either increased relapses or no effect, depending on the Lesch type (Walter et al., 2001
). Lisuride, a D2 agonist and possible D1 antagonist, showed increase in relapse (Schmidt et al., 2002
). In contrast, in a series of unpublished animal studies, tiparide showed evidence of anxiolytic properties comparable to those of diazepam (Steele et al., 1993
), but its mechanism is unclear. Anxiolytic properties might be helpful to treat post-withdrawal anxiety. Additionally, two placebo-controlled and randomized studies have suggested a positive efficacy of tiapride in relapse prevention of alcohol-dependent patients (less drinking, longer periods of abstinence, reduction of neurotic symptoms, higher self-esteem and expressed satisfaction with life situation) (Shaw et al., 1987
, 1994
). In summary, we believe that the relapse-prevention properties of tiapride should be explored further in samples characterized in relevant typologies (e.g. Lesch-typology).
A major shortcoming of this study is its open-label design, possibly causing a bias in evaluating efficacy. However, no double-blind study could be carried out in this severely affected population. For a double-blind study, any patient would have been required to give informed consent before randomization, which was not possible, because of intoxication or withdrawal. Also, the outcome criterion medication not effective (Table 1), defined as clinically rapidly deteriorating AWS, is prone to bias, because of its subjective character. On the other hand, no empirically tested safe and reliable AWS score cut-offs are available and, in our study, we considered our criterion at least sufficiently clearcut. The disadvantages of this open-label design do not refer to all results equally: distinction between intoxicated and non-intoxicated patients by BrAC can be regarded as face-valid, so the basis of the test for our main hypothesis is unimpaired by the open design. Outcome criteria seizure and delirium can be considered rather physiologically determined, being less likely altered by bias (e.g. psychological mechanisms like expectations of patients or physicians). So, we conclude our data could at least suggest that the treatment of intoxicated patients with AWS using tiapride/carbamazepine is effective and safe. However, the other outcome criteria might be biased by expectations. As our findings are not based on a double-blind randomized design, a possible advantage of tiapride/carbamazepine concerning mood results and conclusions from other scales used in the study cannot be stringently inferred from our data. The lack of studies tackling the question of treating intoxicated vs non-intoxicated patients and the vague recommendations underline the need for this study. In turn, the difficulties in performing such a study might be a reason for the lack of those studies. Furthermore, blinding of medication might be difficult, because tiapride/carbamazepine could be distinguished from diazepam or clomethiazole by absence of sedation. The incidence of main criteria is very small, so differences might have been overlooked and results should therefore be replicated in other study samples.
In summary, we suggest that a combination of tiapride/carbamazepine should be considered as a treatment strategy, especially in intoxicated, but also in non-intoxicated, patients with an AWS without delirium, particularly as it does not cause respiratory depression or have a misuse potential.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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