Disulfiram for the treatment of cocaine dependence (Review)

Transcription

1 Pani PP, Trogu E, Vacca R, 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 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure Figure Figure Figure Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Disulfiram vs placebo, Outcome 1 Dropout Analysis 1.2. Comparison 1 Disulfiram vs placebo, Outcome 2 Use of cocaine continuous measures Analysis 1.3. Comparison 1 Disulfiram vs placebo, Outcome 3 Use of cocaine dichotomous measures Analysis 1.4. Comparison 1 Disulfiram vs placebo, Outcome 4 Side effects Analysis 2.1. Comparison 2 Disulfiram vs naltrexone, Outcome 1 Dropout Analysis 2.2. Comparison 2 Disulfiram vs naltrexone, Outcome 2 N. subjects with positive urine Analysis 2.3. Comparison 2 Disulfiram vs naltrexone, Outcome 3 Side effects Analysis 3.1. Comparison 3 Disulfiram vs no pharmacological treatment, Outcome 1 Frequency of cocaine use (maximum weeks of consecutive abstinence) Analysis 3.2. Comparison 3 Disulfiram vs no pharmacological treatment, Outcome 2 Frequency of cocaine use (number of subjects achieving 3 or more weeks of consecutive abstinence during the treatment) APPENDICES HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Disulfiram for the treatment of cocaine dependence Pier Paolo Pani 1, Emanuela Trogu 1, Rosangela Vacca 1, Laura Amato 2, Simona Vecchi 2, Marina Davoli 2 1 Social-Health Division, Health District 8 (ASL 8) Cagliari, Cagliari, Italy. 2 Department of Epidemiology, ASL RM/E, Rome, Italy Contact address: Pier Paolo Pani, Social-Health Division, Health District 8 (ASL 8) Cagliari, Cittadella della Salute, padiglione C, via Romagna 16, Cagliari, Sardinia, 09127, Italy. pallolo@tin.it. Editorial group: Cochrane Drugs and Alcohol Group. Publication status and date: New, published in Issue 1, Review content assessed as up-to-date: 13 October Citation: Pani PP, Trogu E, Vacca R, Amato L, Vecchi S, Davoli M. Disulfiram for the treatment of cocaine dependence. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Cocaine dependence is a disorder for which no pharmacological treatment of proven efficacy exists, advances in the neurobiology could guide future medication development. Objectives To evaluate the efficacy and the acceptability of disulfiram for cocaine dependence. Search methods We searched: PubMed, EMBASE, CINAHL (up to January 2008), the Cochrane Central Register of Controlled Trials (CENTRAL- The Cochrane Library, 1, 2009), reference lists of trials, main electronic sources of ongoing trials, conference proceedings. Selection criteria Randomised and controlled clinical trials comparing disulfiram alone or associated with psychosocial intervention with no intervention, placebo, or other pharmacological intervention for the treatment of cocaine dependence. Data collection and analysis Three reviewers independently assessed trial quality and extracted data. Main results Seven studies, 492 participants, met the inclusion criteria Disulfiram versus placebo: no statistically significant results for dropouts but a trend favouring disulfiram, two studies, 87 participants, RR 0.82 (95% CI 0.66 to 1.03). One more study, 107 participants, favouring disulfiram, was excluded from meta-analysis due high heterogeneity, RR 0.34 (95% CI 0.20 to 0.58). For cocaine use, it was not possible to pool together primary studies, results from single studies showed that, one, out of four comparisons, was in favour of disulfiram (number of weeks abstinence, 20 participants, WMD 4.50 (95% CI 2.93 to 6.07). Disulfiram versus naltrexone: no statistically significant results for dropouts but a trend favouring disulfiram, three studies, 131 participants, RR 0.67 (95% CI 0.45 to 1.01). No significant difference for cocaine use was seen in the only study that considered this outcome. 1

4 Disulfiram versus no pharmacological treatment: for cocaine use: a statistically significant difference in favour of disulfiram, one study, two comparisons, 90 participants: maximum weeks of consecutive abstinence, WMD 2.10 (95% CI 0.69 to 3.51); number of subjects achieving 3 or more weeks of consecutive abstinence, RR 1.88 (95% CI 1.09 to 3.23). Authors conclusions There is low evidence, at the present, supporting the clinical use of disulfiram for the treatment of cocaine dependence. Larger randomised investigations are needed investigating relevant outcomes and reporting data to allow comparisons of results between studies. Results from ongoing studies will be added as soon as their results will be available. P L A I N L A N G U A G E S U M M A R Y Disulfiram as a medication for the treatment of cocaine dependence Cocaine is used as powder for intranasal or intravenous use, or smoked as crack. Dependence on cocaine can cause major public health problems because of its psychological, social and medical impacts, including the spread of infectious diseases such as AIDS, hepatitis and tuberculosis. No proven pharmacological treatment of cocaine dependency exists as yet. Disulfiram is marketed for the treatment of alcoholism and interferes with the metabolism of alcohol. It may also be useful in treating cocaine dependence. Evidence from randomised controlled trials to support the clinical use of disulfiram in people with cocaine dependence is limited. The review authors identified seven controlled studies that randomised a total of 492 participants to receive disulfiram, a placebo, no pharmacological treatment or naltrexone in addition to psychosocial treatment. Their mean age was 38 years and the studies took place in an outpatient setting over a mean time of 12 weeks. All trials but one were conducted in the USA. Five studies enrolled patients with cocaine dependence and alcohol abuse or dependence. Two enrolled people with concurrent opioid addiction who were undergoing treatment with buprenorphine or methadone. Disulfiram showed a trend toward fewer dropouts from psychosocial treatment when compared to placebo (three trials) or naltrexone (three trials) but this was not statistically significant. Assessing cocaine use, single studies were in favour of disulfiram on number of weeks of abstinence in one out of four comparisons when compared with placebo and on maximum weeks of consecutive abstinence and number of people achieving three or more weeks of consecutive abstinence in one study comparing disulfiram to no pharmacological treatment. The included studies did not specifically investigate the adverse effects of disulfiram itself or its potential to increase alcohol and cocaine adverse effects. B A C K G R O U N D Description of the condition Cocaine is an alkaloid derived from the leaf of erythroxylon coca, being commonly used as powder, for intranasal or intravenous use, or as crack, a free-base form which is smoked. Cocaine dependence is a major public health problem that is characterized by recidivism and a host of medical and psychosocial complications (EMCDDA 2008). There is a wide and well documented range of consequences associated to acute and chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure (Higgins 1994). Both injection and non injection cocaine use can increase the risk of HIV infection through high risk injecting and sexual behaviours (Sorensen 1991). The illicit use of cocaine has become a persistent health problem worldwide. According to recent population surveys, between 0.1% 2

5 and 16% of the adult population report having tried cocaine at least once (i.e. lifetime prevalence), with USA (16.2%), Colombia, Mexico, New Zealand, United Kingdom, Italy, and Spain (4.0% to 7.7%) being at the upper end of this range (Degenhardt 2008; SAMSHA 2007; EMCDDA 2008). Recent cocaine use (last 12 months) is, in general, reported by less than 1% of adults. In most countries, the range is between 0.3% and 1%. In Spain, United Kingdom, Italy and USA recent prevalence rates are higher than 2% (SAMSHA 2007; EMCDDA 2008). Although cocaine prevalence figures are much lower than comparable figures for cannabis, the prevalence of use among younger adults can be higher than the population average. In Europe, lifetime experience among 15- to 34-year-olds ranges from 0.7% to 12.7%, with the highest levels being found in Spain (9.6%) and the United Kingdom (12.7%); recent use ranges between 0.2% and 5.4%, with Spain and the United Kingdom having rates over 5% (EMCDDA 2008). In the USA, lifetime experience among 26- to 34-year-olds ranges from 21% to 24%, while recent use ranges from 4.2% to 5.2% (SAMSHA 2007). Recently an increase of cocaine use among addicts seeking treatment has been observed in USA (Craddok 1997; Karch 2006), Australia (Topp 2003), Italy (Davoli 2007; Siliquini 2005) and Spain (Suelves 2001). Description of the intervention Cocaine dependence remains a disorder for which no pharmacological treatment of proved efficacy exists, although considerable advances in the neurobiology of this addiction could guide future medication development. Cocaine effect seems to rely on its ability to increase the availability of monoamines (dopamine, serotonin and noradrenaline) in the brain. The dopamine increase in specific areas of the meso-limbic system, which is shared by cocaine with other drugs, like heroin, alcohol, cannabis and nicotine, has been involved in rewarding effect of drugs and self-administration behaviour in animal and human (Di Chiara 1988; Drevets 1999; Drevets 2001; Volkow 2003). Recently, evidences have started to accumulate on the potential utility of some compounds already used in human for the treatment of other pathologies (Preti 2007; Sofuoglu 2006; Vocci 2005). In particular, the potential usefulness of disulfiram, a medication marketed for the treatment of alcoholism, is supported by preclinical and clinical observations (Baker 2007; Bourdelat-Parks 2005; Carroll 1998; Carroll 2000; Carroll 2004; George 2000; Haile 2003; McCance 1998b; Petrakis 2000; Schank 2006). cocaine use in subjects treated with disulfiram for their alcoholism was thought to be caused by the interruption of the alcohol-related disinhibition and impaired judgement (Carroll 1993). However, recent studies have indicated a more specific mechanism of action in support of disulfiram potential usefulness in cocaine addiction: being this compound a generalized enzyme inhibitor, its effect on cocaine addiction could be ascribed to its ability to interfere with enzymes involved in the metabolism of cerebral monoamines. Particularly the inhibition of dopamine-beta-hydroxylase, resulting in an excess of dopamine and decreased synthesis of norepinephrine, has been proposed to favourably influence the functioning of the meso-limbic circuits disrupted by cocaine addiction (Bourdelat-Parks 2005; Haile 2003; Petrakis 2000; Schank 2006). Why it is important to do this review Although effective pharmacotherapy is available for alcohol and heroin dependence (Faggiano 2003; Mattick 2003; Ntais 2005; O Brian 2001; Polycarpou 2005) none exists currently for cocaine dependence despite two decades of clinical trials primarily involving antidepressant, anticonvulsants and dopaminergic medications. Four Cochrane reviews have been published on the efficacy of antidepressant (Lima 2003), antipsychotic (Amato 2007), anticonvulsants (Minozzi 2007), and dopamine agonists (Soares 2003) for the treatment of cocaine dependence but none of them found support for the efficacy of these treatments. One review has been published on the efficacy of psychosocial treatments for psychostimulants dependence (Knapp 2007) showing that existing treatments result in modest outcomes at best, leading to the conclusion there is still a need to develop and test different formats of existing treatment models and new psychosocial interventions. In the last years the interest in the use of disulfiram for the treatment of cocaine dependence has increased consistently. Both preclinical and clinical studies have investigated the potential efficacy of disulfiram for this substance use disorder, the neurobiological bases for its effect and related safety issues. in particular the relevance of the latter has to be considered in the ligth of the risk of adding to the known adverse effects of disulfiram and disulfiram-alcohol interaction (epathic, psychiatric, cardiovascular, etc.), those due to disulfiram-cocaine interaction (Malcolm 2008). This review will assess the efficacy and safety of disulfiram for the treatment of cocaine dependence. How the intervention might work The effect of disulfiram in alcoholism depends on the inhibition of the aldehyde dehydrogenase, an enzyme which is involved in the metabolism of alcohol. In the past, the observed reduction in O B J E C T I V E S To evaluate the efficacy and the acceptability of disulfiram for the treatment of cocaine dependence. 3

6 M E T H O D S Criteria for considering studies for this review Types of studies All randomised controlled trials and controlled clinical trials which focus on the use of disulfiram for cocaine dependence. 1. Dropouts from the treatment as number of participants who did not complete the treatment; 2. Acceptability of the treatment as number and type of side effects experienced during the treatment; 3. Use of primary substance of abuse as number of participants that reported the use of cocaine during the treatment, and/or number of participants with urine samples positive for cocaine. 4. Results at follow-up as number of participants using cocaine at follow-up. Types of participants Cocaine dependents as diagnosed by the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV-R) or by specialists. Trials including participants with additional diagnoses of substance dependence were also eligible. People under 18 years of age and pregnant women were excluded for the substantially different approach and clinical management of these people. People with comorbid mental health conditions were included and considered in subgroup analysis. Types of interventions Experimental intervention Disulfiram alone or in combination with any psychosocial intervention. Control Intervention Placebo; No intervention; Other pharmacological interventions; Any psychosocial intervention. Furthermore we considered different factors as confounders and take them into account in the analysis whenever possible: -setting (inpatient or outpatient treatment); -starting dose/rate and pattern of dose reduction; -scheduled duration of treatment; -severity of dependence (duration of use, route of administration, frequency of assumption); -health status; -psychiatric comorbidity; -other treatment offered (psychosocial support); -social status; -number of previous treatment attempts and previous treatment outcomes. Types of outcome measures Primary outcomes Secondary outcomes 1. Compliance; 2. Craving as measured by validated scales e.g. Brief Substance Craving Scale (BSCS), Visual Analog Scale (VAS); 3. Severity of dependence as measured by validated scales e.g. Addiction Severity Index (ASI), Clinical Global Impression scale (CGI-S), Clinical Global Impression -Observer Scale (CGI-O), Severity of Dependence Scale (SDS); 4. Amount of cocaine use (as measured by grams used or money spent); 5. Psychiatric symptoms/psychological distress diagnosed using standard instruments e.g. Diagnostic and Statistical Manual of Mental Disorders (DSM) or measured by validated scales e.g. Hamilton Depression Rating Scale (HDRS), Profile of Mood States Scale (POMSS), Positive and Negative Syndrome Scale (PANSS). Search methods for identification of studies Electronic searches Relevant randomised trial were identified searching the following databases: 1. The Cochrane Central Register of Controlled Trials (CENTRAL-The Cochrane Library, issue 1, 2009), which includes the Cochrane Drugs and Alcohol Groups specialised register 2. PubMed (from 1966 to January 2009); 3. EMBASE (from 1988 to January 2009); 4. CINAHL (1982 to January 2009). For details on searches see: Appendix 1, Appendix 2, Appendix 3, Appendix 4. We also searched ongoing trials via the following web sites: Current Controlled Trials ( Clinical Trials.gov; Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali ( Trialsjournal.com 4

7 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; 3. some of the main electronic sources of ongoing 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 (Vacca, Vecchi) inspected the search hits by reading titles and abstracts. Each potentially relevant study located in the search was obtained in full text and assessed for inclusion independently by four authors (Vacca,Trogu, Pani, Amato). Doubts were resolved by discussion among all the authors. For subjective outcomes we judged that also lack of blinding of outcome assessor could influence data. Measures of treatment effect Dichotomous outcomes (retention in treatment, use of primary substance, results at follow up) have been analysed calculating the Relative Risk (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals (CI). Continuous outcomes (use of primary substance) have been analysed calculating the Wighted Mean Difference (WMD) with 95% CI. We have not used data presented as number of positive urine tests over the total number of tests in the experimental and control group as measure of substance use. This decision was made because using number of tests instead of number of subjects as unit of the analysis violates the hypothesis of independence among observations. In fact, the results of test done for each participants are not independent. When studies reported number of missing urine stated that they were considered as positive, we included them in the analysis. Data extraction and management Three authors (Vacca, Pani, Trogu) assessed study quality according to the criteria indicated in Cochrane Reviews Handbook (Higgins 2008) and extracted data. Assessment of risk of bias in included studies We assessed the methodological quality of included studies following the methods outlined in the last Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Each included study was evaluated for six specific domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues. See Appendix 5 for a detailed description of criteria for assessing risk of bias. Blinding of participants, personnel and outcome assessor (avoidance of performance bias and detection bias) was considered separately for objective outcomes (retention in treatment, use of substance of abuse measured by urine analysis, retention in treatment at the end of follow up, abstinence at the end of follow up) and subjective outcomes (craving, psychiatric symptoms/ psychological distress, quality of life, severity of dependence). For retention in treatment we judged that only sequence generation and allocation concealment could be relevant because lack of blinding is unlikely to influence data collection and incomplete outcome data could not be used for retention in treatment. For substance use we judged the sequence generation, allocation concealment and incomplete outcome data could influence results. Unit of analysis issues If all arms of a multi-arm trial had to be included in the meta-analysis and one arm had to be included in more than one comparisons, we divided the number of events and the number of participants in that arm by the number of comparisons made. Such method avoids the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. The precision of the pooled estimate results slightly compromised. Participants in disulfiram groups Pettinati 2008 arm a and Pettinati 2008 arm b were considered twice in Analysis 1.1, Analysis 1.5, Analysis 1.6, Analysis 1.4; and in Analysis 2.1, Analysis 2.2, Analysis 2.3, Analysis 2.3 Assessment of heterogeneity The presence of heterogeneity between the trials was tested using the I-squared (I 2 ) statistic and with Chi-squared (Q) test. A P-value of the test lower than 0.05 indicates a significant heterogeneity. Assessment of reporting biases Funnel plot (plot of the effect estimate from each study against the sample size or effect standard error) was used to assess the potential for bias related to the size of the trials. 5

8 Data synthesis The outcomes from the individual trials, when possible, have been combined through meta-analysis (comparability of intervention and outcomes between trials) using a fixed effect model unless there was significant heterogeneity, in which case a random effect model has been used. Sensitivity analysis To incorporate risk of bias assessment in the review process we first plotted intervention effects estimates stratified for risk of bias for each relevant domain. If differences in results were present among studies at different risk of bias, we performed a sensitivity analysis excluding from the analysis studies with high risk of bias. We also performed subgroup analysis for studies with low and unclear risk of bias. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies. For substantive descriptions of studies see Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies Tables. Results of the search We identified 157 reports, including six ongoing trials and one unpublished study presented at a conference (Schottenfeld 2004).135 were excluded on basis of title and abstract; 16 articles were retrieved for more detailed evaluation, 9 of which were excluded after reading the full text; the six ongoing trials and the unpublished study had insufficient information to be included in the analysis; the remaining 7 studies satisfied all the criteria to be included in the review. See Figure 1. Figure 1. 6

9 Included studies Seven studies with 492 participants met the inclusion criteria for this review, for details see Characteristics of included studies. Duration of trials: The mean duration of the trials was 12 weeks (range 11 to 12 weeks). Treatment regimes and setting: Four studies compared disulfiram with placebo (Carroll 2004 arm a; Carroll 2004 arm b; George 2000; Petrakis 2000; Pettinati 2008 arm a); Three studies compared disulfiram with naltrexone (Carroll 1993; Grassi 2007 arm b; Pettinati 2008 arm b). Two studies compared disulfiram with no pharmacological treatment (Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a). The disulfiram dose was 250 mg/day in five studies (Carroll 1993; Carroll 2004 arm a; Carroll 2004 arm b; George 2000; Petrakis 2000; Pettinati 2008 arm a; Pettinati 2008 arm b); mg/ day (mode mg) in one study (Carroll 1998 arm a; Carroll 1998 arm b) and 400 mg/day in one study (Grassi 2007 arm a; Grassi 2007 arm b). All trials but two (Carroll 1993; Grassi 2007 arm a; Grassi 2007 arm b), clearly defined the psychosocial treatments concomitantly given with disulfiram: Cognitive Behavioral Psychotherapy (Carroll 1998 arm a; Carroll 2004 arm a; Pettinati 2008 arm a; Pettinati 2008 arm b); Twelve Step Facilitation (Carroll 1998 arm b); Interpersonal Psychotherapy (Carroll 2004 arm b); counselling (George 2000; Petrakis 2000). Five studies enrolled patients with cocaine dependence and alcohol abuse or dependence (Carroll 1993; Carroll 1998 arm a; Carroll 1998 arm b; Carroll 2004 arm a; Carroll 2004 arm b; Grassi 2007; Pettinati 2008 arm a; Pettinati 2008 arm b). Two enrolled patients with concurrent opioid addiction, in treatment with buprenorphine (George 2000) or methadone (Petrakis 2000). All the seven studies were conducted in outpatient setting. All the studies, except one (Grassi 2007 arm a; Grassi 2007 arm b), were conducted in USA. Rating instruments utilized in the studies: Addiction Severity Index (ASI) (McLellan 1992): Petrakis 2000; Structured Clinical Interview for DSM-IV (Spitzer 1990; Spitzer 1992; First 1995): Carroll 1993; Carroll 1998 arm a; Carroll 1998 arm b; Petrakis 2000; Carroll 2004 arm a; Carroll 2004 arm b; Pettinati 2008 arm a; Pettinati 2008 arm b; Craving Visual Analogue Scale (VAS) (Nicholson 1978): Grassi 2007 arm a; Grassi 2007 arm b; Alcohol Withdrawal Scale (AWS) derived from the CIWA- Ar (Sullivan 1989): Grassi 2007 arm a; Grassi 2007 arm b; Hamilton Depression Rating Scale (Hamilton 1960): Pettinati 2008 arm a; Pettinati 2008 arm b; Hamilton Anxiety Rating Scale (Hamilton 1959): Pettinati 2008 arm a; Pettinati 2008 arm b; Systematic Assessment for Treatment Emergent Effect (Rabkin 1992): Pettinati 2008 arm a; Pettinati 2008 arm b. Comparisons: 1. Disulfiram versus placebo: four studies, five arms, 315 participants: Carroll 2004 arm a; Carroll 2004 arm b ; George 2000; Petrakis 2000; Pettinati 2008 arm a; 2. Disulfiram versus naltrexone: three studies, three arms, 131 participants: Carroll 1993; Grassi 2007 arm b; Pettinati 2008 arm b; 3. Disulfiram versus no pharmacological treatment: two studies, three arms, 103 participants:carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a. Excluded studies Nine studies did not meet the criteria for inclusion in this review. The grounds for exclusion were: study design not in the inclusion criteria: three studies (Carroll 2000; Easton 2007; Pantalon 2002); objectives and outcomes measures not in the inclusion criteria: six studies (McCance 1996; McCance 1998 a; McCance 1998 b; Milligan 2004; Jofre-Bonet 2004; Baker 2007). Risk of bias in included studies All studies were randomised controlled trials. Of these, 4 were placebo controlled (George 2000; Petrakis 2000; Carroll 2004 arm a; Carroll 2004 arm b; Pettinati 2008 arm a). Participants: 492 cocaine addicts according to DSM criteria (DSM-IV-R). 68.4% were males; mean age was 38 years. Allocation The allocation sequence generation was judged adequate in one study (Carroll 2004 arm a; Carroll 2004 arm b), while in the 7

10 other studies details provided did not allow a specific evaluation on this criteria. Allocation concealment was rated as unclear for all included studies, since none of them reported the procedures adopted to prevent participants and investigators from foresee assignment. Blinding All but three studies included in the review were double-blind controlled trials. Three studies were not blinded (Carroll 1993; Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a; Grassi 2007 arm b) arm b), missing data on patients were considered using appropriate methods. Selective reporting One study (Petrakis 2000) did not give the results on the previously stated assessment of the severity of substance use and substance-related problems measured by ASI. For the other studies information available does not allow to assess selective outcome reporting. Incomplete outcome data All but one study (Petrakis 2000) used an intention to treat analysis. In all but two studies (Carroll 1993; Grassi 2007 arm a; Grassi Other potential sources of bias No other potential threats to validity were detected. See Figure 2 and Figure 3 for a summary of these results. Figure 2. Methodological quality graph: review authors judgements about each methodological quality item presented as percentages across all included studies. 8

11 Figure 3. Methodological quality summary: review authors judgements about each methodological quality item for each included study. 9

12 Beacuse of the small number of studies included in each comparison, sensitivity analysis excluding high risk of bias was not performed, as well as funnel plot to assess the possibility of publication bias. Effects of interventions The results were summarized, with comparison of quantitative data where possible, first for disulfiram versus placebo and then for disulfiram versus naltrexone and for disulfiram versus no pharmacological treatment. For some outcome reported in the included studies, it was impossible to pool data due to the different ways of reporting the results. Different rating methods were utilized and for some of them the authors did not indicate the data needed for proceeding with the meta-analysis. This was the case of the comparison between disulfiram and not pharmacological treatment for the outcome retention in treatment (Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a; Grassi 2007 arm b). 1. Disulfiram versus placebo 1.1 Dropouts from the treatment Number of participants who did not complete the treatment. Three studies, (George 2000; Petrakis 2000; Pettinati 2008 arm a), 194 participants, see Figure 4 or Analysis 1.1, RR 0.64 (95% CI 0.35 to 1.20), the result is not statistically significant. Since the test for heterogeneity was significant (I 2 = 84%; P = 0.002), the analysis was repeated excluding the data of Pettinati 2008 arm a. This sensitivity analysis showed a trend for statistical significance in favour of disulfiram, RR 0.82 (95% CI 0.66 to 1.03). On the other hand the comparison concerning the only study of Pettinati 2008 arm a showed a significant difference in favour of disulfiram, RR 0.34 (95% CI 0.20 to 0.58). Figure 4. Forest plot of comparison: 1 Disulfiram vs placebo, outcome: 1.1 Drop out. 1.2 Use of cocaine continuous measures Two studies (George 2000; Petrakis 2000), 87 participants. It was not possible to pool results because either outcomes measures were not comparable or part of required data were not available. Therefore, we reported results for each study and outcome: Use of cocaine at the end of treatment as mean grams per week in past 30 days One study (Petrakis 2000), 43 participants, WMD 0.18 (95% CI to 0.74), the result is not statistically significant. See Analysis Frequency of cocaine use as mean number of days of cocaine use, past 30 days at end of treatment One study (Petrakis 2000), 53 participants, MD (95% Cl to 2.2), the result is not statistically significant. Authors applied in this study a random regression analysis which indicated a 10

13 significantly higher reduction over time in the frequency of cocaine use for disulfiram (Z 4.62; P< 0.01). See Analysis Frequency of cocaine use as total number of weeks abstinent One study (George 2000), 20 participants, MD 4.50 (95% CI 2.93 to 6.07), the result is statistically significant in favour of disulfiram. See Analysis Use of cocaine dichotomous measures Four studies (Carroll 1998 arm a; Carroll 1998 arm b; George 2000; Pettinati 2008 arm a), 248 participants. It was not possible to pool results because either outcomes measures were not comparable or part of required data were not available. Therefore, we reported results for each study and outcome: Proportion of subjects achieving 3 weeks abstinence One study (George 2000), 20 participants, RR 1.02 (95% CI 0.39 to 2.71), the result is not statistically significant. See Analysis 1.3 The study of Pettinati 2008 arm a, considers also the median percentage of negative urine. The authors of this study, applying a generalized estimating equations model, failed in showing medication effects significant at the 5% level. Data reported in the published article do not allow further standardized Cochrane analyses. Numbers of days per week of cocaine use was considered in Carroll 2004 arm a and Carroll 2004 arm b, 121 participants. Randomeffects regression analysis applied by authors in this study showed a significantly higher reduction in cocaine use for participants assigned to disulfiram in comparison with those assigned to placebo (medication x time, Z -2.82; P< 0.01). This difference in favour of disulfiram is confirmed also by urinalyses specimens (medication x time, Z -2.06; P= 0.04). Data reported in the published article do not allow further standardized Cochrane analyses. 1.4 Acceptability of the treatment as number and type of side effects Three studies (Petrakis 2000; Carroll 2004 arm a; Carroll 2004 arm b; Pettinati 2008 arm a), 295 participants. In the study of Carroll 2004 arm a; Carroll 2004 arm b, the results on side effects were given pooling together the two arms receiving disulfiram and the two arms receiving placebo. No difference between disulfiram and placebo was seen besides the sexual desire which resulted higher in the placebo group. See Figure 5 or Analysis 1.4, subgroup 1.4.8, 107 participants, RR 0.41 (95% CI 0.17 to 0.97). 11

14 Figure 5. Forest plot of comparison: 1 Disulfiram vs placebo, outcome: 1.8 Side effects. 12

15 (02) Disulfiram versus naltrexone 2.1 Dropouts Three studies (Carroll 1993; Pettinati 2008 arm b; Grassi 2007 arm b), 131 participants, RR 0.67 (95% CI 0.45 to 1.01), a trend for a lower dropout in disulfiram treated patients was seen. See Figure 6 or Analysis 2.1 Figure 6. Forest plot of comparison: 2 Disulfiram vs naltrexone, outcome: 2.1 Dropout. 2.2 Percentage of urine screens positive for cocaine One study (Carroll 1993), 18 participants, WMD (95% CI to ), the result is statistically significant in favour of disulfiram. See Analysis 2.2. Furthermore, median percentage of negative urine, considering missing as positive was investigated in the study of Pettinati 2008 arm b, 105 participants; this study considers the median percentage of negative urine. The authors, applying a generalized estimating equations model, failed in showing disulfiram effects significant at the 5% level. Data reported in the published article do not allow further standardized Cochrane analyses. Percentage of positive urine during the first four weeks of treatment was investigated in the study of Grassi 2007 arm b), 8 participants. The difference is reported in the article as statistically significant in favour of disulfiram (Chi square ; P< 0.001). Data reported in the primary study do not allow further standardized Cochrane analyses. 2.3 Acceptability of the treatment as number and type of side effects One study (Pettinati 2008 arm b), 105 participants, the result is not statistically significant. See Figure 7 or Analysis

16 Figure 7. Forest plot of comparison: 2 Disulfiram vs naltrexone, outcome: 2.4 Side effects. (03) Disulfiram versus no pharmacological treatment 3.1 Frequency of cocaine use as maximum weeks of consecutive abstinence from cocaine One study, two arms (Carroll 1998 arm a; Carroll 1998 arm b), 90 participants, WMD 2.10 (95% CI 0.69 to 3.51), the result is statistically significant in favour of disulfiram. See Figure 8 or Analysis

17 Figure 8. Forest plot of comparison: 3 Disulfiram vs no pharmacological treatment, outcome: 3.1 Maximum weeks of consecutive abstinence from cocaine. 3.2 Frequency of cocaine use as Number of subjects achieving 3 or more weeks of consecutive abstinence during treatment One study, two arms (Carroll 1998 arm a; Carroll 1998 arm b), 90 participants, RR 1.88 (95% CI 1.09 to 3.23), the result is statistically significant in favour of disulfiram. See Figure 9 or Analysis 3.2 Figure 9. Forest plot of comparison: 3 Disulfiram vs no pharmacological treatment, outcome: 3.2 Number of subjects achieving 3 or more weeks of consecutive abstinence during treatment. Two open studies (Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a), 98 participants. Only Grassi 2007 arm a, with a very small sample size (8 participants), reported dropout rate as the number of patients not completing the 12 weeks of the trial. Instead, attrition rate by group, expressed as the mean number of weeks of retention in treatment, was available for all arms. Carroll found a better retention for disulfiram (8.4 weeks for subjects assigned to disulfiram treatment, versus 5.8 weeks for those assigned to no medication, F = 8.7, p< 0.05); Grassi found a better retention for the no medication group (6.6 weeks for disulfiram versus 10,7 for no medication). It was not possible to pool these results in a meta-analysis since the standard deviation on the mean was not available for both studies No usable data were reported for Acceptability of the treatment as number and type of side effects in the two studies comparing disulfiram with no pharmacological treatment (Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a). D I S C U S S I O N Summary of main results In the last years the interest in the use of disulfiram for the treatment of cocaine dependence has increased consistently. Both preclinical and clinical studies have investigated the potential efficacy of disulfiram for this substance use disorder, the neurobiological bases for its effect and related safety issues. In this review we have included seven studies, selected according to pre-established criteria. Six more are ongoing studies and will be evaluated for inclusion after their results will be available. Unfortunately, the heterogeneity of included studies limits the possibility to draw confident conclusions on the efficacy and safety of disulfiram for the treatment of cocaine addiction. Selected studies differ for design, quality, characteristics of patients, services and treatments delivered: three are open studies (Carroll 1993; Carroll 2004 arm a; Carroll 2004 arm b; Grassi 2007 arm a; Grassi 15

18 2007 arm b); three include comparison of disulfiram with naltrexone (Carroll 1993; Grassi 2007 arm b; Pettinati 2008 arm b); two involve only patients dependent on alcohol and cocaine (Grassi 2007 arm a; Grassi 2007 arm b; Pettinati 2008 arm a; Pettinati 2008 arm b); two involve subjects co-treated with methadone (Petrakis 2000) or buprenorphine (George 2000) for opioid dependence; two studies offer drug counselling as ancillary intervention (George 2000; Petrakis 2000), four offer CBT (Carroll 1998 arm a; Carroll 2004 arm a; Grassi 2007 arm a; Grassi 2007 arm b; Pettinati 2008 arm a; Pettinati 2008 arm b), one offers TSF (Carroll 1998 arm b), one IPT (Carroll 2004 arm b), and one no specified individual psychotherapy (Carroll 1993). Studies differ also for outcome variables and their definition, conditioning the possibility to pool together data and carry out meta-analyses. Disulfiram versus placebo: for dropouts, it was possible to pool results from two studies (George 2000; Petrakis 2000), that showed a trend for an higher dropout rate in placebo groups. Another study (Pettinati 2008 arm a), 107 participants, showed statistically significant results in favour of disulfiram but these results were excluded from meta-analysis due the high heterogeneity. For cocaine use, the different definition of the outcome variables did not consent pooled analysis, results of single studies showed in Petrakis 2000, 67 participants, no significant difference between disulfiram and control (however, authors, applying in this study a random regression analysis, showed a significantly higher reduction over time in the frequency of cocaine use for disulfiram); in George 2000, 20 participants, the total number of weeks of abstinence was statistically significant in favour of disulfiram, but the proportion of subjects achieving 3 weeks of abstinence was not statistically significant; in Carroll 2004 arm a and Carroll 2004 arm b, 121 participants, random-effects regression analysis applied by authors showed a significantly higher reduction in cocaine use for participants assigned to disulfiram in comparison with those assigned to placebo; finally, in Pettinati 2008 arm a, 107 participants, the authors, applying a generalized estimating equations model, failed in showing medication effects significant at the 5% level. Disulfiram versus naltrexone: results on dropouts were not statistically significant but showed a trend in favour of disulfiram in three studies (Carroll 1993; Pettinati 2008 arm b; Grassi 2007 arm b), 131 participants. Results related to cocaine use were inconsistent, with the two little open studies showing significant differences in favour of disulfiram (Carroll 1993; Grassi 2007 arm b), and a double blind large study, 105 participants, failing in showing significant difference (Pettinati 2008 arm b). Disulfiram versus no pharmacological treatment: for dropout, results from single studies showed a statistically significant difference in favour of disulfiram in Carroll 1998 arm a; Carroll 1998 arm b, while in Grassi 2007 arm a the difference was statistically significant in favour of the no medication group. Regarding cocaine use, pooling results from Carroll 1998 arm a and Carroll 1998 arm b, 90 participants, a significant difference was seen in favour of disulfiram in both maximum weeks of consecutive abstinence from cocaine and number of subjects achieving 3 or more weeks of consecutive abstinence during treatment. Overall, limited evidence can be drawn from the seven trials included in this review on the efficacy of disulfiram compared with placebo, naltrexone or no pharmacological treatment in terms of retention in treatment and reduction of cocaine use. Looking at safety issues, overall studies investigating the subject (Petrakis 2000; Carroll 2004 arm a; Carroll 2004 arm b; Pettinati 2008 arm a; Pettinati 2008 arm b) did not show statistically significant differences in the number of patients reporting side effects. However, these studies did not specifically investigate the potential toxicity coming from the interaction between disulfiram and cocaine. Recently, it has been shown that disulfiram, inhibiting the primary pathways for cocaine metabolism, increases plasma cocaine concentration significantly more than placebo, and, depending on the dosage of the two compounds and the way of administration of cocaine, heart rate, systolic and diastolic blood pressure can result increased (McCance 1998a; McCance 1998b; Baker 2007). Of course, selection criteria for enrolment of patients in the included studies took into account risks due to disulfiram interaction, but in clinical pratice, the possibility of adding further risk factors because of cardiovascular vulnerability or comorbidity should be considered. These risk factors could add to the other disulfiramrelated adverse effects, such as hepatotoxicity, cardiovarcular, psychiatric complication, etc., worsening the medication safety profile. On these bases, we need a better definition of the medical risks before extending the use of disulfiram for the treatment of cocaine dependence. Overall completeness and applicability of evidence Despite the systematic bibliographic search, only one of the included studies was conducted out of the USA and of the six studies conducted in USA, five were carried out at Yale University. This is another limit to the generalizability of the results, since: a) different social contests can influence differently the severity of dependence and the availability to enter an experimental design; b) different clinical contests can influence differently the selection of participants to the trials and the results of the treatment, acting as an effect modifier in the estimation of efficacy of treatment. Quality of the evidence From a methodological perspective, the overall quality of the included studies was not good. Although all studies were randomised, all had unclear allocation concealment, only one had adequate sequence generation, only four were double blind, while three were open (Carroll 1993; Carroll 1998 arm a; Carroll 1998 arm b; Grassi 2007 arm a; Grassi 2007 arm b). Moreover, it must be considered that, due the well known adver- 16

19 sive disulfiram alcohol reaction, participants could easily test the study blindness. Finally, although pre-established outcomes were considered in (all) the included studies, the great heterogeneity of the scales used in the primary studies and the way in which results were reported made not possible to undertake a cumulative analysis. A U T H O R S C O N C L U S I O N S Implications for practice Although caution is needed when assessing results from a limited number of clinical trials, there is low evidence, at the present, supporting the clinical use of disulfiram in the treatment of cocaine dependence. This results could not be considered conclusive due principally to the low quality of evidence, due to study design, small sample size and heterogeneity in terms of outcome operational definition of some of the included studies. Moreover, safety issues, particularly those related to the interaction between disulfiram and cocaine, should be deeply explored. This uncertainty requires that clinicians balance the possible benefits against the potential adverse effects of the treatment. Implications for research Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, larger randomised investigations are needed investigating relevant outcomes and safety issues and reporting data to allow comparison of results between studies. Some of these studies are ongoing and will be added as soon as their results will be available. A C K N O W L E D G E M E N T S We want to thank Zuzana Mitrova for the editorial support R E F E R E N C E S References to studies included in this review Carroll 1993 {published data only} Carroll K, Ziedonis D, O Malley S, McCance-Katz E, Gordon L, Rounsaville B. Pharmacological interventions for alcohol- and cocaine-abusing individuals: A pilot study of disulfiram vs. naltrexone. American Journal on Addictions 1993;2:77 9. Carroll 1998 arm a {published data only} Carroll KM, Ball SA, McCance E, Rounsaville B. Treatment for cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998;93(5): Carroll 1998 arm b {published data only} Carroll KM, Ball SA, McCance E, Rounsaville B. Treatment for cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998;93(5): Carroll 2004 arm a {published data only} Carroll KM, Fenton LR, Ball SA, Nich CN, Frankforter TL, Shi J, et al.efficacy of Disulfiram and cognitive behavioral therapy in cocaine-dependent outpatients. Archives General Psychiatry 2004;61: Carroll 2004 arm b {published data only} Carroll KM, Fenton LR, Ball SA, Nich CN, Frankforter TL, Shi J, et al.efficacy of Disulfiram and cognitive behavioral therapy in cocaine-dependent outpatients. Archives General Psychiatry 2004;61: George 2000 {published data only} George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TDR, Schottenfeld RS. Disulfiram versus placebo for cocaine dependence in Buprenorhine-mantained subjects: a preliminary trial. Biological Psychiatry 2000;47: Grassi 2007 arm a {published data only} Grassi MC, Cioce AM, Giudici FD, Antonilli L, Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: a pilot study. Pharmacological Research 2007;55(2): Grassi 2007 arm b {published data only} Grassi MC, Cioce AM, Giudici FD, Antonilli L, Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: a pilot study. Pharmacol Res 2007;55(2): Petrakis 2000 {published data only} Petrakis IL, Carroll KM, Nich C, Gordon LT, McCance- Katz EF, Frankforte T, et al.disulfiram treatment for cocaine dependence in Methadone maintained opioid addicts. Addiction 2000;95(2): Pettinati 2008 arm a {published data only} Pettinati HM, Kampman KM, Lynch KG, Xie H, Dackis C, Rabinowitz AR, et al.a double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav 2008;33(5): Pettinati 2008 arm b {published data only} Pettinati HM, Kampman KM, Lynch KG, Xie H, Dackis C, Rabinowitz AR, et al.a double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav 2008;33(5):

20 References to studies excluded from this review Baker 2007 {published data only} Baker JR, Jatlow P, McCance-Katz EF. Disulfiram effects on responses to intravenous cocaine administration. Drug and Alcohol Dependence 2007;87(2-3): Carroll 2000 {published data only} Carroll KM, Nich C, Ball SA, McCance E, Frankforter TL, Rounsaville. One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000;95(9): Easton 2007 {published data only} Easton CJ, Babuscio T, Carroll KM. Treatment retention and outcome among cocaine-dependent patients with and without active criminal justice involvement. Journal of the American Academy of Psychiatry and the Law 2007;35(1): Jofre-Bonet 2004 {published data only} Jofre-Bonet M, Sindelar JL, Petrakis IL, Nich C, Frankforter T, Rounsaville BJ, et al.cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients. Journal of Subst Abuse Treatment 2004;26(3): McCance 1996 {published data only} McCance EF, Kosten TR, Hameedi F, Jatlow P. Disulfiram treatment of cocaine abuse; findings from a dose-response study. NIDA Research Monograph. Problems of Drug Dependence 1996: Proceedings of the 58th Annual Scientific Meeting, the College on Problems of Drug Dependence, Inc. Rockville, MD: U.S. Department of Health and Human Services, National Institute on Drug Abuse, 1997; Vol. 174:138. McCance 1998 a {published data only} McCance-Katz EF, Kosten TR, Jatlow P. Disulfiram effects on acute cocaine administration. Drug and Alcohol Dependence 1998;52(1): McCance 1998 b {published data only} McCance-Katz EF, Kosten TR, Jatlow P. Chronic disulfiram treatment effects on intranasal cocaine administration: initial results. Biological Psychiatry 1998;43(7): Milligan 2004 {published data only} Milligan CO, Nich C, Carroll KM. Ethnic differences in substance abuse treatment retention, compliance, and outcome from two clinical trials. Psychiatric Services 2004; 55(2, 11):167-73; Pantalon 2002 {published data only} Pantalon MV, Nich C, Frankforter T, Carroll KM, University of Rhode Island Change Assessment. The URICA as a measure of motivation to change among treatment-seeking individuals with concurrent alcohol and cocaine problems. Psychology of Addictive Behaviors 2002;16 (4): References to studies awaiting assessment Schottenfeld 2004 {unpublished data only} Schottenfeld RS, Chawarski MC, George TP, Cubells JF. Pharmacogenetics of disulfiram for cocaine treatment: Role of DBH genotype. Sixty-Sixth Annual Scientific Meeting of the College on Problems of Drug Dependence. June 12 17, References to ongoing studies Carroll 2006 {unpublished data only} Carroll KM. Maximizing the Efficacy of Cognitive Behavioral Therapy With Medication and Contingency Management. ClinicalTrials.Gov Kosten 1999 {unpublished data only} Kosten TR. Disulfiram for Cocaine-Alcohol Abuse. ClinicalTrials.Gov Kosten 2005 {published data only} Kosten TR. Effectiveness of Disulfiram for Treating Cocaine Dependence in Individuals With Different Dopamine Beta Hydroxylase (DBH) Genes. Clinical.Trials.gov Oliveto 2005 {unpublished data only} Oliveto A. Disulfiram for Cocaine Abuse in Methadone- Patients. ClinicalTrials.Gov Oliveto 2006 {unpublished data only} Oliveto A. Disulfiram for Cocaine Abuse in Methadone Patients. ClincalTrials.Gov Poling 2007 {unpublished data only} Poling J. Clinical Efficacy of Disulfiram in LAAM- Maintained Cocaine Abusers. ClinicalTrials.Gov Additional references Amato 2007 Amato L, Minozzi S, Pani PP, Davoli M. Antipsychotic medications for cocaine dependence. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: / CD pub2] Baker 2007 Baker JR, Jatlow P, McCance-Katz EF. Disulfiram effects on responses to intravenous cocaine administration. Drug and Alcohol Dependence 2007;87(2-3): Bourdelat-Parks 2005 Bourdelat-Parks BN, Anderson GM, Donaldson ZR, Weiss JM, Bonsall RW, Emery MS, et al.effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice. Psychopharmacology 2005;183(1): Carroll 1998 Carroll KM, Nich C, Ball SA, McCance E, Rounsavile BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998;93(5): Carroll 2000 Carroll KM, Nich C, Ball SA, McCance E, Frankforter TL, Rounsaville BJ. One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000;95(9): Carroll 2004 Carroll KM, Fenton LR, Ball SA, Nich C, Frankforter TL, Shi J, et al.efficacy of disulfiram and cognitive behavior 18