Baclofen for alcohol withdrawal

  • Review
  • Intervention

Authors


Abstract

Background

The treatment baclofen can rapidly reduce symptoms of severe alcohol withdrawal syndrome (AWS) in alcoholic patients, with a significant reduction in the cost. Baclofen is easy to manage, and rare euphoria, craving and other pleasant effects are reported by patients treated with baclofen.

Objectives

To assess the efficacy and safety of baclofen for patients with AWS.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (October 2012), MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012) and CINAHL (1982 to October 2012). We also searched registers of ongoing trials, for example ClinicalTrials.gov, Controlled-trials.com, EUDRACT, etc. At the same time, we handsearched the references quoted in the identified trials, and contacted researchers, pharmaceutical companies and relevant trial authors seeking information about unpublished or uncompleted trials. All searches included the non-English language literature.

Selection criteria

All randomized controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for patients with AWS. Uncontrolled, non-randomized or quasi-randomized trials were excluded. Both parallel group and cross-over design were included.

Data collection and analysis

Two review authors independently assessed references retrieved for possible inclusion. All disagreements were resolved by an independent party. Study authors were contacted for additional information. Adverse effects information was collected from the trials.

Main results

We identified a total of 113 references from all electronic databases searched excluding duplicates. After screening of titles and abstracts, full papers of 10 studies were obtained and assessed for eligibility. Finally, two RCTs with 81 participants were eligible according to the inclusion criteria. Regarding the efficacy, one study suggested that both baclofen and diazepam significantly decreased the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) score, without any significant difference between the two interventions. The other study showed no significant difference in CIWA-Ar score between baclofen and placebo but a significantly decreased dependence on high-dose benzodiazepines with baclofen compared to placebo. Meanwhile, only one study reported the safety outcomes and there were no side effects in either the baclofen or diazepam groups.

Authors' conclusions

The evidence for recommending baclofen for AWS is insufficient. More well designed RCTs are needed to prove its efficacy and safety.

Plain language summary

Baclofen for alcohol withdrawal syndrome

In recent years, baclofen has demonstrated its potential to reduce abuse and dependence in alcoholic patients, without producing any obvious side effects. This review attempted to evaluate the efficacy and safety of baclofen as a therapy for alcohol withdrawal syndrome (AWS). In a search of the literature, only two randomized controlled trials (RCTs) with 81 participants met our inclusion criteria. Formal meta-analysis was not performed due to the different controls. The evidence for recommending baclofen for AWS is insufficient. More well designed rRCTs are required to prove its efficacy and safety.

Background

Description of the condition

Nearly 4% of the global disease burden can be attributed to alcohol consumption (Room 2005). Alcohol withdrawal syndrome (AWS) is a distressing and life-threatening condition, which usually affects the alcohol-dependent patients who discontinue or decrease their alcohol consumption (Fiellin 2002). It has been estimated that 8% of primary care and hospitalised patients are found to suffer associated AWS (Dissanaike 2006). The most common manifestations include tremor, restlessness, insomnia, nightmares, paroxysmal sweats, tachycardia, fever, nausea, vomiting, seizures, hallucinations, increased agitation, tremulousness and delirium. In severe cases, symptoms might progress to seizures and coma, even with cardiac arrest and death in 5% to 10% patients (Lerner 1985). Long-term alcohol consumption causes the changes such as reduced brain gamma aminobutyric acid (GABA) levels and GABA receptor sensitivity (Liang 2004) and activation of the glutamate system (Dodd 2000), which lead to the hyperactivity in the absence of alcohol. The advances in knowledge of neuroscience have prompted the use of drugs that act through the GABA pathways in the treatment of AWS.

Description of the intervention

Baclofen is a GABA B (GABAB) receptor agonist with an approved indication to control spasticity (Davidoff 1985). In recent years, its ability to suppress AWS has been found in rats made physically dependent on alcohol (Colombo 2000). Baclofen produces the effect through modulating the GABAB receptor, similar to gamma hydroxybutyrate. Moreover, the therapeutic properties of baclofen appear to be reduced abuse and dependence potential (Carter 2009; McDonald 2008), which are related to the modulation of the GABAB receptor. Based on the preclinical findings, open-label trials showed the ability of baclofen in rapidly reducing symptoms of severe AWS in alcoholic patients (Addolorato 2002). This observation was also confirmed by a case of severe AWS complicated by delirium tremens that was successfully treated with baclofen (Addolorato 2003). Baclofen is easy to manage, with rare euphoria, craving for the drug or other pleasant effects. More importantly, baclofen may also be of benefit in the prophylaxis of AWS in humans (Stallings 2007).

How the intervention might work

The experimental evidence indicates that mesolimbic dopamine neurons might be associated with the mediation of alcohol intake and reinforcement (Weiss 2002). Meanwhile, GABAB receptors are mainly located in the ventral tegmental area where mesolimbic dopamine neurons originate, both on the cell body of dopamine neurons and on the terminals of glutamatergic afferent neurons (Bowery 1987). Baclofen as a GABAB receptor agonist might exert an inhibitory action on the dopamine neurons (Westerink 1996), which is possibly the way that baclofen suppresses alcohol stimulated dopamine release and, in turn, dopamine-mediated, alcohol reinforced and motivated behaviors. In addition, there is a hypothesis that baclofen-induced activation of GABAB receptors offsets AWS-associated and enhanced function of N-methyl-d-aspartate (NMDA)-mediated glutamate excitatory neurotransmission, which results in an attenuation of AWS (Colombo 2000). Another possible mechanism is that baclofen can block the expression and sensitization of anxiety-like behavior in animals because of GABAB and GABAA-related adaptive changes induced by the repeated AWS (Knapp 2007).

Why it is important to do this review

Although benzodiazepines are commonly used as the first-line agent for the treatment of AWS (Amato 2010; Mayo-Smith 1997), they are usually associated with unwanted side effects and addictive properties. Therefore, the discovery of potentially useful and manageable drugs for the treatment of AWS is of considerable practical importance (Leggio 2008). There are already several clinical trials on baclofen for patients with AWS, however no systematic review currently exists in the peer-reviewed literature. This review aims to evaluate the efficacy and safety of treatment of AWS with baclofen.

Objectives

To assess the efficacy and safety of baclofen for patients with AWS.

Methods

Criteria for considering studies for this review

Types of studies

All randomized controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for patients with AWS. Uncontrolled, non-randomized or quasi-randomized trials were excluded. Both parallel group and cross-over designs were included.

Types of participants

Inclusion criteria:

  1. age between 18 and 75 years, no gender limitation;

  2. DSMR IV criteria for AWS met;

  3. agreed to abstain from alcohol for duration of study;

  4. able to provide informed consent.

Exclusion criteria:

  1. severe psychiatric diseases, e.g. major unipolar depression and schizophrenia;

  2. using baclofen at the time of study enrolment;

  3. other active drug dependence in addition to alcohol, with the exception of nicotine;

  4. other severe diseases, such as epilepsy, cardiac failure, diabetes, liver encephalopathy, kidney failure and neoplastic diseases.

Types of interventions

Experimental intervention: baclofen.

Control intervention: placebo or any other treatment, such as benzodiazepines.

Types of outcome measures

Primary outcomes
Efficacy outcomes
  1. Alcohol withdrawal seizures, as number of participants experiencing seizures

  2. Alcohol withdrawal delirium, as number of participants experiencing delirium

  3. Alcohol withdrawal symptoms, as measured by the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) score

  4. Global improvement of overall AWS, as measured in prespecified scales (as number of patients with global improvement, global doctor's assessment of efficacy, patient's assessment of efficacy)

  5. Craving, as measured by prespecified scales

Safety outcomes
  1. Adverse events, as number of participants experiencing at least one adverse event

  2. Severe, life-threatening adverse events, as measured by number of participants experiencing severe, life-threatening adverse events

Acceptability outcomes
  1. Dropouts

  2. Dropouts 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

Trials were identified from systematic searches in the following electronic databases:

  1. Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, October 2012), which includes the Cochrane Drugs and Alcohol Group Specialised Register; 

  2. MEDLINE (1966 to October 2012);

  3. EMBASE (1980 to October 2012);

  4. CINAHL (1982 to October 2012).

The search used a combination of controlled vocabulary and free-text terms relating to alcohol withdrawal in addiction with the Cochrane highly sensitive search strategy for identifying reports of RCTs (Higgins 2011). The search strategy was developed for MEDLINE and has been revised for each database using the appropriate controlled vocabulary as applicable.

See Appendix 1 to Appendix 4 for details of the search terms for each database.

We also searched the following registers of ongoing trials:

  1. ClinicalTrials.gov, USA;

  2. Controlled-trials.com, UK;

  3. Nederlands Trial Register, the Netherlands;

  4. EUDRACT, EU;

  5. UMIN-CTR, Japan;

  6. Australian Clinical Trials Registry, Australia.

Searching other resources

1. References

We inspected the reference lists in all identified studies for further relevant studies.

2. Personal contact

We contacted researchers, pharmaceutical companies and relevant trial authors seeking information about unpublished or uncompleted trials.

Where required for additional data, we contacted authors of trials for this information. We did not systematically contact all authors for additional papers.

All searches included non-English language literature and studies with English abstracts. When we believed they were likely to meet the inclusion criteria, the studies were translated.

Data collection and analysis

Selection of studies

Two review authors (LJ, WL) independently screened titles and abstracts of all the identified trials to determine if the inclusion criteria were met. All the possibly relevant studies were obtained in full text for further consideration. Two review authors (LJ, WL) independently evaluated their eligibility, and assessed the methodological quality of these studies. Any doubts were resolved by discussion or by an independent party, if necessary.

Data extraction and management

Two independent review authors (LJ, WL) extracted eligible data from the published reports onto standardised forms and cross-checked them for accuracy. We used checklists to independently record details including method of generating randomization schedule; method of concealment of allocation; blinding; use of intention-to-treat (ITT) analysis; adverse events and dropouts for all reasons; participants (socio-demographic and related clinical information); interventions (medications and non-pharmacologic interventions); and outcomes. Any disagreements were resolved by discussion and consensus between review authors.

Assessment of risk of bias in included studies

Two review authors (LJ, WL) assessed the risk of bias using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The recommended approach for assessing risk of bias in studies included in a Cochrane review is a two-part tool addressing the specific domains namely random sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessors (detection bias), incomplete outcome data (attrition bias) and selective outcome reporting (reporting bias). 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, in terms of low, high or unclear risk. To make these judgments we used the criteria indicated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) adapted to  the addiction field. See Table 1 for details. The domains of sequence generation and allocation concealment (avoidance of selection bias) are addressed in the tool by a single entry for each study. Blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias) were considered separately for objective outcomes (for example dropouts, use of substance of abuse measured by urine analysis, participants relapsed at the end of follow-up, participants engaged in further treatments) and subjective outcomes (for example duration and severity of signs and symptoms of withdrawal, patient self-reported use of substance, side effects, social functioning as integration at school or at work, family relationships). Incomplete outcome data (avoidance of attrition bias) were considered for all outcomes except for the dropouts from the treatment, which is very often the primary outcome measure in trials on addiction.

Table 1. Criteria to assess risk of bias in RCTs and CCTs
ItemJudgmentDescription
1. Random sequence generation (selection bias)low riskThe investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization
 high riskThe investigators describe a non-random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests;  availability of the intervention
 unclear riskInsufficient information about the sequence generation process to permit judgement of low or high risk
2. Allocation concealment (selection bias)low riskInvestigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based, and pharmacy-controlled, randomization); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes
 high riskInvestigators enrolling participants could possibly foresee assignments because one of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure
 unclear riskInsufficient information to permit judgement of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement

3. Blinding of participants and providers (performance bias)

Objective outcomes 

low risk

No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding;

Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

4. Blinding of participants and providers (performance bias)

Subjective outcomes

low riskBlinding of participants and providers and unlikely that the blinding could have been broken
 high risk

No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding

Blinding of key study participants and personnel attempted, but it is likely that the blinding could have been broken, and the outcome was likely to be influenced by lack of blinding

 unclear riskInsufficient information to permit judgement of low or high risk

5. Blinding of outcome assessor (detection bias)

Objective outcomes 

low risk

No blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding

Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

6. Blinding of outcome assessor (detection  bias)

Subjective outcomes

low risk

No blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding

Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

 high risk

No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding

Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

 unclear riskInsufficient information to permit judgement of low or high risk

7. Incomplete outcome data (attrition bias)

For all outcomes except retention in treatment or dropout

low risk

No missing outcome data

Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias)

Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate

For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size

Missing data have been imputed using appropriate methods

All randomized patients are reported/analysed in the group they were allocated to by randomization irrespective of non-compliance and co-interventions (intention to treat)

 high risk

Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate

For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size

'As-treated' analysis done with substantial departure of the intervention received from that assigned at randomization

 unclear riskInsufficient information to permit judgement of low or high risk (e.g. number randomized not stated, no reasons for missing data provided; number of drop-out not reported for each group)
8 Selective reporting (reporting bias)low risk

The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon)

 high risk

Not all of the study's prespecified primary outcomes have been reported

One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified

One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect)

One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis

The study report fails to include results for a key outcome that would be expected to have been reported for such a study

 unclear riskInsufficient information to permit judgement of low or high risk

Measures of treatment effect

We expect the RCTs and cross-over trials to measure both dichotomous data and continuous data. Continuous data should be expressed as mean differences with 95% confidence intervals (CIs). Meanwhile, dichotomised data should be expressed as risk ratios with 95% CIs. All the data were analyzed by the latest version of the Review Manager software (Review Manager 2011).

Unit of analysis issues

We dealt with unit of analysis issues according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We attempted to contact the authors of the studies for missing data and further details. We used ITT analysis, which consisted of all the randomized participants. Meanwhile, we considered different scenarios (best and worst case) for taking into account missing data.

Assessment of heterogeneity

We tested heterogeneity for all comparisons using the I2 statistic (Higgins 2011). If significant heterogeneity was found (I2 > 50%), we calculated the overall effects using a random-effects model instead of a fixed-effect model.

Assessment of reporting biases

We planned to examine the presence of publication bias by a funnel plot, however there were only two studies fulfilling the inclusion criteria.

Data synthesis

Formal meta-analysis was not performed because only two studies were included with different control groups. One was compared to a diazepam group (Addolorato 2006) and the other one was (Lyon 2011) compared to a placebo group.

Subgroup analysis and investigation of heterogeneity

We planned to analyse subgroups of studies categorized according to demographic characteristics (for example age and gender) and the dosage and duration of treatment with baclofen. However, formal meta-analysis was not performed.

Sensitivity analysis

We planned to carry out sensitivity analyses to assess the robustness of a random-effects model versus fixed-effect model and the inclusion or exclusion of studies at high risk of bias (for example inadequate allocation concealment and lack of blinded outcome assessors) as well as use of different scenarios for missing data. However, formal meta-analysis was not performed.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

For substantive descriptions of the studies see: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

We identified a total of 113 references from the electronic database searches after excluding duplicates. After screening of titles and abstracts, the full papers of 10 studies were obtained and assessed for eligibility. Eight studies were excluded. There were no ongoing RCTs.

Included studies

Two RCTs with 81 participants were eligible according to the inclusion criteria. One study (Addolorato 2006) compared baclofen with diazepam for AWS, by measurement of the CIWA-Ar score. The other study (Lyon 2011) focused on baclofen for AWS in comparison with placebo, by assessing the CIWA-Ar score and monitoring the need for benzodiazepines.

Excluded studies

Studies were excluded for the following reasons: (i) the participants did not abstain from alcohol during the study (Addolorato 2002 a; Garbutt 2010); (ii) the participants were patients with liver cirrhosis, which met the exclusion criterion 'liver encephalopathy' (Addolorato 2007; Leggio 2012); (iii) the paper was a commentary, rather than a study (Garbutt 2007); (iv) the participants neither met the DSM-IV criteria of AWS nor were known to abstain from alcohol during the study (Addolorato 2011; Krupitsky 1993; Krupitskiī 1995).

Risk of bias in included studies

Allocation

Neither of the two RCTs reported the concrete methods of sequence generation and concealment. Therefore, we assessed them as unclear risk of bias.

Blinding

One study (Addolorato 2006) had a single-blind design with the investigators who assessed the CIWA-Ar score unaware of allocation. Therefore, we regarded detection bias as low risk. In the other study (Lyon 2011), participants and study personnel were blinded to treatment group with low risk of bias.

Incomplete outcome data

One study (Addolorato 2006) was performed with ITT principles, with low risk of bias. In the other study (Lyon 2011), 31 of 44 randomized participants completed 72 hours of CIWA-Ar assessment and the study was assessed as high risk of bias.

Selective reporting

In both of the two included RCTs, all prespecified outcomes were reported. Therefore, we assessed this as low risk of bias.

Other potential sources of bias

Because only two RCTs were included, we could not carry out a funnel plot analysis for publication bias.

Effects of interventions

Efficacy

The study by Addolorato 2006 found that both baclofen and diazepam significantly decreased the CIWA-Ar score and its four subscales (anxiety, agitation, sweating and tremor) on days 1, 2, 3, 4, 5 and 10. At baseline, the mean total CIWA-Ar score and four subscores were significantly higher in the baclofen group than the diazepam group, however there were no significant differences in the decreases in CIWA-Ar, anxiety, sweating and tremor scores in the baclofen and diazepam groups. Concerning agitation score, baclofen was slightly slower in its benefit than diazepam, with significantly higher scores on days two and three compared to the diazepam group. In the following days, the efficacies of baclofen and diazepam were comparable. The study by Lyon 2011 showed no significant difference in the CIWA-Ar scores between the baclofen and placebo groups in eight-hour periods from days one to five, but a significantly decreased dependence on high-dose benzodiazepines (mean lorazepam dose and cumulative dose) in the baclofen group compared to the placebo group. There were no reports for other efficacy outcomes such as seizures, delirium, global improvement and craving.

Safety

In Addolorato 2006, there were no side effects reported in either the baclofen group or diazepam group. Concerning the discontinuation of treatment, no withdrawal symptoms or side effects were observed. In Lyon 2011, no outcomes on safety were reported; and there were seven participants in the baclofen group and six in the placebo group who did not complete the study.

Discussion

Summary of main results

According to the inclusion criteria, two RCTs with 81 participants were included. Methodological defects were found in both of the RCTs and the details are provided in Characteristics of included studies. Due to the different controls, we did not carry out a meta-analysis. Only one study (Addolorato 2006) reported on the safety of baclofen, without any side effects. Concerning the efficacy, both RCTs investigated CIWA-Ar score. The study by Addolorato 2006 found that the CIWA-Ar score and its four subscales (anxiety, agitation, sweating and tremors) were decreased by both baclofen and diazepam, with no significant differences between baclofen and diazepam. The study Lyon 2011 showed no difference in the CIWA-Ar score between baclofen and placebo. There was a significantly decreased dependence on high-dose benzodiazepines in the baclofen group compared to placebo.

Overall completeness and applicability of evidence

Only one study (Addolorato 2006) reported on safety, with no side effects. In addition, this study concluded that baclofen and diazepam decreased the CIWA-Ar and subscale scores, without differences between baclofen and diazepam. The other study (Lyon 2011) suggested no significant difference in CIWA-Ar score between baclofen and placebo, but there was a decreased dependence on high-dose benzodiazepines in the baclofen group. Therefore, we believe the conclusions of the two RCTs are not consistent and more well designed RCTs are required to confirm the usefulness of baclofen in AWS.

Quality of the evidence

From a methodological perspective, the defects of the included RCTs were mainly: (i) random sequence generation and allocation concealment methods were unknown (Addolorato 2006; Lyon 2011); (ii) a single-blind design, only for the investigators who performed the CIWA-Ar (Addolorato 2006); (iii) more than 5% dropouts in the endpoint measurement (Lyon 2011). Therefore, any conclusions should be used with caution.

Potential biases in the review process

None known.

Agreements and disagreements with other studies or reviews

There is a Cochrane overview on pharmacological interventions for the treatment of AWS (Amato 2011), which also refers to baclofen. Not enough evidence on the effectiveness and safety of baclofen was found. This is consistent with our conclusion.

Authors' conclusions

Implications for practice

(1) Baclofen seems to be well tolerated and has comparable efficacy to diazepam. It potentially reduces the need for benzodiazepines in the treatment of AWS.

(2) The evidence is insufficient for recommending baclofen for AWS. More well designed RCTs are required to prove its efficacy and safety.

Implications for research

More research is required. Double-blind RCTs should be conducted where:

(1) the participants meet the DSMR IV criteria for AWS, rather than DSMR IV criteria for alcohol dependence;

(2) the participants agree to abstain from alcohol for the duration of the study in order to observe AWS;

(3) the CIWA-Ar score, a standard scale to measure AWS, is in the study design.

Acknowledgements

The authors would like to acknowledge the help provided by the Cochrane Drugs and Alcohol Group.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy  

Free text: (((alcohol) AND (withdraw* or detox* or abstinen* or abstain*)) AND (baclofen)))

Appendix 2. PubMed search strategy

  1. alcohol-related disorders [MeSH]

  2. abuse[tiab] OR dependen*[tiab] OR disorder* OR consumption [tiab]

  3. withdraw*[tiab] OR abstinen*[tiab] OR abstain*[tiab] OR detox*[tiab] OR neuropathy[tiab] OR delirium [tiab]

  4. #1 OR #2 OR #3

  5. alcohol [tiab]

  6. #4 AND #5

  7. Baclofen [MeSH]

  8. Chlorophenyl GABA [tiab]

  9. beta-(p-Chlorophenyl)-gamma-aminobutyric Acid [tiab]

  10. "gamma-amino butyric acid-B receptor agonists"

  11. Lioresal [tiab]

  12. #7 OR #8 OR #9 OR #10 OR #11

  13. randomized controlled trial [pt]

  14. controlled clinical trial [pt]

  15. random* [tiab]

  16. placebo [tiab]

  17. drug therapy [MeSH]

  18. trial [tiab]

  19. groups [tiab]

  20. #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

  21. animals [mh] NOT human [mh]

  22. #20 NOT #21

  23. #6 AND #12 AND #22

Appendix 3. EMBASE search strategy

  1. 'alcohol withdrawal'/exp

  2. 'withdrawal syndrome'/exp

  3. (disorder* or withdr* or abstinen* or abstain* or detox* or neuropathy):ti,ab

  4. alcohol:ti,ab

  5. #1 or #2 or #3

  6. #4 and #5

  7. 'benzodiazepine derivative'/exp

  8. (Baclofen or Chlorophenyl GABA or beta-(p-Chlorophenyl)-gamma-aminobutyric Acid or Lioresal).ti,ab

  9. #7 or #8

  10. random*:ti,ab

  11. placebo:ti,ab

  12. ((singl* or doubl* or trebl* or tripl*) and (blind* or mask*)):ti,ab

  13. crossover*:ti,ab

  14. 'randomized controlled trial'/exp

  15. 'double blind procedure'/exp

  16. 'single blind procedure'/exp

  17. 'triple blind procedure'/exp

  18. 'latin square design'/exp

  19. 'crossover procedure'/exp

  20. 'Latin square design'/exp

  21. 'placebos'/exp

  22. 'multicenter study'/exp

  23. #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22

  24. #6 and #9 and #23

  25. limit 24 to human

Appendix 4. CINAHL search strategy

  1. MH "alcohol related disorders"

  2. MH "alcohol withdrawal delirium"

  3. TX (disorder* or withdr* or abstinen* or abstain* or detox* or neuropathy)

  4. TX alcohol

  5. S1 or S2 or S3

  6. S4 AND S5

  7. MH "GABAB receptor agonist, Baclofen"

  8. TX (Baclofen or Chlorophenyl GABA or beta-(p-Chlorophenyl)-gamma-aminobutyric Acid or gamma-amino butyric acid-B receptor agonists or Lioresal)

  9. S7 or S8

  10. MH "Random Assignment"

  11. MH "Clinical Trials"

  12. TX random*

  13. TX placebo*

  14. TX group*

  15. TX (singl* or doubl* or tripl* or trebl*) and (mask* or blind*)

  16. MH "crossover design"

  17. TX crossover*

  18. TX allocate*

  19. TX assign*

  20. S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19

  21. S6 and S9 and S20

What's new

DateEventDescription
28 October 2012New citation required but conclusions have not changedThe previous onging study (NCT00597701) has been finished and included in this update (Lyon 2011).
25 October 2012New search has been performedNew search has been performed.

Contributions of authors

Liu J and Wang LN formulated the idea for the review and developed the basis for the review.

Liu J took the lead in searching, identifying and assessing studies, in data extraction and analyses, and in writing up the full review.

Wang LN gave general advice on this review as well as helping in identifying trials, assessing studies and data extraction.

Liu J supervised the quality assessment of the methodology.

All authors wrote or revised this review.

Liu J will be in charge of updating the review.

Declarations of interest

None known

Differences between protocol and review

None

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Addolorato 2006

MethodsRandomized controlled trial
Participants

130 subjects affected by current alcohol dependence referred to our Alcohol Treatment Unit requesting alcohol detoxification treatment were consecutively considered for the study. Finally, there were 37 patients included in this trial.

Inclusion criteria: age between 18 and 75 years; a daily alcohol consumption of more than 80g alcohol per day during the previous 24 hours; diagnosis of alcohol dependence according to DSM-IV criteria (American Psychiatric Association 1994); only subjects with a CIWA-Ar score equal to or higher than 10 (defined as moderate or severe AWS requiring pharmacological treatment) were ultimately enrolled in the study.

Exclusion criteria: the current presence of: delirium tremens or hallucinosis; severe psychiatric diseases; epilepsy; severe cardiac failure; diabetes mellitus; severe liver impairment; liver encephalopathy; kidney failure; neoplastic diseases; lack of co-operating relatives; abuse of or dependence on other drugs, with the exception of nicotine.

Interventions

Baclofen group: treated with oral doses of baclofen of 30mg/day, fractionated in 3 daily administrations for 10 consecutive days. There were 18 patients allocated to the baclofen group.

Diazepam group: a total of 0.5-0.75 mg/kg diazepam was divided in 6 daily administrations for 10 consecutive days. Doses were tapered by 25% daily from day 7 to day 10 (Lejoyeux 1998). There were 19 patients allocated to the diazepam group.

OutcomesCIWA-Ar was administered once a day (immediately before the first daily administration of the drug) on days 1, 2, 3, 4, 5 and 10. Baseline values were those collected on day 1 before the first drug administration.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThere was no description of the concrete method used (i.e. random number table; computer random number generator; coin tossing, etc).
Allocation concealment (selection bias)Unclear riskThe method of concealment was unknown.
Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "The whole study was performed on a single blind design; in particular, investigators who performed CIWA-Ar at the different times of treatment were always the same and were unaware as to which drug was being administered to patients."
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "The whole study was performed on a single blind design; in particular, investigators who performed CIWA-Ar at the different times of treatment were always the same and were unaware as to which drug was being administered to patients."
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Analysis of the efficacy of the 2 drugs on the severity of AWS was intended to be performed with the intention-to-treat principles."
Selective reporting (reporting bias)Low riskAll prespecified outcomes were reported.

Lyon 2011

  1. a

    AWS: alcohol withdrawal syndrome

    CIWA-Ar: Clinical Institute Withdrawal Assessment of Alcohol Scale Revised

MethodsRandomized, double-blind, placebo-controlled trial
ParticipantsThe adult inpatients who were at high risk for AWS were screened. Those who developed signs of AWS, met DSM-IV criteria and had at least 11 scores in CIWA-Ar were enrolled for randomization. Meanwhile, all the participants received benzodiazepine for symptom-triggered treatment.
InterventionsEither baclofen (10 g) or placebo was orally given every 8 hours with observation for at least 72 hours. 44 patients were randomized to baclofen (n=19) and placebo (n=25) groups.
OutcomesA total of 31 patients completed the 72 hours of assessments (18 in baclofen group and 13 in placebo group). There was a decreased need for high doses of benzodiazepine to control AWS in the baclofen group, compared to placebo group.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of random sequence generation was not described.
Allocation concealment (selection bias)Unclear riskThe allocation concealment was not reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "Subjects and study personnel were blinded to treatment group (baclofen vs placebo)."
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Subjects and study personnel were blinded to treatment group (baclofen vs placebo)."
Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "Of the 44 subjects who were randomized, 31 (18 in the baclofen group, 13 in the placebo group) completed 72 hours of CIWA-Ar assessments."
Selective reporting (reporting bias)Low riskAll prespecified outcomes were reported.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Addolorato 2002 aThe subjects did not abstain from alcohol during the study, which can not meet inclusion criteria.
Addolorato 2007The subjects of the study were patients with liver cirrhosis, which met exclusion criteria "liver encephalopathy".
Addolorato 2011The subjects neither met the DSM-IV criteria of AWS nor abstained from alcohol during the study.
Garbutt 2007It was only a comment on the study by Addolorato 2007.
Garbutt 2010The subjects did not abstain frome alcohol during the study, which can not meet inclusion criteria.
Krupitskiī 1995Neither the subjects met DSM-IV criteria of AWS nor they abstained for alcohol during the study was known.
Krupitsky 1993Neither the subjects met DSM-IV criteria of AWS nor they abstained for alcohol during the study was known.
Leggio 2012The subjects of study were patients with liver cirrhosis, which met exclusion criterion "liver encephalopathy".

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