Antipsychotic medications for cocaine dependence (Review)

Transcription

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

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS Figure RESULTS Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Any antipsychotic versus placebo, Outcome 1 Dropouts Analysis 2.1. Comparison 2 Risperidone versus Placebo, Outcome 1 Dropouts Analysis 3.1. Comparison 3 Olanzapine versus Placebo, Outcome 1 Dropouts Analysis 3.2. Comparison 3 Olanzapine versus Placebo, Outcome 2 Side effects Analysis 3.3. Comparison 3 Olanzapine versus Placebo, Outcome 3 Use of cocaine during the treatment (self reported). 27 Analysis 3.4. Comparison 3 Olanzapine versus Placebo, Outcome 4 Craving (Brief Substance Craving Scale) Analysis 3.5. Comparison 3 Olanzapine versus Placebo, Outcome 5 Craving (Cocaine Craving Questionnaire) Analysis 3.6. Comparison 3 Olanzapine versus Placebo, Outcome 6 Severity of Dependence (Addiction Severity Index). 29 Analysis 3.7. Comparison 3 Olanzapine versus Placebo, Outcome 7 Severity of Dependence (Clinical Global Impression Scale) Analysis 3.8. Comparison 3 Olanzapine versus Placebo, Outcome 8 Depression (Hamilton Depression Rating Scale). 30 Analysis 3.9. Comparison 3 Olanzapine versus Placebo, Outcome 9 Anxiety (Hamilton Anxiety Rating Scale) Analysis Comparison 3 Olanzapine versus Placebo, Outcome 10 Withdrawal symptoms (Cocaine Selective Severity Assessment) Analysis 4.1. Comparison 4 Olanzapine versus Haloperidol, Outcome 1 Dropouts Analysis 4.2. Comparison 4 Olanzapine versus Haloperidol, Outcome 2 Craving (Voris Cocaine Craving Questionnaire). 32 Analysis 4.3. Comparison 4 Olanzapine versus Haloperidol, Outcome 3 Psychopathology (Positive and Negative Syndrome Scale) APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS i

3 [Intervention Review] Antipsychotic medications for cocaine dependence Laura Amato 1, Silvia Minozzi 1, Pier Paolo Pani 2, Marina Davoli 1 1 Department of Epidemiology, ASL RM/E, Rome, Italy. 2 Social-Health Division, Health District 8 (ASL 8) Cagliari, Cagliari, Italy Contact address: Laura Amato, Department of Epidemiology, ASL RM/E, Via di Santa Costanza, 53, Rome, 00198, Italy. amato@asplazio.it. Editorial group: Cochrane Drugs and Alcohol Group. Publication status and date: Edited (no change to conclusions), published in Issue 3, Review content assessed as up-to-date: 9 May Citation: Amato L, Minozzi S, Pani PP, Davoli M. Antipsychotic medications for cocaine dependence. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Cocaine dependence is a public health problem characterized by recidivism and a host of medical and psychosocial complications. Cocaine dependence remains a disorder for which no pharmacological treatment of proven efficacy exists, although considerable advances in the neurobiology of this addiction could guide future medication development Objectives To evaluate the efficacy and the acceptability of antipsychotic medications for cocaine dependence Search methods We searched the following sources: MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006), CINAHL (1982 to October 2006), Cochrane Drug and Alcohol Group Specialised Register (October 2006). We also searched the reference lists of trials, the main electronic sources of ongoing trials (National Research Register, meta-register of Controlled Trials; Clinical Trials.gov) and conference proceedings likely to contain trials relevant to the review. All searches included also non-english language literature. Selection criteria All randomised controlled trials and controlled clinical trials with focus on the use of any antipsychotic medication for cocaine dependence Data collection and analysis Two authors independently evaluated the papers, extracted data, rated methodological quality Main results Seven small studies were included (293 participants): the antipsychotic drugs studied were risperidone, olanzapine and haloperidol. No significant differences were found for any of the efficacy measures comparing any antipsychotic with placebo. Risperidone was found to be superior to placebo in diminishing the number of dropouts, four studies, 178 participants, Relative Risk (RR) 0.77 (95% CI 0.77 to 0.98). Most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during treatment and craving.the results on olanzapine and haloperidol come from studies too small to give conclusive results. 1

4 Authors conclusions Although caution is needed when assessing results from a limited number of small clinical trials there is no current evidence, at the present, supporting the clinical use of antipsychotic medications in the treatment of cocaine dependence. Furthermore, most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during the treatment and craving. 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 should be designed investigating relevant outcomes and reporting data to allow comparison of results between studies. Moreover some efforts should be done also to investigate the efficacy of other type medications, like anticonvulsant, currently used in clinical practice. P L A I N L A N G U A G E S U M M A R Y Antipsychotic medications for cocaine dependence Cocaine dependence is often associated with medical, psychological and social problems for the individual and public health problems for the community. Users have a role in the spread of the infectious diseases AIDS, hepatitis and tuberculosis as well as crime, violence and neonatal drug exposure. Medication with antidepressants, anticonvulsants such as carbamazepine, and dopamine agonists to assist in stopping cocaine use is not supported by evidence from Cochrane reviews. Use of antipsychotic agents has also been considered, particularly because cocaine can induce hallucinations and paranoia that mimic psychosis. When all trial results comparing any antipsychotic drug to placebo were grouped together, antipsychotic drugs did not have any benefit in reducing dependency on cocaine. The review authors identified seven controlled trials involving a total of 293 adults, mean age 40 years. The studies were conducted in USA in both inpatient and outpatient settings and had a duration of 5 to 168 days (mean 61 days). Six trials randomised participants to receive an antipsychotic drug or placebo; the seventh compared olanzapine to haloperidol. The antipsychotic medications used were risperidone (three studies, 1 to 4 mg/day); olanzapine (three studies, 10 mg/ day); and haloperidol (two studies, 4 and 10 mg/day). Risperidone treatment reduced the number of people who dropped out from treatment (three studies, 144 participants; relative risk 0.77, range 0.77 to 0.98); in individual studies olanzapine and haloperidol showed better results than placebo but the results come from studies to small to give them conclusive (34 participants) and (31participants) respectively. Information on acceptability of treatment in terms of side effects, abstinence from cocaine use and withdrawal symptoms was limited.the methodological quality of the small number of identified trials was good but the number of participants was small and a variety of ways of reporting results were used. B A C K G R O U N D Cocaine is an alkaloid derived from the leaf of 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 2006). 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 are thought to 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 national population surveys, between 0.5 % and 6 % of the adult population report having tried cocaine at least once (i.e. lifetime prevalence), with Italy (4.6 %), Spain (4.9 %) and the United Kingdom (6.8 %) being at the upper end of this range. 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 and the United Kingdom, recent prevalence rates are higher than 2 %. Although cocaine prevalence figures are much lower than comparable figures for cannabis, levels of use among younger adults can be higher than the population average. Lifetime experience among 15- to 34-year-olds ranges from 1 % to 11.6 %, with the highest levels again being found in Spain (7.7 %) and the United Kingdom (11.6 2

5 %). Recent use ranges between 0.2 % and 4.6 %, with Denmark, Ireland, Italy and the Netherlands all having rates of about 2 %; Spain and the United Kingdom over 4 %. (EMCDDA 2006). In the USA in 2004, an estimated 2.0 million persons (0.8 percent) were current cocaine users; of these, 467,000 used crack during the same time period (0.2 percent) (NSDUH 2005). More recently an increase of cocaine use among addicts seeking treatment has been observed in Italy (Davoli in press; Siliquini 2005), Spain (Suelves 2001), Australia (Topp 2003) and USA (Craddok 1997; Karch 2006). 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, anti convulsivant and dopaminergic medications. There has been extensive consideration of optimal pharmacological approaches to the treatment of cocaine dependence with consideration of both dopamine antagonists and agonists (Grabowski 1997; Kosten 1996). Three Cochrane reviews has been published on the efficacy of antidepressant (Lima 2003), carbamazepine (Lima Reisser 2000) and dopamine agonists (Soares 2003) for the treatment of cocaine dependence but none of them found support for the efficacy of these treatments. One protocol has been published on the efficacy of psychosocial treatments for psychostimulants dependence (Soares 2001) and we will wait the results of the review to see if these approaches are effective. 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 relay on its ability to increase the availability of monoamines (dopamine, serotonin and noradrenaline) in the brain. The dopamine increase in specific areas of the mesolimbic 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). Antipsychotics have been candidates for the treatment of addiction for their ability to block dopamine receptors and counterbalance the increase in dopaminergic activity related with drugs effects. However, while short-term effect of cocaine is associated with dopamine increase in definite brain areas, acute and protracted withdrawal from this drug is associated with diminished dopaminergic neurotransmission. This reduced dopaminergic tone may underlie impaired hedonic function and increased craving, so maintaining addictive behaviour (Dackis 2002; Kuhar 1996). On these bases, the supposed efficacy of dopamine antagonists in cocaine addiction could be doubted, since their use could even further reduce dopamine tone. While these observations apply well to classical neuroleptics, which exert their action essentially through the dopaminergic system, the so called atypical ones, like risperidone and olanzapine, extend their action to other brain systems which have been involved in drug addiction. Particularly, their action on serotoninergic system has been regarded with interest, given the involvement of serotonin neurotransmission in addictive behaviour (Filip 2005). Criticism to the use of neuroleptics in cocaine addiction refer also to atypical ones, given their antagonist effect on dopamine receptors. However, their interference with serotoninergic system and less severe side effect profile (Berk 1999; Leucht 1999) could favourable influence compliance of patients and promote their retention in treatment. These considerations have been proposed to support the use of atypical neuroleptics in cocaine addiction. Furthermore cocaine use can lead to symptoms mimicking psychosis with hallucinations, paranoia etc and the use of anti psychotics relieve these symptoms. Some of the antipsychotic more commonly studied for this purpose are for example haloperidol, olanzapine, quetiapine, clozapine, risperidone and lamotrigine. There are no systematic reviews already published on the efficacy of antipsychotic agents for the treatment of cocaine dependence. This review assesses the efficacy of antipsychotic pharmacotherapy for the treatment of cocaine dependence. O B J E C T I V E S To evaluate the efficacy and the acceptability of antipsychotic medications for cocaine dependence 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 any antipsychotic medication for cocaine dependence Types of participants Cocaine dependents patients as diagnosed by the Diagnostic and Statistical Manual of Mental Disorder (DSM IV R) or by specialists. Trials including patients with additional diagnoses of substance dependence were also eligible. People under 18 years of age 3

6 and pregnant women were excluded for the substantially different approach to clinical management of these people. People with comorbid mental health conditions were included and considered in a subgroup analysis. Types of interventions Experimental intervention: Any antipsychotic medication alone or in combination with any psychosocial intervention Control Intervention Placebo No intervention Other pharmacological interventions Any psychosocial intervention When we found trials that compared different antipsychotic medications, we made separate subgroup analysis. Furthermore we considered different factors as confounders and took them into account in the analysis wherever 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 (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 Secondary outcomes (5) Compliance (6) Craving as measured by validated scales e.g. Brief Substance Craving Scale (BSCS), Visual Analog Scale (VAS) (7) 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,) (8) Amount of cocaine use (as measured by grams used or money spent) (9) Psychiatric symptoms/psychological distress diagnosed using standard criteria e.g. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria or measured by validated scales e.g. Hamilton depression scale, Profile of Mood States Scale (POMSS), Positive and Negative Syndrome Scale (PANSS) Search methods for identification of studies 1. Electronic searches: We identified relevant studies that meet the predefined inclusion criteria by searching the following sources from the earliest available date to 2006: MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006), CINAHL (1982 to October 2006), Cochrane Drug and Alcohol Group Specialised Register (October 2006) Additional searches We also searched: (1) the reference lists of all relevant papers to identify further studies. (2) some of the main electronic sources of ongoing trials (National Research Register, meta-register of Controlled Trials; Clinical Trials.gov) (3) conference proceedings likely to contain trials relevant to the review (College on Problem of Drug Dependence (1992 to date) and European College of Neuropsychopharmacology (2003 to date) We contacted investigators seeking information about unpublished or incomplete trials. All searches included non-english language literature and studies with English abstracts were assessed for inclusion. When considered likely to meet inclusion criteria, studies were translated. Data collection and analysis (1) Study selection: One author (Amato) 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 two authors (Minozzi, Amato). Doubts were solved by discussion between all the authors. (2) Assessment of the methodological quality: One author (Minozzi) assessed study quality according to the criteria indicated in Cochrane Reviews Handbook 4.2 (Higgins 2006): Selection bias: Empirical research has shown that lack of adequate allocation concealment is associated with bias (Chalmers 1993; Moher 1998; Moher 1999; Schulz 1995). Iindeed, concealment has been found to be most important in preventing bias than other components of allocation, such as the generation of the allocation sequence. Performance bias: 4

7 Systematic differences in the care provided to the participants in the comparison groups and the placebo effect could take place in the addiction field. Blinding of providers avoids co intervention and ascertainment bias whereas blinding of participants avoids contamination, systematic differences in compliance, systematic differences in the placebo effect and detection bias. Attrition bias: Loss to follow up and drop out from the study is one of the major problem in the field of addiction. Retention in treatment is very often the primary outcome measure in these trials; for this reason the information on people who left the study will not be used as a validity criterion. Detection bias: To keep blind the people who will assess outcomes is particularly important when subjective outcome measures are used. Selection bias, performance bias and detection bias have been assessed and rated as follow: (1) Selection bias: allocation concealment A: adequate allocation concealment, central randomizations (e.g. allocation by a central office unaware of subject characteristics), pre-numbered or coded identical bottles or containers which are administered serially to participants, drug prepared by the pharmacy, serially numbered, opaque, sealed envelopes, on-site computer system combined with allocations kept in a locked unreadable; computer file that can be accessed only after the characteristics of an enrolled participant have been entered or other description that contained elements convincing of concealment.; B: unclear allocation concealment: when the authors either did not report an allocation concealment approach at all or report an approach that did not fall in the category A or C. C: inadequate allocation concealment: alternation or reference to case numbers, dates of birth, day of the week. Any procedure that is entirely transparent before allocation, such as an open list of random numbers or other description that contained elements convincing of not concealment (2) Performance bias: blinding of those providing and receiving the intervention A: double blind B: single blind (blinding of participants) C: unclear D: no blinding (3) Detection bias: blinding of the outcome assessor A) Blind to treatment allocation at outcome assessment B) Unclear C) Not blind to treatment allocation at outcome assessment The methodological quality has not been used as a criterion for inclusion; in order to assess the effect of the low quality studies a sensitivity analysis, either including or excluding the classes C studies from meta-analysis was performed. (3) Data extraction Data were extracted independently by two authors (Amato, Minozzi). Any disagreement was discussed. Key findings were summarized narratively in the first instance and assessed for meta-analysis where possible. (4) Data synthesis: Dichotomous outcomes have been analysed calculating the Relative risk (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals. Continuous outcomes have been analysed calculating the Weighted Mean Difference (WMD) with 95%CI. For craving score (Brief Substance Craving Scale BSCS) we compared the post intervention mean score of the experimental and control group. For severity of dependence (Addiction Severity Index - Drug ASI, Clinical Global Impression - Observer CGI-S), depression (Hamilton Depression scale HAM- D), anxiety (Hamilton anxiety scale Ham-A) we compared the mean score differences from the end of treatment to baseline in the experimental and control group. In case of missing standard deviation of the differences from baseline to the end of treatment, the standard deviation were imputed using the standard deviation of the mean score at the end of treatment for each group. The outcomes from the individual trials have been combined through meta-analysis where possible (comparability of intervention and outcomes between trials) using a fixed effect model unless there was significant heterogeneity, in which case a random effect model have been used. A P-value of the chi-square test less than 0.05 indicates a significant heterogeneity. We have not used data presented as number of positive urine tests over total number of tests in the experimental and control group as measure of substance abuse. This is because using tests instead of the participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent. 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, which could indicate possible publication bias. See Figure 1 5

8 Figure 1. Funnel plot showing precision of trials versus treatment effect R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. We identified 96 reports, 76 were excluded on basis of title and abstract; 21 articles were retrieved in full text for more detailed evaluation, 12 of which were excluded, two are awaiting assessment and seven satisfied all the criteria to be included in the review. See Figure 2 For substantive descriptions of studies see Characteristics of Included studies and Characteristics of excluded studies tables. Furthermore we identified five ongoing studies retrieved in see Characteristics of ongoing studies table 6

9 Figure 2. 7

10 Excluded studies Twelve studies did not meet the criteria for inclusion in this review. The grounds for exclusion were the following: study design not in the inclusion criteria: four studies (De La Garza 2005; Gawin 1989; Smelson 2002; Stone 1993); objective of the studies and outcomes measures not in the inclusion criteria: four studies ( Evans 2001; Farren 2000; Price 1997; Sherer 1988) ; impossibility to extract useful data: four studies (Grabowski 2000; Landabaso 2003; Sayers 2005; Tsuang 2002). Ongoing studies We found five ongoing studies: Brown S; Grabowski J; Haney M; Nejtek VA; Rush CR Studies awaiting assessment We found two studies (Nunes EV; Price L); Nunes EV presented as poster at 36 th Annual Meeting of the American College of Neuropsychopharmacology in the 1997, is a study on risperidone for cocane dependence for which we were unable to find a published article. We wrote to the author requesting data to evaluate the possibility of including the study in the review, we did not receive a response. Price L is the first author of a trial found on on risperidone versus placebo, the sudy started in January 1996 and ended in January 2000, but apparently was never published; we wrote to the author requesting data to evaluate the possibility of including the study in the review and we are waiting answer. Included studies Seven studies with a total of 293 participants meet the inclusion criteria for this review. Duration of trials: The mean duration of the trials was 61 days (range 5 to 168 days) Treatment regimes and setting: All seven studies were conducted in USA. The antipsychotic medication utilized in the included studies were: Risperidone: three studies (Grabowski arm a 2004; Grabowski arm b 2004; Levin 1999; Smelson 2004), mean dose 2.27 mg/day (range 1 to 4 mg); Olanzapine: three studies (Kampman 2003; Reid 2005; Smelson 2006), all using a dose of 10 mg/day; Haloperidol: two studies (Berger 1996; Smelson 2006), using doses of 4 and 10 mg/day respectively. Four studies were conducted in outpatient setting and 3 in inpatient. Participants: 293 cocaine addicts according to DSM criteria (DSM IV R). 169/ 293 (58%) were males but two studies (Smelson 2004; Smelson 2006) did not report data on gender; mean age years. Rating instruments utilized in the studies: Craving: Brief Substance Craving Scale (Somoza 1995) utilised by Kampman 2003 and Reid 2005 Cocaine Craving Questionnaire (Tiffany 1993) utilised by Reid 2005 Visual Analogue Scale (McCormack 1988) utilised by Berger 1996 and Levin 1999 Voris Cocaine Craving Questionnaire (Smelson 1999) utilised by Smelson 2004 and Smelson 2006 Within Session Rating Scale (Childress 1986) utilised by Berger 1996 Severity of dependence Addiction Severity Index (McLellan 1992) utilised by Kampman 2003 and Reid 2005 Clinical Global Impression Scale (Guy 1976) utilised by Kampman 2003 and Reid 2005 Anxiety Hamilton Anxiety Rating Scale (Hamilton 1959) utilised by Kampman 2003 and Reid 2005 Depression Hamilton Depression Rating Scale (Hamilton 1967) utilised by Kampman 2003 and Reid 2005 Psychopathology Positive and Negative Syndrome Scale (Kay 1992);utilised by Smelson 2006 Withdrawal symptoms Cocaine Selective Severity Assessment (Kampman 1998) utilised by Kampman 2003 Comparisons: 01 Any antipsychotic versus placebo: seven studies, 293 participants (Berger 1996; Grabowski arm a 2004; Grabowski arm b 2004; Kampman 2003; Levin 1999; Reid 2005; Smelson 2004) 02 Risperidone versus placebo: three studies, 144 participants ( Grabowski arm a 2004; Grabowski arm b 2004; Smelson 2004) 03 Olanzapine versus placebo: two studies, 98 participants ( Kampman 2003; Reid 2005) 04 Olanzapine versus haloperidol: one study, 31 participants ( Smelson 2006) 05 Haloperidol versus placebo: one study, 20 paricipants (Berger 1996) The study of Grabowski 2004 has three arms comparing risperidone 2 mg (Grabowski arm a 2004) and 4 mg (Grabowski arm b 2004) versus placebo, the 33 participants in the placebo arm were considered in each of the comparisons 01 and 02. 8

11 Risk of bias in included studies Six studies were randomised controlled trial. One study was a randomized cross over trial (Berger 1996) Selection bias Three studies (Grabowski arm a 2004; Grabowski arm b 2004; Reid 2005) had an adequate allocation concealment. In all the other studies the concealment of allocation was unclear. Performance bias All the studies included in the review were double-blind controlled trials Detection bias In only one study (Reid 2005) the outcome assessor was blind to treatment allocation. In all the other studies it was unclear wheter the outcome assessor was blinded. Sensitivity analysis excluding studies with inadequate allocation concealment was not performed because none of the included studies had inadequate allocation concealment. Effects of interventions The results were summarized, with comparison of quantitative data where possible, first for any antipsychotic versus placebo and then comparing separately the different types of antipsychotic medications versus placebo and olanzapine versus haloperidol. For some outcomes reported in the included studies, it was impossible to make comparisons and pool results due to the different ways of reporting the results. Different rating instruments were utilized and for many of them the authors did not indicate the scores considered to represent boundaries of mild, moderate and severe to allow comparison of results between studies. Primary outcomes Dropouts from the treatment Number of participants who did not complete the treatment (01) Any antipsychotic versus placebo Six studies (Grabowski arm a 2004; Grabowski arm b 2004; Kampman 2003; Levin 1999; Reid 2005; Smelson 2004), 208 participants, see comparison 01, outcome 01, Relative Risk (RR) 0.79 (95% confidence interval (CI) 0.62 to 1.01), the result is not statistically significant but show a trend in favour of antipsychotic. (02) Risperidone versus placebo Four studies ( Grabowski arm a 2004 ; Grabowski arm b 2004 ; Levin 1999 Smelson 2004 ), 178 participants, see comparison 02, outcome 01, RR 0.77 (95% CI 0.61 to 0.98), the result is statistically significant in favour of risperidone (03) Olanzapine versus placebo One study (Kampman 2003), 30 participants, see comparison 03, outcome 01, there is no statistically significant difference between olanzapine and placebo (04) Olanzapine versus haloperidol One study (Smelson 2006) 31 participants, see comparison 04, outcome 01, there is no statistically significant difference between olanzapine and placebo Acceptability of the treatment Number of participants presenting side effects and type of side effects experienced (03) Olanzapine versus placebo One study (Reid 2005) 34 participants, see comparison 03, outcome 02, there is no statistically significant difference between olanzapine and placebo Use of primary substance of abuse Number of participants that reported the use of cocaine during the treatment ( 03) Olanzapine versus placebo One study (Reid 2005) 31 participants, see comparison 03, outcome 03, there is no statistically significant difference between olanzapine and placebo Results at follow up None of the included studies presented results on compliance in a way suitable for iuse in a metanalysis or narrative description Secondary outcomes Compliance None of the included studies presented results on compliance in a way suitable for iuse in a metanalysis or narrative description Craving The included studies used different scales to rate this outcome limiting the possibility to pool data (02) Risperidone versus placebo Measured by Mean Increase of Visual Analog Scale One study (Levin 1999),14 participants, in a scale from 0 to 100, the percentage reduction of the score after treatment was of -31% in the risperidone group and of -49% in the placebo group the result was not statistically significant (03) Olanzapine versus placebo Measured by Brief Substance Craving Scale Two studies (Kampman 2003; Reid 2005), 61 participants see comparison 03, outcome 04, Weighted Mean Difference (WMD) (95% CI to 0.02) the result is not statistically significant measured by Cocaine Craving Questionnaire One study (Reid 2005), 34 participants see comparison 03, outcome 05, WMD (95% CI to -0.26) the result is favour of olanzapine, but the generalizability is really low due the very small sample size (04) Olanzapine versus haloperidol Measured by Voris Cocaine Craving Questionnaire One study (Smelson 2006), 31 participants see comparison 04, outcome 02, there is no difference between olanzapine and haloperidol (05) Haloperidol versus placebo measured by Mean Increase of Visual Analogue Scale 9

12 One study (Berger 1996), 20 participants, in a scale from 0 to 100, after a cue exposure, the craving increase of 3.5 in the haloperidol group and of 20.4 in the placebo group, p=0.03, the result is statistically significant in favour of placebo but the generalizability is low due to the very small sample size Severity of dependence (03) Olanzapine versus placebo Measured by Addiction severity Index Two studies (Kampman 2003; Reid 2005), 61 participants see comparison 03, outcome 06, WMD (95% CI to 0.07) the result is not statistically significant Measured by Clinical Global Impression Scale Two studies (Kampman 2003; Reid 2005), 61 participants see comparison 03, outcome 07, WMD 0.05 (95% CI to 0.80) the result is not statistically significant Amount of cocaine use Measured by grams used or money spent None of the included studies reported data on this outcome Psychiatric symptoms/psychological distress Depression (03) Olanzapine versus placebo measured by Hamilton depression Rating Scale Two studies (Kampman 2003; Reid 2005), 61 participants see comparison 03, outcome 08, WMD (95% CI to 1.05) the result is not statistically significant Anxiety (03) Olanzapine versus placebo Measured by Hamilton Anxiety Rating Scale Two studies (Kampman 2003; Reid 2005), 61 participants see comparison 03, outcome 09, WMD 0.01 (95% CI to 3.48) the result is not statistically significant (05) Haloperidol versus placebo Measured by Mean Increase of Visual Analogue Scale One study (Berger 1996), 20 participants, in a scale from 0 to 100, the anxiety increase of 0.00 in the haloperidol group and of 7.8 in the placebo group, p=0.01, the result is statistically significant in favour of haloperidol but the generalizability is really low due to the very small sample size Psychopathology (04) Olanzapine versus haloperidol Measured by Positive and Negative Syndrome Scale One study (Smelson 2006), 31 participants see comparison 04, outcome 03, WMD 7.80 (95% CI 2.97 to 12.63) the result is in favour of haloperidol, but the generalizability is really low due the very small sample size Withdrawal symptoms (03) Olanzapine versus placebo Measured by Cocaine Selective Severity Assessment One study (Kampman 2003), 30 participants see comparison 03, outcome 10, WMD (95% CI to 0.31) the result is not statistically significant D I S C U S S I O N Very limited evidence can be drawn from the seven small trials included in this review. They considered risperidone, olanzapine and haloperidol as antipsychotic agents for the treatment of cocaine dependence comparing them with placebo and in one study (Smelson 2006) comparing olanzapine versus haloperidol. Unfortunately, the only outcome considered by all studies was drop out from treatment.. Overall, no significant differences were found for any of the efficacy measures comparing any antipsychotic with placebo. Risperidone was found to be superior to placebo for the number of people that dropped out from the treatment in four studies (Grabowski arm a 2004; Grabowski arm b 2004; Levin 1999; Smelson 2004) involving 178 participants. Furthermore also olanzapine showed better results compared with placebo for craving in one study (Reid 2005) involving 34 participants, and haloperidol was found better than placebo in decreasing craving and anxiety in one study involving 20 participants (Berger 1996) and better than olanzapine in reducing psychiatric symptoms in one study (Smelson 2006) involving 31 participants, but the three studies were too small to give conclusive results. Although the methodological quality of the included studies was good, the sample sizes were quite small, and the outcomes considered in the included studies did not include measures of side effects, use of cocaine during the treatment and craving. When these outcomes were reported it was not possible to undertake a cumulative analysis because of the great heterogeneity of the scales used in the primary studies and the way in which results are reported. This is a significant deficit given that the primary aim of a treatment of cocaine dependence is to enable withdrawal to be completed in safety and comfort. Furthermore, in spite of a comprehensive bibliographic search, all the seven included studies were conducted in the USA and this is another limit to the generalizability of the results because health effects of various substances of abuse seem to be strongly dependent on social context, and the location of the conduct of the studies could act as an effect modifier in the estimation of efficacy of treatment. In conclusion, the results of the present review do not support the use of antipsychotic medication for cocaine dependence, but these results could not be considered conclusive due principally to the small sample size and lack of information on relevant outcomes. A funnel plot showed no evidence of publication bias or other bias 10

13 potentially related with the small sample size of studies included in the meta-analysis. However, the power of this method to detect bias is limited in situation like this one where only few small studies could have been included in the meta-analysis Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, researchers should agree in designing larger randomised investigations, studying relevant outcomes and achieving greater consistency in the means of assessing and reporting those outcomes to enable meaningful cumulative analysis in the future. To enable comparison and pooling of results when different rating instruments are used researchers should indicate the scores to represent boundaries of mild, moderate and severe withdrawal to allow comparison of results between studies. 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 small clinical trials at present there is no current evidence supporting the clinical use of antipsychotic medications in the treatment of cocaine dependence, but these results could not be considered conclusive due principally to the small sample size and lack of information on relevant outcomes. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Implications for research In general, overall quality of the included studies was reasonable, but most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during the treatment and craving or, when reported them it was not possible to undertake a cumulative analysis because of the great heterogeneity of the scales used in the primary studies and in the way in which results are reported. Furthermore, most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during the treatment and craving or, when reported them it was not possible to undertake a cumulative analysis because of the great heterogeneity of the scales used in the primary studies and in the way in which results are reported. Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, we need to improve the primary research in the field of addictions in order to make the best possible use out of a single study. Researchers should agree in designing larger randomised investigations analysing relevant outcomes and achieving greater consistency in outcomes that are assessed and the means of assessing and reporting those outcomes to enable meaningful cumulative analysis in the future. For example, to enable comparison and pooling of results when different rating instruments are used researchers should indicate the scores to represent boundaries of mild, moderate and severe withdrawal to allow comparison of results between studies. Moreover some efforts should be done also to investigate the efficacy of other type medications, like anticonvulsant, currently used the clinical practice and the efficacy of non-pharmacological interventions. A C K N O W L E D G E M E N T S We want to thank Simona Vecchi, the trial search co-ordinator for her help in retrieve articles for the review R E F E R E N C E S References to studies included in this review Berger 1996 {published data only} Berger SP, Hall S. Mickallan JD, Reid MS, Crawford CA, Delucchi K, et al.haloperidol antagonism of cue-elicited cocaine craving. Lancet 1996;347(9000): Grabowski arm a 2004 {published data only} Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C, Dougherty A, et al.agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 2004;29(7): Grabowski arm b 2004 {published data only} Grabowski J, Rhoades H, Stotts A, Cowan K, Kopecky C, Dougherty A, et al.agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 2004;29(7): Kampman 2003 {published data only} Kampman KM, Pettinati H, Lynch KG, Sparkman T, O Brien CP. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug and Alcohol Dependence 2003;70 (3): Levin 1999 {published data only} Levin FR, McDowell D, Evans SM, Brooks D, Spano C, Nunes EV. Pergolide mesylate for cocaine abuse: a controlled preliminary trial. The American Journal on Addiction 1999;8(2):

14 Reid 2005 {published data only} Reid MS, Casadonte P, Baker S, Sanfilippo M, Braunstein D, Hitzemann R, et al.a placebo-controlled screening trial of olanzapine, valproate and coenzyme Q10/L-carnitine for the treatment of cocaine dependence. Addiction 2005;100( (Sup 1)): Smelson 2004 {published data only} Smelson DA, Williams J, Ziedonis D, Sussner BD, Losonczy MF, Engelhart C, et al.a double-blind placebo controlled pilot study of risperidone for decreasing cueelicited craving in recently withdrawn cocaine dependent patients. Journal of Substance Abuse Treatment 2004;27(1): Smelson 2006 {published data only} Smelson DA, Ziedonis D, Williams J, Losonczy MF, Williams J, Steinberg ML, et al.the efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence. Journal of Clinical Psychopharmacology 2006;26(1):9 12. References to studies excluded from this review De La Garza 2005 {published data only} De La Garza R, Newton TF. Risperidone diminishes cocaine-induced craving. Psychopharmacology 2005;178(2-3): Evans 2001 {published data only} Evans SM, Walsh SL, Levin FR, Foltin RW, Fischman MW, Bigelow GE. Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans. Drug and Alcohol Dependence 2001;64(3): Farren 2000 {published data only} Farren CK, Hameedi FA, Rosen MA, Woods S, Jatlow P, Kosten TR. Significant interaction between clozapine and cocaine in cocaine addicts. Drug and Alcohol Dependence 2000;59(2): Gawin 1989 {published data only} Gawin FH, Allen D, Humblestone B. Outpatient treatment of crack cocaine smoking with flupenthixol decanoate. Archives of General Psychiatry 1989;46(4): Grabowski 2000 {published data only} Grabowski J, Rhoades H, Silverman P, Schmitz JM, Stotts A, Creson D, et al.risperidone for the treatment of cocaine dependence: randomized, double trial. Journal of Clinical Psychopharmacology 2000;20(3): Landabaso 2003 {published data only} Landabaso M, Iraurgi I, Jimenez JM, Hormaechea JA, Sanz J, Larrazabal A, et al.olanzapina and cocaine consumption in methadone maintenance programs: new results [Olanzapina y consumo de cocaina en programas de mantenimiento con metadona: nuevos resultados]. Psiq Biol 2003;10(5): Price 1997 {published data only} Price LH, Pelton GH, McDougle CJ, Malison RT, Jatlow P, Carpenter L, et al.effects of acute pretreatment with risperidone on responses to cocaine in cocaine addicts. Poster presented at the 36th Annual Meeting of the American College of Neuropsychopharmacology, Waikoloa, Hawai, USA Sayers 2005 {published data only} Sayers SL, Campbell EC, Kondrich J, Mann SC, Cornish J, O Brien C, et al.cocaine abuse in schizophrenic patients with olanzapine versus haloperidol. The Journal of Nervous and Mental Diseases 2005;139(6): Sherer 1988 {published data only} Sherer MA, Kumor KM, Jaffe JH. Effects of intravenous cocaine are partially attenuated by haloperidol. Psychiatry Research 1988;27(2): Smelson 2002 {published data only} Smelson DA, Losonczy MF, Craig WD, Kaune M, Williams J, Ziedonis D. Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence.. Canadian Journal of Psychiatry 2002;47(7): Stone 1993 {published data only} Stone AM, Greenstein RA, Gamble G, McLellan TA. Cocaine use by schizophrenic outpatients who receive depot neuroleptic medication. Hospital and Community Psychiatry 1993;44(2): Tsuang 2002 {published data only} Tsuang J, Marder SR, Han A, Hsieh W. Olanzapine treatment for patients with schizophrenia and cocaine abuse. J Clin Psychiatry 2002;63: References to studies awaiting assessment Nunes EV {unpublished data only} Price L {unpublished data only} References to ongoing studies Brown S {unpublished data only} A Randomized, Double-Blind, Placebo-Controlled Add-On Trial of Quetiapine in Patients With Bipolar Disorder and Cocaine Dependence. Ongoing study November Grabowski J {published data only} Pharmacotherapy Dosing Regimen in Cocaine and Opiate Dependent Individuals. Ongoing study June Haney M {unpublished data only} Effects of Aripiprazole on Cocaine Craving and Self- Administration. Ongoing study April Nejtek VA {unpublished data only} A Randomized Control Trial Comparing Quetiapine to Risperidone in Bipolar Disorder Outpatients With Current Stimulant Dependence. Ongoing study October Rush CR {unpublished data only} Preventing Cocaine Relapse: Developing Pharmacotherapies. Ongoing study January Additional references Berk 1999 Berk M, Brooks S, Trandafir A. A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: 12

15 a double blind, randomized controlled trial. Int. Clin. Psychopharmacol 1999;14(3): Chalmers 1993 Chalmers I. The Cochrane collaboration: preparing, maintaining, and disseminating systematic reviews of the effects of health care. Annals of the New York Academy of Sciences 1993;703:156-63; discussion Childress 1986 Childress AR, McLellan AT, O Brien CP. Abstinent opiate abusers exhibit conditioned craving, conditioned withdrawal and reductions in both through extinction. British Journal of Addiction 1986;81(5): Craddok 1997 Craddok SG, Rounds-Bryant JL, Flinn PM, Hubbard RL. Characteristics and pre-treatment behaviours of clients entering drug abuse treatment: 1969 to American Journal of Drug and Alcohol Abuse 1997;23(1): Dackis 2002 Dackis CA, O Brien CP. Cocaine dependence: the challenge for pharmacotherapy. Current Opinion in Psychiatry 2002; 15: Davoli in press Davoli M, Pasqualini F, Belleudi V, Bargagli AM, Perucci CA. Changing pattern of drug abuse among patients entering treatment in Lazio, Italy, : transition from heroin to cocaine use. European Addiction Research. Di Chiara 1988 Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988;85(14): Drevets 1999 Drevets WC, Price JC, Kupfer DJ, Kinahan PE, Lopresti B, Holt D, et al.pet Measures of Amphetamine-Induced Dopamine Release in Ventral versus Dorsal Striatum. Neuropsychopharmacology 1999;21(6): Drevets 2001 Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, et al.amphetamine-induced Dopamine Release in Human Ventral Striatum Correlates with Euphoria. Biol. Psychiatry 2001;49(2): DSM IV R AAVV. Diagnostic and Statistical Manual of Mental Disorders. 4 edition. Washington DC: American Psychiatric Association, EMCDDA 2006 The state of the drugs problem in the European Union and Norway. European Monitoring Centre for Drug and Drug Abuse; Luxemburg Faggiano 2003 Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: / ] Filip 2005 Filip M, Frankowska M, Zaniewska M, Golda A, Przegalinski E. The serotonergic system and its role in cocaine addiction.. Pharmacol Rep 2005;57(6): Grabowski 1997 Grabowski J, Roache JD, Scmitz JM, Rhoades H, Creson D, Korszun A. Replacement medication for cocaine dependence. Journal of Clinical Psychopharmacology 1997; 17(6): Guy 1976 Guy W. Assessment Manual for Psychopharmacology. Vol. Publication ADM , Washington DC: US Department of Health Education and Welfare, Hamilton 1959 Hamilton M. The assessment of anxiety states by rating. British Journal Med Psycol 1959;32(1):50 5. Hamilton 1967 Hamilton M. Development of a rating scale for primary depressive illness. British Journal Soc Clin Psychol 1967;6(4): Higgins 1994 Higgins ST, Budney AJ, Bickel WK, Foerg FE, Donham R, Badjer GJ. Incentives Improve Outcome in Outpatient Behavioral Treatment of Cocaine Dependence. Archives of General Psychiatry 1994;51(7): Higgins 2006 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions [updated May 2005]. The Cochrane Library 2006, issue 3. Kampman 1998 Kampman K, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, D Angelo L, et al.reliability and validity of the cocaine selective severity assessment. Addict Behav 1998;23(4): Karch 2006 Karch SB. A Brief History of Cocaine. 2nd Edition. New York, NY: CRC Press, Kay 1992 Karch SB. A Brief History of Cocaine. Vol. 2nd edition, New York NY: CRC Press, Kosten 1996 Kosten T, McCance E. A review of pharmacotherapies for substance abuse. American Journal of Addiction 1996;5(1): Kuhar 1996 Kuhar MJ, Pilotte NS. Neurochemical changes in cocaine withdrawal. Trends in Pharmacological Sciences 1996;17(7): Leucht 1999 Leucht S, Pitschel-Waltz G, Abraham D, Kissling W. Efficacy and extrapyramidal side effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomised controlled trials. Schizophr Res 1999;35(1):

16 Lima 2003 Lima MS, Reisser AAP, Soares BGO, Farrell M. Antidepressants for cocaine dependence. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: / ] Lima Reisser 2000 Lima Reisser A, Lima MS, Soares BGO, Farrell M. Carbamazepine for cocaine dependence. Cochrane Database of Systematic Reviews 2000, Issue 2. [DOI: / ] Mattick 2003 Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: / ] McCormack 1988 Mc Cormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales. A critical review. Psychological Medicine 1988;18: McLellan 1992 McLellan AT, Kushner H, Metzger D, Peters R, Smith I, Grissom G, et al.the fifth edition of the Addiction Severity Index. Journal Substance Abuse Treatment 1992;9 (3): Moher 1998 Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet 1998;352(9128): Moher 1999 Moher D, Cook DJ, Eastwood S, Olkin I, Drummond R, Stroup DF for the Quorum Group. Improving the quality of reports of metananalysis of randomised controlled trials: the QUORUM statement. Lancet 1999;354(9193): NSDUH 2005 Substance Abuse and Mental Health Services Administration (2005). Overview of Findings from the 2004 National Survey on Drug Use and Health (Office of Applied Studies, NSDUH Series H-27, DHHS Publication No. SMA ). Rockville, MD.. Ntais 2005 Ntais C, Pakos E, Panayiotis K, Ioannidis JPA. Benzodiazepines for alcohol withdrawal. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: / ] O Brian 2001 O Brian C. Drug addiction and drug abuse. In: Hardman JG, Lee CL editor(s). The pharmacological basis of Therapeutics. New York: MCGraw-Hill, 2001: Polycarpou 2005 Polycarpou A, Papanikolaou P, Contopoulos-Ioannidis DG, Ioannidis JPA. Anticonvulsants for the management of alcohol withdrawal. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: / ] Schulz 1995 Schulz, KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5): Siliquini 2005 Siliquini R, Morra A, Versino E, Renga G. Recreational drug consumers: who seek treatment?. European Journal of Public Health 2005;15(6): Smelson 1999 Smelson DA, McGee-Caulfield E, Bergstein P, Engelhart C. Initial validation of the v oris cocaine craving scale: a preliminary report. Journal of Clinical Psychology ;55(1): Soares 2001 Soares BGO, Lima MS, Farrell M (Protocol). Psychosocial treatments for psychostimulants dependence. Cochrane Database of Systematic Reviews 2001, Issue 3. [DOI: / ] Soares 2003 Soares BGO, Lima MS, Reisser AAP, Farrell M. Dopamine agonists for cocaine dependence. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: / ] Somoza 1995 Somoza E, Dyrenforth S, Goldsmith J, Mezinskis J, Cohen M. In search of a universal drug craving scale. Annual Meeting of the American Psychiatric Association Sorensen 1991 Sorensen JL, Wermuth LA, Gibson DR, Choi K, Guydish JR. Preventing AIDS in drug abusers and their sexual partners. New York: Guilford, Suelves 2001 Suelves JM, Brugal MT, Cayla JA, Torralba L. Change in health-related problems of cocaine consumption in Catalonia, Spain. Med Clin (Barc) 2001;117(15): Tiffany 1993 Tiffany ST, Singleton E, Haertzen CA, Henningfield JE. The development of a cocaine craving questionnaire. Drug and Alcohol dependence 1993;34(1): Topp 2003 Topp L, Day C, Degenhardt L. Changes in patterns of drug injection concurrent with a sustained reduction in the availability of heroin in Australia. Drug & Alcohol Dependence 2003;70(3): Volkow 2003 Volkow ND, Fowler JS, Wang GJ. The addicted human brain: Insights for imaging studies. Journal of Clinical Investigation 2003;111(10): Indicates the major publication for the study 14

17 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Berger 1996 Methods Randomised cross over placebo controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: unclear Participants Participants: 20, mean age 47.4 years, all males; mean educational level 13.6 years; Cocaine use last 30 days: mean 11.2 days; lifetime 13.9 years Inclusion criteria: DSM IV criteria for cocaine dependence. Exclusion criteria: acute mood disorder, psychotic disorders, not responsive to cue exposure test Interventions Single dose, crossover, (1) Haloperidol 4 mg and (2) placebo Cue exposure 5 min following after one hour the medication/placebo (videotape) Inpatient. Duration: 5 days. Country of origin: USA Outcomes Craving (VAS,WSRS ) Notes Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Grabowski arm a 2004 Methods Participants Interventions Randomised placebo controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: adequate Participants 96, mean age 36.9 years, 40.6% female, 79.2% white, 10.4% Hispanic, 10.4% black; mean educational level 12.3 years; 68% unemployed, 25% employed, 7% student or retired; use of cocaine: 20.9% less once/week, 6.3% once a week, 38.5% several times/week, 28.1% once a day, 6.3% greater than three times/day. Inclusion criteria: meet DSM criteria for cocaine dependence, good medical health and no other psychiatric diagnoses (1) Risperidone 2 mg/day (32 participants) versus (2) Placebo (33 participants). Outpatient. Duration: 24 weeks. Country of origin: USA 15

18 Grabowski arm a 2004 (Continued) Outcomes Retention, Side effects, Cocaine use, Changes in blood pressure Notes Risk of bias Item Authors judgement Description Allocation concealment? Yes A - Adequate Grabowski arm b 2004 Methods Participants Interventions Outcomes Randomised placebo controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: adequate Participants 96, mean age 36.9 years, 40.6% female, 79.2% white, 10.4% Hispanic, 10.4% black; mean educational level 12.3 years; 68% unemployed, 25% employed, 7% student or retired; use of cocaine: 20.9% less once/week, 6.3% once a week, 38.5% several times/week, 28.1% once a day, 6.3% greater than three times/day. Inclusion criteria: meet DSM criteria for cocaine dependence, good medical health and no other psychiatric diagnoses (1) Risperidone 4 mg/day (31 participants) versus (2) Placebo (33 participants). Outpatient. Duration: 24 weeks. Country of origin: USA Retention, Side effects, Cocaine use, Changes in blood pressure Notes Risk of bias Item Authors judgement Description Allocation concealment? Yes A - Adequate Kampman 2003 Methods Participants Randomised placebo controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: unclear Participants 30, mean age 41 years, 73.3% males, 93.3% Africa American, 3.3% Caucasian, 3.3% Native American; mean educational level years; cocaine use: past 30 days mean 12.5 days, use lifetime mean 12 years, numbers of prior treatments mean 2.5; route of administration: 10% intranasal, 86.6% 16

19 Kampman 2003 (Continued) smoked, 10% intravenous. Inclusion criteria: age 18-60, cocaine addiction (certified by a psychiatrist), self reported at least $100 worth of cocaine use in the month prior to entry. Exclusion criteria: dependence on any additional drug (except nicotine and alcohol), psychosis, dementia, use of psychotropic medications, unstable medical illness, pregnancy, hypersensitivity to olanzapine Interventions Outcomes (1) Olanzapine 10 mg/day (15 participants) versus (2) placebo (15 participants). Outpatient. Duration: 12 weeks. Country of origin: USA Retention, Craving (BSCS); Severity of Dependence (ASI); Anxiety (HARS); Depression (HDRS); Withdrawal symptom (CSSA) Notes Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear Levin 1999 Methods Participants Interventions Outcomes Randomised placebo controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: unclear Participants 14, mean age 39.9 years, 71% males, 43% Africa American, 43% Hispanic, 14% Caucasian; mean educational level 13.6 years; cocaine use: past 30 days mean 16.1 days, mean amount spent last 30 days $ 70.3; route of administration: 50% intranasal, 50% intravenous/freebase. Inclusion criteria: DSM IV criteria for cocaine dependence Exclusion criteria: physiologic dependence on alcohol, opiates or sedatives; current major depression or dysthymia or any other Axis I disorder requiring psychiatric treatment; pregnancy (1) Risperidone mean 2.1 mg/day (9 participants) versus (2) placebo (5 participants). Outpatient. Duration 12 weeks. Country of origin: USA Dropouts, Cocaine use (urinalysis and self report), Craving (VAS) Notes Risk of bias Item Authors judgement Description Allocation concealment? Unclear B - Unclear 17

20 Reid 2005 Methods Participants Interventions Outcomes Randomised placebo controlled trial. Double blind. Blinding of outcome assessor: yes Allocation concealment: adequate Participants 68, mean age 38.7 years, 50 males, 7 Hispanic, 11 white, 51 black, 1 other; mean educational level 13 years, use of cocaine, lifetime men 14 years, last 30 days mean 16.8 days; route of administration: 20.8% intranasal, 76% smoked, 3% injected. Inclusion and exclusion criteria: CREST criteria Olanzapine 10 mg/day (18 participants), versus placebo (16 participants). Outpatient. Duration: 8 weeks. Country of origin: USA Dropouts; Side effects; Use of cocaine (self reported); Craving (BSCS, CCQ); Severity of dependence (ASI, CGIS); Anxiety (HARS); Depression (HDRS) Notes Risk of bias Item Authors judgement Description Allocation concealment? Yes A - Adequate Smelson 2004 Methods Randomised controlled trial. Double blind. Blinding of outcome assessor: unclear Allocation concealment: unclear Participants Participants 34, mean age 41.2, cocaine use in the last 30 days: mean 5.4; years of cocaine use: 6.3. Inclusion criteria: DSM IV criteria for cocaine dependence, use of at least 6 gr of cocaine in the past month, responded to cue exposure increased craving. Exclusion criteria: DSM IV criteria for any additional AXIS I disorder and dependence (excluded nicotine), taking prescribed medication that could affect the central nervous system, history of seizures, pregnancy Interventions Outcomes Risperidone 1 mg/day (19 participants), Placebo (16 participants). Cue exposure: videotape. Inpatient. Duration: 2 weeks. Country of origin: USA Dropouts, Craving (VCCQ) Notes Risk of bias Item Authors judgement Description 18