Anticonvulsants for alcohol withdrawal (Review)

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1 Minozzi S, Amato L, Vecchi S, Davoli M This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 3

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure ADDITIONAL SUMMARY OF FINDINGS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Anticonvulsant versus Placebo, Outcome 1 Alcohol Withdrawal Seizures post treatment. 101 Analysis 1.2. Comparison 1 Anticonvulsant versus Placebo, Outcome 2 Adverse events Analysis 1.3. Comparison 1 Anticonvulsant versus Placebo, Outcome 3 Dropout Analysis 1.4. Comparison 1 Anticonvulsant versus Placebo, Outcome 4 Dropout due to adverse events Analysis 2.1. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 1 Alcohol withdrawal seizures Analysis 2.2. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 2 Alcohol withdrawal delirium Analysis 2.3. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 3 CIWA-Ar score (48 hrs) Analysis 2.4. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 4 CIWA-Ar score (end of treatment) Analysis 2.5. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 5 Global Doctor s Assessment of Efficacy. 109 Analysis 2.6. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 6 Adverse events Analysis 2.7. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 7 Severe, life-treatening adverse events Analysis 2.8. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 8 Dropout Analysis 2.9. Comparison 2 Anticonvulsant versus Other Drugs, Outcome 9 Dropout due to adverse events Analysis 3.1. Comparison 3 Anticonvulsant 1 versus Anticonvulsant 2, Outcome 1 Adverse events Analysis 3.2. Comparison 3 Anticonvulsant 1 versus Anticonvulsant 2, Outcome 2 Dropout Analysis 4.1. Comparison 4 (Anticonvulsant + Other) versus Other, Outcome 1 Alcohol withdrawal delirium Analysis 4.2. Comparison 4 (Anticonvulsant + Other) versus Other, Outcome 2 Severe, life-threatening adverse events. 117 Analysis 4.3. Comparison 4 (Anticonvulsant + Other) versus Other, Outcome 3 Dropout Analysis 5.1. Comparison 5 Anticonvulsant1 + other vs anticonvulsant 2, Outcome 1 alcohol withdrawal seizures i

3 Analysis 5.2. Comparison 5 Anticonvulsant1 + other vs anticonvulsant 2, Outcome 2 alcohol withdrawal delirium Analysis 5.3. Comparison 5 Anticonvulsant1 + other vs anticonvulsant 2, Outcome 3 adverse events Analysis 5.4. Comparison 5 Anticonvulsant1 + other vs anticonvulsant 2, Outcome 4 severe, life threatening adverse events Analysis 5.5. Comparison 5 Anticonvulsant1 + other vs anticonvulsant 2, Outcome 5 drop out ADDITIONAL TABLES APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT NOTES INDEX TERMS ii

4 [Intervention Review] Anticonvulsants for alcohol withdrawal Silvia Minozzi 1, Laura Amato 1, Simona Vecchi 1, Marina Davoli 1 1 Department of Epidemiology, ASL RM/E, Rome, Italy Contact address: Silvia Minozzi, Department of Epidemiology, ASL RM/E, Via di Santa Costanza, 53, Rome, 00198, Italy. Editorial group: Cochrane Drugs and Alcohol Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, Review content assessed as up-to-date: 29 December Citation: Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD DOI: / CD pub3. Background A B S T R A C T Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Besides benzodiazepines, anticonvulsants are often used for the treatment of alcohol withdrawal symptoms. Anticonvulsants drugs are indicated for the treatment of alcohol withdrawal syndrome, alone or in combination with benzodiazepine treatments. In spite of the wide use, the exact role of the anticonvulsants for the treatment of alcohol withdrawal has not yet bee adequately assessed. Objectives To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal. Search methods We searched Cochrane Drugs and Alcohol Group Register of Trials (December 2009), PubMed, EMBASE, CINAHL (1966 to December 2009), EconLIT (1969 to December 2009). Parallel searches on web sites of health technology assessment and related agencies, and their databases. Selection criteria Randomized controlled trials (RCTs) examining the effectiveness, safety and overall risk-benefit of anticonvulsants in comparison with a placebo or other pharmacological treatment. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. Data collection and analysis Two authors independently screened and extracted data from studies. Main results Fifty-six studies, with a total of 4076 participants, met the inclusion criteria. Comparing anticonvulsants with placebo, no statistically significant differences for the six outcomes considered. Comparing anticonvulsant versus other drug, 19 outcomes considered, results favour anticonvulsants only in the comparison carbamazepine versus benzodiazepine (oxazepam and lorazepam) for alcohol withdrawal symptoms (CIWA-Ar score): 3 studies, 262 participants, MD (-1.89 to -0.20), none of the other comparisons reached statistical significance. Comparing different anticonvulsants no statistically significant differences in the two outcomes considered. 1

5 Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results from one study, 72 participants, favour paraldehyde plus chloral hydrate versus chlordiazepoxide, for the severe-life threatening side effects, RR 0.12 (0.03 to 0.44). Authors conclusions Results of this review do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS. There are some suggestions that carbamazepine may actually be more effective in treating some aspects of alcohol withdrawal when compared to benzodiazepines, the current first-line regimen for alcohol withdrawal syndrome. Anticonvulsants seem to have limited side effects, although adverse effects are not rigorously reported in the analysed trials. P L A I N L A N G U A G E S U M M A R Y Anticonvulsants for alcohol withdrawal syndrome There are limited data on anticonvulsants versus placebo for alcohol withdrawal syndrome, while comparisons with other drugs show no clear differences. This Cochrane review summarizes evidence from forty-eight randomised controlled trials evaluating the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal symptoms. There are limited data comparing anticonvulsants versus placebo and no clear differences between anticonvulsants and other drugs in the rates of therapeutic success. Data on safety outcomes are sparse and fragmented. There is a need for larger, well-designed studies in this field. 2

6 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Anticonvulsant versus Placebo for alcohol withdrawal Patient or population: patients with alcohol withdrawal Settings: Intervention: Anticonvulsant versus Placebo Outcomes Illustrative comparative risks*(95% CI) Relative effect (95% CI) No of Participants (studies) Assumed risk Corresponding risk Control Anticonvulsant versus Placebo Alcohol Withdrawal Seizures post treatment - Any Anticonvulsant vs. Placebo Study population RR 0.61 (0.31 to 1.2) 110per per1000 (34to132) 883 (9 studies) Medium risk population 167per per1000 (52to200) Alcohol Withdrawal Seizures post treatment - Phenytoin vs. Placebo Study population RR 0.78 (0.35 to 1.77) 180per per1000 (63to319) 381 (4 studies) Medium risk population 176per per1000 (62to312) Adverse events Study population RR 1.56 (0.74 to 3.31) 663 (7 studies) Quality of the evidence (GRADE) moderate 1 moderate 2 moderate 3 Comments 3

7 50per per1000 (37to165) Medium risk population 34per per1000 (25to113) Dropout - Any Anticonvulsant vs. Placebo Study population RR 0.82 (0.5 to 1.34) 208per per1000 (104to279) 344 (7 studies) moderate 4 Medium risk population 182per per1000 (91to244) Dropout - Chlormethiazole vs. Placebo Study population RR 1.05 (0.22 to 5.11) 44per per1000 (10to225) 140 (3 studies) moderate 5 Medium risk population 21per per1000 (5to107) *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention(and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. Very low quality: We are very uncertain about the estimate. 4

8 1 Allocationconcealmntadequateonlyin1on9includedstudies 2 Allcationconcealmentadequatein1/4studies 3 In3studiesresultswerenotestimableduenoadverseeventsoccurred 4 Allocationconcealmentadequatein2on7includedstudies 5 only3studiesconsidered xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 5

9 B A C K G R O U N D Description of the condition Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Dependence on alcohol is associated with both physiological symptoms such as tolerance and withdrawal, and behavioural symptoms such as impaired control over drinking (Hasin 1990). Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use that has been heavy or prolonged. The clinical presentation varies from mild to serious and the onset of symptoms typically occurs a few hours after the last alcohol intake. The most common manifestations are tremor, restlessness, insomnia, nightmares, paroxysmal sweats, tachycardia, fever, nausea, vomiting, seizures, hallucinations (auditory, visual, tactile), increased agitation, tremulousness and delirium. These symptoms involve a wide range of neurotransmitter circuits that are implicated in alcohol tolerance and reflect a homeostatic readjustment of the central nervous system (De Witte 2003; Koob 1997; Nutt 1999; Slawecki 1999). Long-term alcohol consumption affects brain receptors that undergo adaptive changes in an attempt to maintain normal function. Some of the key changes involve reduced brain gamma-amino butyric acid (GABA) levels and GABA- receptor sensitivity (Dodd 2000; Gilman 1996; Kohl 1998; Petty 1993) and activation of glutamate systems (Tsai 1995), which lead to nervous system hyperactivity in the absence of alcohol. The advances in knowledge of neurobiology and neurochemistry have prompted the use of drugs in the treatment of alcohol dependence and withdrawal that act through these GABA pathways. Description of the intervention Besides benzodiazepines, anticonvulsants are often used for the treatment of alcohol withdrawal symptoms. A meta-analysis of studies concerning pharmacological therapies of alcohol withdrawal (Mayo-Smith 1997) has suggested that carbamazepine, an anticonvulsant agent that is widely used in particular in Europe, may have modest beneficial effects on selected signs and symptoms of withdrawal. Carbamazepine may also be considered as adjunctive therapy to benzodiazepines, the classic treatment for alcohol withdrawal. How the intervention might work Anticonvulsants drugs are indicated for the treatment of alcohol withdrawal syndrome, alone or in combination with benzodiazepine treatments. In spite of the wide use, the exact role of the anticonvulsants for the treatment of alcohol withdrawal has not yet been adequately assessed. Moreover not all patients may need pharmacological treatment and it is unknown whether different anticonvulsants and different regimens of administration (e.g. symptom-triggered versus fixed schedule) may have the same merits. Why it is important to do this review The need to research non-benzodiazepines effective in Alcohol Withdrawal is related to the risks of side-effects and the potential of abuse of benzodiazepine (Leggio 2008). Since there are several anticonvulsant agents and a large amount of evidence of their use in the management of alcohol withdrawal has been published during the last years, an updated systematic is needed in order to clarify the exact role of anticonvulsants in the management of alcohol withdrawal. The purpose of this systematic review is to examine the evidence in the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal symptoms. Results of a previous version of a Cochrane Systematic review (Polycarpou 2005) on anticonvulsants efficacy and safety are not conclusive. New trials have been published and the review needs update. This review has a parallel one on benzodiazepines for alcohol withdrawal (Amato 2010) and together they are part of a series of reviews and protocols on the efficacy of pharmacological treatment (Acamprosate GHB, nitrous oxide, magnesium) for alcohol withdrawal (Gillman 2007; Leone 2010; Fox 2003; Tejani 2010). O B J E C T I V E S The objectives of this systematic review are: 1. To evaluate the effectiveness of anticonvulsants in the treatment of alcohol withdrawal. 2. To evaluate the safety of anticonvulsants in the treatment of the alcohol withdrawal symptoms (AWS). M E T H O D S Criteria for considering studies for this review Types of studies Randomized Controlled Trials (RCT) and Controlled Clinical Trials (CCT) evaluating the efficacy, safety and overall risk-benefit of anticonvulsants for the treatment of alcohol withdrawal. 6

10 Types of participants Alcohol dependent patients diagnosed in accordance with appropriate standardized criteria (e.g., criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R) or ICD) who experienced alcohol withdrawal symptoms regardless of the severity of the withdrawal manifestations. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. The history of previous treatments was considered, but it was not an eligibility criterion. Types of interventions - Experimental intervention Anticonvulsants drugs alone or in combination with other drugs - Control Intervention Placebo; Other pharmacological interventions Types of comparisons 1. anticonvulsant versus placebo; 2. anticonvulsant versus other drugs; 3. different anticonvulsants between themselves; 4. anticonvulsant combined with other drugs versus other drugs. 5. anticonvulsant 1 combined with other drugs versus anticonvulsant 2 Types of outcome measures Primary outcomes Efficacy outcomes 1. Alcohol withdrawal seizures as number of subjects experiencing seizures 2. Alcohol withdrawal delirium as number of subjects experiencing delirium 3. Alcohol withdrawal symptoms as measured by prespecified scales(as the CIWA-Ar score) 4. Global improvement of overall alcohol withdrawal syndrome as measured in pre-specified scales ( as number of patients with global improvement, global doctors assessment of efficacy, Patients assessment of efficacy) 5. Craving as measured by prespecified scales Safety outcomes 1. Adverse events as number of subjects experiencing at least one adverse event 2. Severe, life-threatening adverse events as measured by number of subjects experiencing severe, life threatening adverse events Acceptability outcomes 1. Dropout 2. Dropout due to adverse events Secondary outcomes 1. Additional medication needed 2. Length of stay in intensive therapy 3. Mortality 4. Quality of life Search methods for identification of studies Electronic searches Relevant trials were obtained from the following sources: 1. Cochrane Drugs and Alcohol Group Register of Trials (December 2009) 2. PubMed (January December 2009) 3. EMBASE (January December 2009) 4. CINAHL (January December 2009) 5. EconLIT (1969 to December 2009) We compiled detailed search strategies for each database searched, for detail see Appendix 1; Appendix 2; Appendix 3; Appendix 4 Searching other resources We also searched: 1. the reference lists of all relevant papers to identify further studies. 2. conference proceedings likely to contain trials relevant to the review. We contacted investigators seeking information about unpublished or incomplete trials.all searches included non-english language literature and studies with English abstracts were assessed for inclusion. When considered likely to meet inclusion criteria, studies were translated. Data collection and analysis Selection of studies Two authors independently screened the titles and abstracts of all publications, obtained through the search strategy. All potentially eligible studies were obtained as full articles and two authors independently assessed these for inclusion. In doubtful or controversial cases, all identified discrepancies were discussed and reached consensus on all items. Data extraction and management Two authors independently extracted data from published sources, where differences in data extracted occurred this was resolved through discussion. Where required additional information was obtained through collaboration with the original authors. 7

11 Assessment of risk of bias in included studies The risk of bias assessment for RCTs and CCTs in this review was performed using four out of the six criteria recommended by the Cochrane Handbbok (Higgins 2008). The recommended approach for assessing risk of bias in studies included in Cochrane Review is a two-part tool, addressing four specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data). The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry. This is achieved by answering a pre-specified question about the adequacy of the study in relation to the entry, such that a judgement of indicates low risk of bias, No indicates high risk of bias, and Unclear indicates unclear or unknown risk of bias. To make these judgments we will use the criteria indicated by the handbook adapted to the addiction field. See Appendix 5 for details. The domains of sequence generation and allocation concealment (avoidance of selection bias) will be addressed in the tool by a single entry for each study. Blinding of participants, personnel and outcome assessor (avoidance of performance bias and detection bias) was considered separately for objective outcomes (e.g. drop out, drop out due to adverse events, seizures, delirium, adverse events) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, craving, psychiatric symptoms; improvements assessed by doctors and patients). Incomplete outcome data (avoidance of attrition bias) was considered for all outcomes except for the drop out from the treatment, which is very often the primary outcome measure in trials on addiction. Assessment of reporting biases Funnel plot (plot of the effect estimate from each study against the sample size or effect standard error) was not used to assess the potential for bias related to the size of the trials, because all the included studies had small sample size and not statistically significant results. Data synthesis The outcomes from the individual trials have been combined through meta-analysis where possible (comparability of intervention and outcomes between trials) using a fixed effect model unless there was significant heterogeneity, in which case a random effect model have been used. If all arms in a multi-arm trial are to be included in the metaanalysis and one treatment arm is to be included in more than one of the treatment comparisons, then we divided the number of events and the number of participants in that arm by the number of treatment comparisons made. This method avoid the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. It compromise the precision of the pooled estimate slightly. Sensitivity analysis To assess the effect of methodological quality on the results, we first performed a graphical inspection of any effect sorting the results on the forest plots according to risk of bias for sequence generation, allocation concealment, blinding (subjective outcomes) ; if we found a difference in the results between studies at low, unclear, high risk of bias, we performed a sensitivity analysis excluding studies at high risk of bias Measures of treatment effect Dichotomous outcomes were analysed calculating the Relative risk (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals. Continuous outcomes were analysed calculating the MD or the SMD with 95%CI. In case of missing standard deviation of the differences from baseline to the end of treatment, the standard deviation were imputed using the standard deviation of the mean at the end of treatment for each group. Assessment of heterogeneity Statistically significant heterogeneity among primary outcome studies will be assessed with Chi-squared (Q) test and I-squared (Higgins 2008). A significant Q ( P<.05) and I-squared of at least 50% will be considered as statistical heterogeneity R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification. Results of the search We identified 993 reports from all electronic databases searched excluding duplicate, 899 were excluded on basis of title and abstract; 91 articles were retrieved in full text for more detailed evaluation, 35 of which were excluded, 56 satisfied all the criteria to be included in the review. Three studies are awaiting assessment because we are trying to find the full text. See Figure 1 to see the Flow chart showing the identification of included trials. 8

12 Figure 1. Flow chart showing identification of studies Included studies 56 studies met the inclusion criteria, with a total of 4076 participants. For a description of the characteristics of the included studies, see Characteristics of included studies table Country of origin of the included studies 33 studies were conducted in Europe, 18 in North America, 4 in Australia/New Zealand, and one in Asia. Number of studies per type of comparison 1. Anticonvulsant versus placebo (No. = 17 studies, 17 comparisons) (Alldredge 1989; Bjorkqvist 1976; Blanchard 1985; Bonnet 2003; Burroughs 1985a; Chance 1991; Gann 2004; Glatt 1966; Golbert 1967; Koethe 2007; Krupitsky 2007; Lambie 1980; Murphy 1983; Rathlev 1994; Reoux 2001; Sampliner 1974; Stanhope 1989) 2. Anticonvulsant versus other drug (No. = 32 studies, 36 comparisons) (Agricola 1982; Borg 1986; Borg 1986; Burroughs 1985a; Burroughs 1985a; Burroughs 1985b; Burroughs 1985b; Choi 2005; Dencker 1978; Elsing 1996; Elsing 2009; Golbert 1967; Kaim 1972; Kaim 1972; Kalyoncu 1996; Koppi 1987; Kramp 1978; Krupitsky 2007; Lapierre 1983; Longo 2002; Lucht 2003; Madden 1969; Malcolm 1989; Malcolm 2002; Malcolm 2007; Manhem 1985; McGrath 1975; Murphy 1983; Nimmerichter 2002; Radouco-Thomas 1989; Robinson 1989; Santo 1985; Stuppaeck 1992; Stuppaeck 1998; Thompson 1975; Tubridy 1988) 3. Different anticonvulsants between themselves (No.= 10 studies, 11 comparisons) (Flygering 1984; Golbert 1967; Kaim 1972; Krupitsky 2007; Krupitsky 2007; Mariani 2006; Ritola 1981; Rosenthal 1998; Schik 2005; Seifert 2004; Teijeiro 1975) 4. Anticonvulsant combined with other drug versus other drug (No. = 6 studies, 7 comparisons) (Balldin 1986; Golbert 1967; Lucht 2003; Myrick 2000; Spies 1996; Spies 1996; Rothstein 1973) 5. Anticonvulanst combined with other drug vs different anticonvulsant (No=1 study) (Croissant 2009) For a more detailed information about the comparisons considered in the studies, see Additional Table 1; Table 2; Table 3; Table 4; Table 5 9

13 Excluded studies 35 studies did not meet the criteria for inclusion in this review. The grounds for exclusion were: type of intervention not in the inclusion criteria: 13 studies; study design not in the inclusion criteria: 12 studies; type of outcomes measures not in the inclusion criteria: 6 studies; duplicate publication: 2 studies, outcome measures presented in a way not suitable for meta-analysis: 2 studies. See Excluded studies Table Risk of bias in included studies All the studies were randomised controlled trials. Allocation The sequence generation was adequate in 17 studies, unclear in 34 and inadequate in 5 studies; the allocation concealment was adequate in 9 studies, unclear in 42 and inadequate in 5 studies Blinding Blinding for subjective outcomes was adequate in 33 studies, it was unclear in 10 and inadequate in 13 Blinding for objective outcomes was adequate in 52 studies and unclear in 4 studies Incomplete outcome data Incomplete outcome data were addressed in 48 studies, it was unclear in 6 studies and were not addressed in 2 studies. See Included studies Table and Figure 2 and Figure 3 for a more detailed description of risk of bias across the studies. Figure 2. Methodological quality graph: review authors judgements about each methodological quality item presented as percentages across all included studies. 10

14 Figure 3. Methodological quality summary: review authors judgements about each methodological quality item for each included study. 11

15 With a graphical inspection of the forest plots sorting studies according to the risk of bias, we didn t find any systematic difference in the results between studies at high risk of bias and studies at low or unclear risk of bias. So sensitivity analysis excluding studies at high risk of bias was not performed Effects of interventions See: Summary of findings for the main comparison Anticonvulsant versus Placebo for alcohol withdrawal; Summary of findings 2 Anticonvulsant versus Other Drugs for alcohol withdrawal We only performed meta-analysis for the studies that had directly comparable interventions and used exactly the same rating scales for continuous outcome measures or had the same binary outcomes. The rest of the data retrieved from the studies (single comparison data) were not synthesized quantitatively. The following results refer to the cases where quantitative synthesis was performed. The Results are split into four sections referring to the four main comparisons: 1. Anticonvulsant versus Placebo, 2. Anticonvulsant versus Other Drug, 3. Anticonvulsant 1 versus Anticonvulsant 2, 4. (Anticonvulsant + Other drug) versus Other Drug. 5. (Anticonvlusant 1 + other drug) versus Anticonvulsant 2 The outcomes are categorized as primary efficacy outcomes and secondary efficacy outcomes, according to the protocol. We dived them according to efficacy, safety and acceptability. We decided to not consider separately the comparison between anticonvulsants and benzodiazepines because this is due in the parallel review (Amato 2010) on benzodiazepines for alcohol withdrawal For a summary of results of some important outcomes see Summary of findings table 1 and Summary of findings table 2 Comparison 1 Anticonvulsant versus placebo: Efficacy 1.1 Alcohol withdrawal seizures Any Anticonvulsants versus placebo, 9 studies (Alldredge 1989; Bonnet 2003; Chance 1991; Koethe 2007; Lambie 1980; Murphy 1983; Rathlev 1994; Sampliner 1974; Stanhope 1989), 883 participants, RR 0.61 (0.31 to 1.20), the result is not statistically significant, see Analysis 1.1 or Figure 4 Figure 4. Forest plot of comparison: 1 Anticonvulsant versus Placebo, outcome: 1.1 Alcohol Withdrawal Seizures post treatment. 12

16 1.1.2 Phenytoin versus placebo, 4 studies, (Alldredge 1989; Chance 1991; Rathlev 1994; Sampliner 1974), 381 participants, RR 0.78 (0.35 to 1.77), the result is not statistically significant, see Analysis 1.1 or Figure 4 Safety 1.2 Adverse events as number of participants with at least one adverse event 7 studies (Bjorkqvist 1976; Bonnet 2003; Burroughs 1985b; Chance 1991; Krupitsky 2007; Lambie 1980; Stanhope 1989), 516 participants, RR 1.56 (0.74, 3.31), the result is not statistically significant, see Analysis 1.2 or Figure 5 Figure 5. Forest plot of comparison: 1 Anticonvulsant versus Placebo, outcome: 1.4 Adverse events (N. of patients with at least one adverse event). Acceptability 1.3 Dropout Any Anticonvulsants versus placebo, 7 studies (Bjorkqvist 1976; Blanchard 1985; Bonnet 2003; Burroughs 1985a; Gann 2004; Glatt 1966; Reoux 2001), 344 participants, RR 0.82 (0.50 to 1.34), the result is not statistically significant, see Analysis 1.3 or Figure 6 13

17 Figure 6. Forest plot of comparison: 1 Anticonvulsant versus Placebo, outcome: 1.5 Dropout Chlormethiazole versus placebo, 3 studies (Burroughs 1985a; Gann 2004; Glatt 1966), 140 participants, RR 1.05 (0.22 to 5.11), the result is not statistically significant, see Analysis 1.3 or Figure Dropout due to adverse events 8 studies (Bjorkqvist 1976; Blanchard 1985; Bonnet 2003; Burroughs 1985a; Chance 1991; Koethe 2007; Lambie 1980; Stanhope 1989), 623 participants, 0.67 (0.13, 3.36), the result is not statistically significant, see Analysis 1.4 or Figure 7 Figure 7. Forest plot of comparison: 1 Anticonvulsant versus Placebo, outcome: 1.6 Dropout due to adverse events Comparison 2 Anticonvulsant versus Other: Efficacy 2.1 Alcohol withdrawal seizures Any Anticonvulsants versus any Other, 12 studies (Agricola 1982; Borg 1986; Kaim 1972; Koppi 1987; Kramp 1978; Lucht 2003; Murphy 1983; Nimmerichter 2002;Radouco-Thomas 1989 ;Robinson 1989; Stuppaeck 1992; Tubridy 1988), 880 par- 14

18 ticipants, RR 0.58 (0.22 to 1.58), the result is not statistically significant, see Analysis 2.1 or Figure 8 Figure 8. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.1 Alcohol Withdrawal Seizures Chlormethiazole versus Benzodiazepine, 2 studies (Lucht 2003; Tubridy 1988), 155 participants, RR 0.35 (0.01 to 8.33), the result is not statistically significant, see or Figure Alcohol withdrawal delirium Any Anticonvulsants versus any Other, 6 studies (Kalyoncu 1996; Lucht 2003; Manhem 1985;McGrath 1975; Murphy 1983; Stuppaeck 1992; ), 394 participants, RR 0.88 (0.23, 3.42), the result is not statistically significant, see Analysis 2.2 or Figure 9 15

19 Figure 9. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.2 Alcohol Withdrawal Delirium Carbamazepine versus Benzodiazepine, 2 studies (Kalyoncu 1996; Stuppaeck 1992), 125 participants, RR 1.01 (0.04 to 24.43), the result is not statistically significant, see Analysis 2.2 or Figure CIWA-Ar score at 48 hours Any Anticonvulsants versus any Other, 4 studies (Malcolm 1989; Malcolm 2002; Nimmerichter 2002; Stuppaeck 1992), 358 participants, MD (-0.95 to 0.53), the result is not statistically significant, see Analysis Carbamazepine versus Benzodiazepine, 3 studies (Malcolm 1989; Malcolm 2002; Stuppaeck 1992), 260 participants MD (-1.88 to 0.67), the result is not statistically significant, see Analysis CIWA-Ar score at the end of treatment Any Anticonvulsants versus any Other, 4 studies (Malcolm 1989; Malcolm 2002; Nimmerichter 2002; Stuppaeck 1992), 358 participants, MD (-1.76 to 0.31), the result is not statistically significant, see Analysis Carbamazepine versus Benzodiazepine, 3 studies (Malcolm 1989; Malcolm 2002; Stuppaeck 1992), 260 participants MD (-1.89 to -0.20), the result is statistically significant in favour of carbamazepine, see Analysis Global Doctor s Assessment of Efficacy 2 studies (Kramp 1978; Tubridy 1988), 181 participants, RR 0.97 (0.88 to 1.08), the result is not statistically significant, see Analysis 2.5 Safety 2.6 Adverse events as number of participants with at least one adverse event Any Anticonvulsants versus any Other (Agricola 1982; Burroughs 1985a; Burroughs 1985b;Elsing 2009; Krupitsky 2007; Lapierre 1983; Longo 2002; Lucht 2003; Nimmerichter 2002; Radouco-Thomas 1989 ;Robinson 1989; Santo 1985; Stuppaeck 1992; Tubridy 1988), 14 studies, 726 participants, RR 0.71(0.45 to 1.12), the result is not statistically significant, see Analysis 2.6 or Figure 10 16

20 Figure 10. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.14 Adverse events (number of patient with at least one adverse event) Chlormethiazole versus Benzodiazepine, (Burroughs 1985a; Burroughs 1985b; Lapierre 1983; Lucht 2003; Tubridy 1988), 5 studies, 235 participants, RR 0.75 (0.35 to 1.59), the result is not statistically significant, see Analysis 2.6 or Figure Severe, life-treating adverse events Any Anticonvulsants versus any Other, 12 studies (Agricola 1982; Burroughs 1985a; Burroughs 1985b; Dencker 1978;Elsing 2009; Koppi 1987; Krupitsky 2007; Lapierre 1983; Radouco- Thomas 1989; Santo 1985; Thompson 1975; Tubridy 1988), 578 participants, RR 2.38 (0.33 to 17.24), the result is not statistically significant, see Analysis 2.7 or Figure 11 17

21 Figure 11. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.15 Severe, life-treating adverse events Chlormethiazole versus Benzodiazepine, (Burroughs 1985a; Burroughs 1985b; Lapierre 1983; Tubridy 1988), 4 studies, 170 participants, RR 0.69 (95% CI, 0.09 to 5.33), the result is not statistically significant, see Analysis 2.7 or Figure 11 Acceptability 2.8 Dropout Any Anticonvulsants versus any Other, 20 studies (Agricola 1982; Borg 1986; Burroughs 1985a; Burroughs 1985b; Dencker 1978; Elsing 2009; Kaim 1972; Kalyoncu 1996; Koppi 1987; Kramp 1978; Lucht 2003; Manhem 1985;McGrath 1975; Murphy 1983; Nimmerichter 2002; Radouco-Thomas 1989 ;Robinson 1989; Santo 1985; Stuppaeck 1992; Tubridy 1988), 1359 participants, RR 0.92 (0.67, 1.26), the result is not statistically significant, see Analysis 2.8 or Figure 12 18

22 Figure 12. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.18 Dropout Chlormethiazole versus Benzodiazepine, 5 studies (Burroughs 1985a; Burroughs 1985b; Lucht 2003;McGrath 1975; Tubridy 1988), 311 participants, RR 0.68 (0.37, 1.24), the result is not statistically significant, see Analysis 2.8 or Figure Dropout due to adverse events Any Anticonvulsants versus any Other, 10 studies (Agricola 1982; Burroughs 1985a; Burroughs 1985b; Dencker 1978; Elsing 2009; Kaim 1972; Koppi 1987; Lapierre 1983; Stuppaeck 1992; Tubridy 1988), 596 participants, RR 2.28 (0.67 to 7.70), the result is not statistically significant, see Analysis 2.9 or Figure 13 19

23 Figure 13. Forest plot of comparison: 2 Anticonvulsant versus Other, outcome: 2.19 Dropout due to adverse events Chlormethiazole versus Benzodiazepine, 4 studies (Burroughs 1985a; Burroughs 1985b; Lapierre 1983; Tubridy 1988), 170 participants, RR 1.09 (0.12 to 9.97), the result is not statistically significant, see Analysis 2.9 or Figure 13 Comparison 3 Anticonvulsant 1 versus Anticonvulsant 2: Safety 3.1 Adverse events as number of participants with at least one adverse event Carbamazepine versus Chlormethiazole, 2 studies (Lucht 2003; Ritola 1981), 121 participants, RR 3.12 (0.50 to 19.27), the result is not statistically significant Carbamazepine versus Barbital, 1 study (Flygering 1984), 61 participants, RR 1.81 (0.70 to 4.68), the result is not statistically significant Carbamazepine versus Oxcarbazepine, 1 study (Schik 2005), 29 participants, the result is not estimable because there were no side effects in both groups Chlormethiazole versus Pentobarbital, 1 study (Mariani 2006), 27 participants, RR 2.80 (0.12 to 63.20), the result is not statistically significant See Analysis 3.1 or Figure 14 20

24 Figure 14. Forest plot of comparison: 3 Anticonvulsant 1 versus Anticonvulsant 2, outcome: 3.1 Adverse events (number of patients with at least one adverse event). Acceptability 3.2 Dropout Carbamazepine versus Chlormethiazole, 2 studies (Lucht 2003; Ritola 1981), 121 participants, RR 0.51 (0.08 to 3.11), the result is not statistically significant Carbamazepine versus Barbital, 1 study (Flygering 1984), 60 participants, RR 0.94 (0.34 to 2.57), the result is not statistically significant Carbamazepine versus Oxcarbazepine, 1 study (Schik 2005), 29 participants, RR 3.20 (0.14 to 72.62), the result is not statistically significant Pentobarbital versus Paraldehyde, 1 study (Kaim 1972), 96 participants, RR 0.37 (0.03 to 3.97), the result is not statistically significant Chlormethiazole versus Pentobarbital, 1 study (Mariani 2006), 27 participants, RR 1.39 (0.28 to 7.05), the result is not statistically significant See Analysis 3.2 or Figure 15 21

25 Figure 15. Forest plot of comparison: 3 Anticonvulsant 1 versus Anticonvulsant 2, outcome: 3.2 Dropout. Comparison 4 (Anticonvulsant + Other drug) versus Other Drug: Efficacy 4.1 Alcohol withdrawal delirium 3 studies (Golbert 1967; Lucht 2003; Rothstein 1973), 311 participants, RR 0.79 (0.18 to 3.52), the result is not statistically significant, see Analysis 4.1 or Figure 16 22

26 Figure 16. Forest plot of comparison: 4 (Anticonvulsant + Other) versus Other, outcome: 4.1 Alcohol Withdrawal Delirium post treatment. Safety 4.2 Severe, life-threatening adverse events 1 study, (Golbert 1967; ), 49 participants, RR 0.13 (0.02 to 0.89), the result is statistically significant in favour of the association Paraldehyde+ chloral hydrate in respect of chlordiazepoxide, see Analysis 4.2 Acceptability 4.3 Dropout Three studies (Golbert 1967; Lucht 2003; Spies 1996), 267 participants, RR 0.56 (0.18 to 1.72), the result is not statistically significant, see Analysis 4.3 or Figure 17 Figure 17. Forest plot of comparison: 4 (Anticonvulsant + Other) versus Other, outcome: 4.3 Dropout. Comparison 5 (Anticonvulsant 1 + Other drug) versus Anticonvulsant 2 Efficacy 1 study( Croissant 2009), 56 participants, compared Oxcarbaxepine plus Tiapride versus Chlormethiazole. No alcohol withdrawal seizures or delirium happened in both groups. See Analysis 5.1 and Analysis 5.2 Safety 5.3. Adverse events 1 study (Croissant 2009) 56 participants, compared Oxcarbaxepine plus Tiapride versus Chlormethiazole, RR 0.68 (0.45 to 1.04), the result is not statistically significant, see Analysis Severe, life-threatening adverse events 1 study ( Croissant 2009), 56 participants, compared Oxcarbaxepine plus Tiapride versus Chlormethiazole. No severe adverse events happened in both groups.analysis 5.4 Acceptability 5.5 Drop out 1 study (Croissant 2009) 56 participants, compared Oxcarbaxepine plus Tiapride versus Chlormethiazole, RR 5.36 (0.27 to ) the result is not statistically significant. See Analysis

27 A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation] Anticonvulsant versus Other Drugs for alcohol withdrawal Patient or population: patients with alcohol withdrawal Settings: Intervention: Anticonvulsant versus Other Drugs Outcomes Illustrative comparative risks*(95% CI) Relative effect (95% CI) Assumed risk Corresponding risk Control Anticonvulsant versus Other Drugs Alcohol withdrawal seizures - Any Anticonvulsant vs any Other Study population RR 0.58 (0.22 to 1.58) 27per per1000 (6to43) Medium risk population 19per per1000 (4to30) Adverse events - Any Anticonvulsant vs any Other Study population RR 0.71 (0.45 to 1.12) 287per per1000 (129to321) Medium risk population 188per per1000 (85to211) Dropout - Any Anticonvulsant vs any Other Study population RR 0.92 (0.67 to 1.26) No of Participants (studies) 880 (12 studies) 726 (14 studies) 1359 (20 studies) Quality of the evidence (GRADE) low 1,2 moderate 3 moderate 4 Comments 24

28 114per per1000 (76to144) Medium risk population 99per per1000 (66to125) *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention(and its 95% CI). CI: Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. Very low quality: We are very uncertain about the estimate. 1 Allocationconcealmentadequatein2on12includedstudies 2 In5studiesnoeventsandresultsnotestimable 3 Allocationconcealmentadeqatein4/14includedstudies 4 Allocationconcealmentadequatein5on20includedstudies 25

29 D I S C U S S I O N Summary of main results Fifty-six studies, with a total of 4076 participants, met the inclusion criteria for this review. However, despite the considerable number of randomised controlled trials, the large variety of outcomes and rating scales considerably limited a quantitative synthesis of data. A large chunk of information could not be synthesized. - No statistically significant differences were found in the four outcomes considered in the comparisons of anticonvulsants versus placebo. Anticonvulsant showed a potentially protective benefit against seizures. The adverse events were non-significantly more common among the anticonvulsant-treated patients, but the discontinuations due to adverse events tended to be more common in the placebo-group. None of these trends, however, reached statistical significance. - For the anticonvulsant versus other drug, results favour anticonvulsants only in one of the nine outcomes considered: comparing carbamazepine with benzodiazepine (oxazepam and lorazepam), results favour carbamazepine for alcohol withdrawal symptoms rated with CIWA-Ar score. None of the other comparisons reached statistical significance. This can suggests that anticonvulsants and specifically carbamazepine may actually be more effective in treating some aspects of alcohol withdrawal when compared to benzodiazepines, the current first-line regimen for alcohol withdrawal syndrome. The incidence of seizures tended to be more common among the participants that were treated with other drugs (e.g. benzodiazepines) than anticonvulsants, but delirium tremens favoured the other-treatment participants. Adverse events showed a potentially better profile for the anticonvulsants. - Comparing different anticonvulsants (2 outcomes considered), when carbamazepine was compared to Chlormethiazole the incidence of adverse events tended to be more common among the carbamazepine-treated participants, whereas withdrawals tended to be more common among the Chlormethiazole participants. When carbamazepine was compared to barbital, the side effects were not statistically significant but more common among the carbamazepine patients, and no difference was found regarding the withdrawals between the compared drugs. Out of eleven studies comparing different anticonvulsant agents, no participant died during the treatment period. - Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results favour paraldehyde plus chloral hydrate versus chlordiazepoxide, for the severe-life threatening side effects, but only one study, with four arms, and 72 participants was included in this comparison. - Comparing anticonvulsant plus other drug versus another anticonvulsant, no significant difference were found in all the outcome considered (seizures, delirium, adverse events and drop out). But only one study with 56 participants, which compared oxcarbazepine plus Tiapride versus Chlormethiazolewas included in this comparison. Overall completeness and applicability of evidence Our review has some important limitations. First, most studies involve a very small sample size and have been conducted in different years, and in diverse patient populations. Another potential limitation is the unavoidable grouping of drugs. All anticonvulsants were analysed together compared to the other drugs. Differences between specific anticonvulsant agents could not be seen, because of the limited number of studies comparing different anticonvulsants between themselves. Other drugs included a large variety of medicines such as benzodiazepines, neuroleptics, hypnotics, etc. These drugs do not belong to the same class and do not share the same mechanism of action. The grouping of all these drugs together, could have led to the loss of possibly important between-drugs differences concerning effectiveness or safety. While we made an effort to address drug-specific comparisons as well, these data are definitely more limited and even more inconclusive. It was also not possible to examine dose-response effects, since participants were not treated with even similar doses of various anticonvulsants across RCTs. Moreover, data on side effects should be interpreted cautiously, as they were derived from participants with different co-morbidity. Many trials tended to exclude participants in severe, medical conditions such as hepatic, heart or lung disease. However, these participants may be more sensitive to various adverse events of anticonvulsants or comparator drugs. Quality of the evidence Although randomisation was an inclusion criterion, indicating a degree of methodological quality for these studies, many of them are quite old, the mode of randomisation is not described, allocation of concealment is often unclear and information on followup is frequently missing. On the other hand, this makes the metaanalysis potentially more useful, since small trends that could not reach statistical significance due to the small number of participants in these trials, could now be revealed after the data synthesis. Also highlighting reporting deficits is important for improving future research. A U T H O R S C O N C L U S I O N S Implications for practice Results of this review do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS. Anticonvulsants seem to have limited side effects, although adverse effects are not rigorously reported in the analysed trials. Implications for research Although a significant number of trends has emerged, most of 26

30 these were small and the data for most outcomes did not reach statistical significance; the need for further studies should be carefully evaluated on the basis of these findings. If these studies are going to be carried out, they should be limited to few important efficacy and safety measures such as the severity of the alcohol withdrawal syndrome, the incidence of seizures and delirium tremens, side effects, withdrawals and mortality. In the case of continuous outcomes the same rating scale (e.g. CIWA-Ar) should preferably be used, in order to have more comparable information across studies and to be able to estimate the real effect of all these agents. A C K N O W L E D G E M E N T S We thank the author of the first version of the review that did an excellent work that was very helpful for this update and Zuzana Mitrova for providing helpful assistance during all the process R E F E R E N C E S References to studies included in this review Agricola 1982 {published data only} Agricola R, Mazzarino M, Urani R, Gallo V, Grossi E. Treatment of acute alcohol withdrawal syndrome with carbamazepine: a double-blind comparison with tiapride. Journal of Internal Medical Research 1982;10(3): Alldredge 1989 {published data only} Alldredge BK, Lowenstein DH, Simon RP. Placebocontrolled trial of intravenous diphenylhydantoin for shortterm treatment of alcohol withdrawal seizures. American Journal of Medicine 1989;87(6): Balldin 1986 {published data only} Balldin J, Bokstrom K. Treatment of alcohol abstinence symptoms with the alpha 2-agonist clonidine. Acta Psychiatrica Scandinavica Supplementum 1986;327: Bjorkqvist 1976 {published data only} Bjorkqvist SE, Isohanni M, Makela R, Malinen L. Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal Multicentre double-blind comparison with placebo. Acta Psychiatrica Scandinavica 1976;53(5): Blanchard 1985 {published data only} Blanchard C. Atrium 300 and Alcohol Withdrawal: Double-Blind Placebo-Controlled Study in 38 hospitalised patients [Atrium 300 et Sevrage Alcoolique. Etude en Double Aveugle Versus Placebo chez 38 malades hospitalises]. Psychological Medicine (Paris) 1985;17(1): Bonnet 2003 {published data only} Bonnet U, Banger M, Leweke FM, Specka M, Muller BW, Hashemi T, et al.treatment of acute alcohol withdrawal with gabapentin: results from a controlled two-centre trial. Journal of Clinical Psychopharmacology 2003;23(5): Bonnet U, Speeka M, Leweke FM, Nyhuis P, Banger M. Gabapentin s acute effect on mood profile - a controlled study on patients with alcohol withdrawal. Progress in Neuro-Pharmacology & Biological Psychiatry 2007;31: Borg 1986 {published data only} Borg S, Kvande H, Valverius P. Clinical conditions and central dopamine metabolism in alcoholics during acute withdrawal under treatment with different pharmacological agents. Psychopharmacology (Berlin) 1986;88(1):12 7. Burroughs 1985a {published data only} Burroughs AK, Morgan MY, Sherlock S. Double-blind controlled trial of bromocriptine, chlordiazepoxide and Chlormethiazole for alcohol withdrawal symptoms. Alcohol and Alcoholism 1985;20(3): Burroughs 1985b {published data only} Burroughs AK, Morgan MY, Sherlock S. Double-blind controlled trial of bromocriptine, chlordiazepoxide and Chlormethiazole for alcohol withdrawal symptoms. Alcohol and Alcoholism 1985;20(3): Chance 1991 {published data only} Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Annals of Emergency Medicine 1991;20(5): Choi 2005 {published data only} Choi EA, Ki SW, Kim SE, Kim JW, Park JK. The efficacy and safety of topiramate in the treatment of alcohol withdrawal. Journal of Korean Neuropsychiatric Association 2005;44: Croissant 2009 {published data only} Croissant B, Loeber S, Diehl A, Nakovics H, Wagner F, Kiefer F, et al.oxcarbazepine in combination with Tiaprid in inpatient alcohol-withdrawal--a RCT. Pharmacopsychiatry 2009;42: Dencker 1978 {published data only} Dencker SJ, Wilhelmson G, Carlsson E, Bereen FJ. Piracetam and Chlormethiazole in acute alcohol withdrawal: a controlled clinical trial. Journal of Internal Medical Research 1978;6(5): Elsing 1996 {published data only} Elsing C, Schimanski U, Stremmel W. Randomized controlled trial for the treatment of alcohol withdrawal syndrome: gamma-hydroxybutyric acid abstract. European Journal of Clinical Investigation 1996;26 S:A17. Elsing 2009 {published data only} Elsing C, Stremmel W, Grenda U, Herrmann T. Gammahydroxybutyric acid versus clomethiazole for the treatment of alcohol withdrawal syndrome in a medical intensive care unit: an open, single-center randomized study. The 27

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