Description of the condition
Alcohol consumption varies enormously among countries, over time and among different population groups (Alcohol and Public Policy Group 2010). In 2009, the average consumption of alcohol by adults (aged over 15 years) in the European region was 12.5 litres of pure alcohol per person per year, which corresponds to nearly three drinks per day. This is the highest alcohol consumption in the world, and nearly double the world average (WHO 2012). Alcohol accounts for approximately 4% of all deaths and 4.65% of the global burden of injury and disease (Rehm 2009; WHO 2011).
Alcohol Use Disorders (AUDs) include alcohol dependence and harmful alcohol use, which are both recognised as mental health disorders by the World Health Organization (NCCMH 2011; WHO 2011). Alcohol dependence is defined as a cluster of behavioural, cognitive and physiological symptoms that may develop after repeated alcohol use, whereas harmful use refers to alcohol consumption that results in consequences to physical and mental health (WHO 2010). Worldwide, approximately 3% of the population suffer from AUDs. The prevalence among men is 6% compared to less than 1% among women (Rehm 2009).
Description of the intervention
Non-pharmacological treatment of AUDs include brief interventions and specialised treatment programmes, and the effect of these interventions has been evaluated in different settings and populations (Kaner 2007; McQueen 2011). Interventions originating from mutual self-help groups such as Alcoholics Anonymous have been evaluated in research (Ferri 2006).There are few pharmacological interventions for treating AUD, and many are alternative treatments with no evidence. The current pharmacological interventions involve acamprosate, naltrexone and disulfiram. New treatments under evaluation include GHB, ondansetron, baclofen and topiramate (Leone 2010; Edwards 2011).
Disulfiram has been available for more than 60 years as an effective supplement to behavioral treatment of alcoholism (Krampe 2010). Today, disulfiram is primarily used in a supervised manner and, like acamprostae and n(altrexone, combined with behavioral therapy in the treatment of AUDs.
How the intervention might work
Disulfiram inhibits the liver enzyme aldehyde dehydrogenase. Alcohol intake during treatment leads to accumulation of acetaldehyde, which probably causes the disulfiram-ethanol reaction in the form of increased pulse and respiration, tachycardia, facial flushing, nausea, vomiting, hypotension, and - at worst - cardiovascular collapse. Disulfiram is therefore indicated for patients who wish to remain abstinent (Martin 2007). A recent review showed that supervised treatment with disulfiram has some effect on short-term abstinence and relapse prophylaxsis (Jørgensen 2011).
Why it is important to do this review
Alcohol-related disease and injuries kill and harm millions of people each year. Effective prevention and treatment strategies can reduce these alcohol-related consequences. Even though disulfiram is the o ldest of the available pharmacological options for treatment, many questions remain unanswered including the long-term effect of disulfiram on abstinence, which may help to reduce alcohol-related diseases and consequences. It is therefore important to systematically summarise the effects of disulfiram in order to help clinicians and other staff working with AUD patients to make the best possible treatment option for their patients.
To assess the efficacy and safety of disulfiram in the treatment of patients with alcohol use disorders on short-term and long-term outcomes compared to other pharmacological treatment, placebo or no treatment.
Criteria for considering studies for this review
Types of studies
Randomised clinical trials (RCTs). Trials studying disulfiram in various doses and/or trials investigating disulfiram against other pharmacological treatment, placebo or no treatment will be considered.
We will exclude subanalyses of already published material and studies where disulfiram is used in combination with other medical treatment.
Types of participants
Patients with alcohol use disorder (AUD) diagnosed with appropriate standardised criteria (e.g. DSM-IV, ICD-10). AUDs can therefore include a harmful drinking pattern as well as alcohol dependency.
Types of interventions
We will compare:
- Disulfiram at one dose compared with another dose
- Disulfiram versus other pharmacological treatment
- Disulfiram versus placebo
- Disulfiram versus no treatment
Types of outcome measures
- Abstinence at the end of study (short-term) and at 6 and 12 months (long-term). Abstainers are people who have refrained from drinking alcoholic beverages (WHO 2010). Consumption can be self-reported and/or biochemically-validated.
- Alcohol consumption at the end of study (short-term) and at 6 and 12 months (long-term). We will measure treatment effect on alcohol consumption by self-reported intake and validated questionnaires such as Alcohol Use Disorder Identification Test (AUDIT) (Saunders 1993), Michigan Alcohol Screening Test (MAST) (Selzer 1971), and CAGE (Cut down; Annoyed; Guilty; Eye-opener) (Mayfield 1974) with or without biochemical validation.
- Adverse events at the end of study (short-term) and at 6 and 12 months (long-term). Adverse drug events are defined as “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function" (WHO 1972).
We allow for within-study definitions of abstinence, alcohol consumption and adverse events to be included.
- Days until relapse and number of drinking days at the end of study (short-term) and at 6 and 12 months (long-term). Days until relapse is defined as number of days until a return to drinking alcohol after a period of abstinence, and number of drinking days as total number of days with any alcohol consumption (WHO 2010).
We will exclude studies without relevant primary and secondary outcomes. Other study-specific outcomes such as retention in treatment, relapse rate, controlled drinking and alcohol craving will be considered as secondary outcomes.
Search methods for identification of studies
We will search the following electronic databases for potentially relevant studies:
- Cochrane Drugs and Alcohol Group Specialised Register
- The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, latest Issue).
- Ovid MEDLINE - 1950 to present
- Ovid EMBASE - 1980 to present
- EBSCO CINAHL - 1982 to present
We will search databases using MeSH and free-text terms relating to alcohol use disorders and disulfiram as shown in Appendix 1. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity-maximising version (2008 revision) (Lefebvre 2011). We will revise this strategy appropriately for each database to take account of differences in controlled vocabulary and syntax rules.
Searching other resources
We will identify trials by manually searching abstracts of appropriate conference proceedings. We will check the reference lists of relevant articles and contact relevant trial authors to identify any additional or ongoing studies. We will contact pharmaceutical companies to get information on old or new published trials on disulfiram. We will also search for trials on specific websites:
No language or publication restrictions will be set.
Data collection and analysis
Selection of studies
Two authors (KO and BB) will independently scan the titles and abstracts of the papers identified by the search strategies. All potentially relevant studies, chosen by at least one author, will be retrieved and evaluated using full-text versions.
Two authors (KO and BB) will assess the congruence of trials with the review's inclusion criteria. Any disagreement will be resolved by discussion with a third author (GA).
Data extraction and management
Two authors (KO and BB) will independently extract data using a tool based on guidance in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved involving a third author (GA).
Assessment of risk of bias in included studies
The 'Risk of bias' assessment for RCTs and controlled clinical trials (CCTs) in this review will be performed using the criteria recommended in the Cochrane Handbook (Higgins 2011). The recommended approach for assessing risk of bias in studies included in Cochrane reviews is a two-part tool, addressing seven specific domains, namely sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other sources of 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 will use the criteria indicated by the Cochrane Handbook adapted to the addiction field. See Appendix 2 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) will be considered separately for objective outcomes (e.g. drop out, use of substance of abuse measured by urine analysis, subjects relapsed at the end of follow up, subjects engaged in further treatment) and subjective outcomes (e.g. 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 relationship).
Incomplete outcome data (avoidance of attrition bias) will be considered for all outcomes except for drop out from the treatment, which is very often the primary outcome measure in trials on addiction.
Measures of treatment effect
Dichotomous outcomes will be analysed by calculating the relative risk (RR) for each trial, with the uncertainty in each result expressed with 95% confidence intervals (CI). Continuous outcomes will be analysed by calculating the standardised mean difference (SMD) with 95% CI. For outcomes assessed by scales we will compare and pool the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control group.
Unit of analysis issues
If all arms in a multi-arm trial are to be included in the meta-analysis and one treatment arm is to be included more than once in some comparisons, then we will divide the number of events and the number of participants in that arm by the number of treatment comparisons made. This method avoids the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. It compromises the precision of the pooled estimate slightly.
Dealing with missing data
Where necessary, we will contact the authors of included studies regarding missing data. Where data are found to be missing and the authors are not contactable we will, if possible, calculate missing statistics (such as standard deviations) from other quoted statistics (such as standard errors and confidence intervals). If missing data remain missing, we will exclude results with unavailable information from the analyses.
Assessment of heterogeneity
We will assess clinical heterogeneity by comparing the distribution of important patient characteristics across trials, including age, sex and characteristics of interventions. Heterogeneity among studies will be calculated using the I
Assessment of reporting biases
A thorough search for unpublished studies through grey literature searches and contact with known experts in the field will assist to reduce the risk of publication bias. If we find more than 10 trials, we will use funnel plot analysis to examine possible publication bias.
Data from all included trials in the systematic review will be entered into Review Manager (RevMan 5.1) and we will combine data quantitatively, where possible. We will calculate pooled estimates using a random-effects model.
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analyses where data are available, as recommended in Section 9.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will, if possible, compare:
- Supervised disulfiram versus unsupervised disulfiram
- Disulfiram only versus disulfiram combined with behavioral therapy
- Patients with different diagnoses (harmful drinking, alcohol abuse, alcohol dependency etc.)
- Duration of studies: 6 months versus 12 months
We will perform sensitivity analyses to explore the risk of bias,by:
- Excluding studies without biochemical validation of self-reported alcohol consumption, and
- Exculding studies with a high risk of bias on trial factors such as sequence generation, allocation concealment, blinding, losses to follow-up etc.
Appendix 1. MEDLINE search strategy
- exp Alcohol-Related Disorders/
- Alcohol Drinking/
- (alcohol adj3 (drink$ or intoxicat$ or use$ or abus$ or misus$ or risk$ or consum$ or withdraw$ or detox$ or treat$ or therap$ or excess$ or reduc$ or cessation or intervention$)).tw.
- (drink$ adj3 (excess or heavy or heavily or harm or harmful or hazard$ or binge or problem$)).tw.
- 1 or 2 or 3 or 4 or 5
- 7 or 8 or 9
- randomized controlled trial.pt.
- controlled clinical trial.pt.
- drug therapy.fs.
- 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
- exp animals/ not humans.sh.
- 19 not 20
- 6 and 10 and 21
Appendix 2. Criteria for 'Risk of bias' assessment
Contributions of authors
BP and KO have drafted the protocol, developed the search strategy and reviewed the protocol. GA has reviewed the protocol.
Declarations of interest
Bolette Pedersen is co-author of a recently released review on disulfiram (Jørgensen 2011).
Sources of support
- Clinical Health Promotion Centre, Health Sciences, Lund University, Sweden.Salary: Bolette Pedersen
- No sources of support supplied