ALCOHOL WITHDRAWAL TREATMENT IN INTOXICATED VS NON-INTOXICATED PATIENTS: A CONTROLLED OPEN-LABEL STUDY WITH TIAPRIDE/CARBAMAZEPINE, CLOMETHIAZOLE AND DIAZEPAM

M. Lucht*, K. U. Kuehn, J. Armbruster, G. Abraham, M. Gaensicke, S. Barnow, H. Tretzel and H. J. Freyberger

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


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims and Methods: Alcohol withdrawal treatment efficacy of tiapride/carbamazepine (A) vs clomethiazole (B) vs diazepam (C) in non-intoxicated patients and vs tiapride/carbamazepine in intoxicated patients (D; breath alcohol concentration >= 1 g/l) was tested (n = 127) in a controlled randomized open-label study. Results: Efficacy and safety were not different between groups (total group: delirium, 3.9%; seizure, 0.8%), except for a lack of efficacy in 18% of intoxicated tiapride/carbamazepine patients. A change of medication in this group was necessary only when primarily intoxicated patients had reached the non-intoxicated range. Conclusions: Treatment with tiapride/carbamazepine in alcohol-intoxicated patients proved to be safe.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Frequently, sedative drugs like benzodiazepines (e.g. diazepam) or clomethiazole are recommended as a standard pharmacological treatment for the alcohol withdrawal syndrome (AWS) (Schuckit, 1995Go; Mayo-Smith, 1997Go). However, clomethiazole is not registered in the USA. These sedatives, however, show two main disadvantages: (1) benzodiazepines and clomethiazole demonstrate a high misuse potential; and (2) both medications can cause respiratory depression, especially in patients intoxicated with alcohol. Thus, administration of diazepam or clomethiazole to patients with blood/breath alcohol concentrations above 100 mg/dl is usually discouraged (Wetterling and Veltrup, 1997Go). However, intoxicated patients seek treatment for AWS quite frequently. Among alternative treatment strategies, some evidence has emerged that tiapride is an effective medication for treating AWS (Peters and Faulds, 1994Go).

In alcohol withdrawal, dopamine and N-methyl-d-aspartate (NMDA) levels are increased and GABA is decreased (Glue and Nutt, 1990Go). Benzodiazepines act as GABAA- and clomethiazole as GABAA- and glycine agonists reducing CNS hyperexcitability (Benkert and Hippius, 1998Go). Withdrawal symptomatology has also been found to be positively correlated with peripheral dopamine levels on day 1 of a detoxification treatment (Heinz et al., 1996Go); 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., 1983Go; Synthélabo archive data report No. 1347F690Go; Synthélabo archive data report No. 1347F694Go). In all of six controlled and randomized studies available, tiapride has been found to be effective in reducing global withdrawal symptomatology (Peters and Faulds, 1994Go). In these studies, tiapride was compared with the following substances: carbamazepine (Agricola et al., 1982Go), chlordiazepoxide (Lepola et al., 1984Go), clomethiazole and placebo (Murphy et al., 1983Go), tetrabamate (Renaudin and Lemant, 1981Go), diazepam (Synthélabo archive data report No. 1347F694Go) and meprobamate (Synthélabo archive data report No. 1347F690Go). 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, 1994Go). 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, 1981Go; Agricola et al., 1982Go). 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., 2001Go).

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., 1989Go, 1992Go; DiBello et al., 1995Go; Addolorato et al., 1996Go, 1999Go; Maître, 1997Go; Poldrugo and Addolorato, 1999Go; Beghe and Carpanini, 2000Go; Maremmani et al., 2001Go; Nimmerrichter et al., 2002Go). Hertling et al.(2001)Go 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., 1998Go; Williams et al., 1998Go; Boyce et al., 2000Go; Miotto et al., 2001Go). 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.


    PATIENTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients
The study was performed in a specialized hospital for addictive disorders with approximately 1000 admissions per annum (emergency as well as scheduled). A total of 127 Caucasian patients of German origin with alcohol dependence (ICD-10) admitted for alcohol detoxification therapy (118 males, nine females, mean age ± SD of 43.1 ± 9.3 years) were eligible for the study. Patients were included after developing an AWS. Those with withdrawal symptomatology beginning with breath alcohol concentration (BrAC) < 1 g/l were assigned to treatment groups (A) tiapride/carbamazepine (n = 28), (B) clomethiazole (n = 31) or (C) diazepam (n = 34) in this open-label study. Assignment took place in blocks of 10 in order of admission (first 10 patients into group A, next 10 patients into group B, next 10 patients into group C, next 10 patients again into group A, etc.). Patients with BrAC >= 1 g/l were assigned to a fourth group (D) and treated with tiapride/carbamazepine (n = 34). Erroneously, one patient with a 1 g/l BrAC was included in group (B); however, the patient was not excluded, because of the tiny difference between >=1 and <1 g/l. Patients had to meet inclusion criteria, but no exclusion criteria (Table 1Go). Informed consent was obtained as soon as patients were clinically no longer impaired by intoxication, AWS or both. Some patients could give informed consent on admission, other patients gave informed consent on day 2 of treatment. Although patients, physicians and nurses were not blind to the study medication, the study design allowed a randomization. This procedure and the study have been approved by the Joint Ethics Committee of the Ernst Moritz Arndt University Greifswald and the Chamber of Physicians Mecklenburg-Pomerania.


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Table 1. Inclusion, exclusion and main efficacy criteria
 
Methods
Within a treatment duration of 9 days, medication was given up to the following maximum doses (tiapride, 1800 mg/day; carbamazepine, 1200 mg/day; clomethiazole, 20 capsules equivalent to 3840 mg/day; diazepam, 80 mg/day). Within this range, medication was score-guided to achieve a minimum of withdrawal symptomatology as measured with the Alcohol Withdrawal Scale (Wetterling et al., 1997Go), a revised version of the CIWA-A scale (Shaw et al., 1981Go). The administration of score-guided or symptom-triggered medication as part of an individualized treatment decreased both treatment duration and amount of benzodiazepine used, and was as efficacious as standard fixed-schedule therapy for alcohol withdrawal in a study published by Saitz et al.(1994)Go. The dosage of orally administered medication was adjusted to the individual Alcohol Withdrawal Scale score based on published guidelines: for clomethiazole, Benkert and Hippius (1998)Go recommend the administration up to 3840 mg/day (=20 capsules) with a maximum dose of 1536 mg (eight capsules) within 2 h. For diazepam, a maximum dose of 80 mg/day was given, but 10 mg every 2–4 h was not exceeded. In our study, tiapride and carbamazepine were given in a ratio of 1.5 (±0.1):1 (tiapride: carbamazepine) on days 1–4 and 1.0 (±0.4):1 on days 5–9 [tiapride/carbamazepine (BrAC < 1 g/l)] according to the long-standing clinical routine of our hospital [tiapride/carbamazepine (BrAC >= 1 g/l): 1.4 (±0.1):1 and 1.0 (±0.1):1, respectively]. A tiapride:carbamazepine ratio of 1.5 in the study performed by Franz et al. (2001)Go was similar to that used in our study; daily dosages are given in Table 2Go. Alcohol Withdrawal Scale score, incidence of delirium, seizures and side effects were assessed daily; subjective withdrawal symptomatology was rated by patients with visual analogue scales (VAS) assessing energy, tension, sweating, restlessness, tremor, subjective medication efficacy and sleep for the first 7 days [for missing values, the last observation carried forward (LOCF) method was used]. For psychiatric symptomatology, SCL-90-R, a 90-item self-report rating scale widely used to measure current psychopathology [recent 7 days (Derogatis, 1983Go)] was used. SCL-90-R has been found to be associated with aspects of outcome of alcohol detoxification and rehabilitation treatment in a pilot study (Lucht et al., 2002Go). SCL-90-R was applied on admission (t1) and on discharge (t2). For this study, we only used t2 measures of patients with treatment durations between 12 and 15 days to control for time dependence of change of psychopathology. Other study criteria are given in Table 1Go.


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Table 2. Medication dosages by medication group and day of treatment
 
Data were analysed with SPSS for Windows 10.0. Differences between groupings were analysed by analysis of variance (ANOVA). Outcome variables as dependent variables over time with medication as the independent variable were analysed with repeated-measures multivariate analysis of variance (MANOVA). Categorical tests were examined for significance with the {chi}2 test.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Sample, outcome and safety
No differences in sociodemographic and history variables between the four medication groups were observed (Table 3Go), with a few exceptions: in the diazepam group, a surplus of separated/divorced patients was found and, as expected, breath alcohol concentrations in group D were higher, compared with the other groups. Main outcome criterion safety (delirium, seizures) during therapy was similar across all four groups (Table 4Go). However, change of medication due to lack of treatment efficacy showed a higher incidence in the tiapride/carbamazepine (BrAC >= 1 g/l) group D ({chi}2 = 11.587, df = 3; P = 0.009) but not in the groups below 1 g/l, with only two such events in the clomethiazole group. It is, however, important to state that necessity of change occurred only when BrAC was below 1 g/l. So, the therapeutic dilemma of giving a respiratory depressant as a withdrawal medication in patients with BrAC >= 1g/l did not occur. In all patients with a change of medications, further therapy after change was without problems. Within the criterion side effects, a significantly higher incidence in both tiapride/carbamazepine groups with transient ataxia or diplopia due to carbamazepine was observed ({chi}2 = 11.995, df = 3; P = 0.007). In no case was a change of medication necessary, as side effects faded during scheduled discontinuation of carbamazepine. Also, no change of medication was necessary for those leaving the 2-week detoxification programme earlier (transferral, early discharge); such patients left after scheduled discontinuation of medications (Table 4Go).


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Table 3. Sociodemography and history of patients with alcohol withdrawal syndrome (AWS)
 

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Table 4. Therapy outcome: course, efficacy and safety
 
Alcohol Withdrawal Scale
Differences between Alcohol Withdrawal Scale scores (dependent variable) were tested for differences between four medication groups as the independent variable with ANOVA for each time point (9 days, morning and evening) separately. No differences (5% level of significance) were observed in Alcohol Withdrawal Scale total scores (evening), only in the morning of day 6 group B (clomethiazole) showed a higher score than group D [tiapride/carbamazepine (BrAC >= 1 g/l); ANOVA: F = 3.041; df = 3; P = 0.033; post hoc test (Scheffé): P = 0.085]. Alcohol Withdrawal Scale scores were assessed during pharmacotherapy days only, so the number of probands varied between each of the analyses. Alcohol Withdrawal Scale scores represent withdrawal symptomatology being already reduced by medication and thus therapeutic efficacy.

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. 1Go). 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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Fig. 1. Visual analogue scale (VAS) ‘energetic/fresh vs tired/unenthusiastic’. For missing values the intention-to-treat, last observation carried forward (LOCF) approach was used. Missing values within a row of known values were calculated with linear interpolation. Repeated measures ANOVA: effects between subjects: F = 4.046; P = 0.020. Post hoc tests: tiapride/carbamazepine (tia/CBZ) vs diazepam (dzp), P = 0.895; tiapride/carbamazepine vs clomethiazole (clomt), P = 0.058; diazepam vs clomethiazole, P = 0.038.

 
Psychopathology was assessed with SCL-90-R. Changes of scores (admission t1 – discharge t2) were not significantly different across medication groups (ANOVA), except for paranoid ideation and psychoticism. We only included patients with a duration of 12–15 days of treatment in order to control for time dependence in psychopathology (Table 5Go).


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Table 5. Psychopathology in alcohol withdrawal syndrome treatment by medication
 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
According to a MEDLINE search, this is the first controlled study comparing AWS treatment between intoxicated and non-intoxicated patients. Patients with the AWS beginning with a BrAC >= 1 g/l could all be treated effectively with tiapride/carbamazepine within this higher BrAC range. Crossing the threshold towards BrAC below 1 g/l during treatment, six patients had to be given other medications because of lack of efficacy. Although a treatment change was necessary in these six patients, the strategy starting with tiapride/carbamazepine above a 1 g/l BrAC was therefore effective and safe. Patient groups treated with tiapride/carbamazepine (intoxicated as well as non-intoxicated) were not different regarding safety (delirium and seizure), compared with the standard medications diazepam and clomethiazole. In the non-intoxicated groups, efficacy was also similar. Overall, a delirium incidence rate of 3.9% in our study was considerably lower, compared with literature reports of about 10% in patients undergoing detoxification (Victor and Laureno, 1978Go; Wetterling et al., 1994Go). In general, findings of tiapride efficacy are in line with the literature; however, comparability with the cited studies is limited, because, apart from differences in the study design, dose regimens varied widely from 600 mg tiapride per day to 1800 mg/day (plus carbamazepine in our study) (Peters and Faulds, 1994Go). Patients with a wide range of AWS severities were included in our study. As medication administration was score-guided, widely varying doses reflect this variation in AWS severity.

We finally support the finding that the Alcohol Withdrawal Scale is effective and safe for use in score-guided withdrawal therapy (Wetterling et al., 1997Go; 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, 1978Go). 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., 1987Go, 1994Go). However, results in the VAS ‘energy’ score were not replicated in the SCL-90-R depression subscale. Different time points of assessment (VAS: days 1–9; 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., 2001Go).

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., 2001Go). Dopaminergic hypofunction, as indicated by blunted apomorphine response (Heinz et al., 1996Go) or SPECT (Guardia et al., 2000Go), 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., 2001Go). Lisuride, a D2 agonist and possible D1 antagonist, showed increase in relapse (Schmidt et al., 2002Go). In contrast, in a series of unpublished animal studies, tiparide showed evidence of anxiolytic properties comparable to those of diazepam (Steele et al., 1993Go), 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., 1987Go, 1994Go). 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 1Go), 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.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
We gratefully acknowledge staff of the Hospital for Addictive Disorders, Stralsund, for excellent collaboration, and I. Ulrich, C. Boeck and D. Niemann for data processing. This study was supported by Sanofi-Synthélabo, Berlin.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed at: Department of Psychiatry and Psychotherapy, University of Greifswald, Rostocker Chaussee 70, D-18437 Stralsund, Germany. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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