Dopamine agonists for the treatment of cocaine dependence
Abstract
Background
Cocaine misuse is a disorder for which no pharmacological treatment of proven efficacy exists. Advances in neurobiology could guide future medication development.
Objectives
To investigate the efficacy and acceptability of dopamine agonists alone or in combination with any psychosocial intervention for the treatment of of people who misuse cocaine.
Search methods
We run the search on 12 January 2015. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE, CINAHL, PsycINFO, ICTRP, clinicaltrials.gov and screened reference lists.
Selection criteria
Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing dopamine agonists alone or associated with psychosocial intervention with placebo, no treatment or other pharmacological interventions.
Data collection and analysis
We used standard Cochrane methodological procedures.
Main results
Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants, we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence.
The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes.
Authors' conclusions
Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update.
PICOs
Plain language summary
Dopamine agonists for the treatment of people who misuse cocaine
Background
A pharmacological agent with proven efficacy does not exist for treatment of cocaine misuse. Cocaine is an alkaloid derived from the erythroxylon coca leaf that is used as powder for intranasal or intravenous use or as crack, a free‐base form which is smoked. Cocaine misuse is a major public health problem because its use can be associated with medical and psychosocial complications including the spread of infectious diseases (such as AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. In this Cochrane Review we looked at the evidence on the efficacy and acceptability of dopamine agonists as a treatment, used either alone or in combination with any psychosocial intervention, for people addicted to cocaine.
Study characteristics
We searched scientific databases and internet resources to identify randomised controlled trials (where participants are allocated at random to any dopamine agonist drug or placebo or another type of drug aimed to reduce use of cocaine. We also assessed dropout from treatment and frequency of side effects. We included adults of any gender, age or ethnicity.
Key results
We included 24 studies with 2147 participants, who were all addicted to cocaine. Most were men (82.%)with an average age of 37 years. The mean duration of the included trials was seven weeks (range 1.5 to 16 weeks) Twenty‐two studies were conducted in USA, one in Brazil and one in Spain; all but four were outpatients.
The included trials studied the following drugs: amantadine, bromocriptine, L dopa/Carbidopa, pergolide, cabergoline hydergine, and pramipexole. All compared dopamine agonist versus placebo. Four studies compared amantidine versus antidepressants.
No differences were found between the drugs and placebo for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). Antidepressants was found to be better than the dopamine agonist amantidine for abstinence, but this was based on two studies with very few participants and low quality of evidence. There is no current evidence supporting the clinical use of dopamine agonist medications in the treatment of cocaine misuse. The evidence is current to 12 January 2015.
Authors' conclusions
Summary of findings
| Any dopamine agonist versus placebo for the treatment of cocaine dependence | ||||||
| Patient or population: patients with the treatment of cocaine dependence | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Any dopamine agonist versus placebo | |||||
| Dropouts | Study population | RR 1.04 | 1656 | ⊕⊕⊕⊝ | ||
| 456 per 1000 | 474 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 416 per 1000 | |||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 1.27 | 252 | ⊕⊕⊕⊝ | ||
| 272 per 1000 | 345 per 1000 | |||||
| Moderate | ||||||
| 200 per 1000 | 254 per 1000 | |||||
| Abstinence (objective) | Study population | RR 1.12 | 731 | ⊕⊕⊝⊝ | ||
| 308 per 1000 | 345 per 1000 | |||||
| Moderate | ||||||
| 355 per 1000 | 398 per 1000 | |||||
| Abstinence at follow‐up (objective) | Study population | RR 1.1 | 136 | ⊕⊕⊝⊝ | ||
| 625 per 1000 | 688 per 1000 | |||||
| Moderate | ||||||
| 541 per 1000 | 595 per 1000 | |||||
| Severity of dependence (difference before and after) | The mean severity of dependence (difference before and after) in the intervention groups was | 202 | ⊕⊕⊝⊝ | SMD 1.69 (0.17 to 3.2) | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Most studies were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | ||||||
| Amantadine versus placebo for the treatment of cocaine dependence | |||||
| Patient or population: patients with the treatment of cocaine dependence | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Amantadine versus placebo | ||||
| Dropouts | Study population | RR 0.98 | 484 | ⊕⊕⊕⊝ | |
| 378 per 1000 | 371 per 1000 | ||||
| Moderate | |||||
| 286 per 1000 | 280 per 1000 | ||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 1.19 | 128 | ⊕⊕⊕⊝ | |
| 329 per 1000 | 391 per 1000 | ||||
| Moderate | |||||
| 300 per 1000 | 357 per 1000 | ||||
| Abstinence (objective) | Study population | RR 1.13 | 275 | ⊕⊕⊝⊝ | |
| 307 per 1000 | 347 per 1000 | ||||
| Moderate | |||||
| 355 per 1000 | 401 per 1000 | ||||
| Abstinence at follow‐up (objective) | Study population | RR 1.49 | 76 | ⊕⊕⊕⊝ | |
| 512 per 1000 | 763 per 1000 | ||||
| Moderate | |||||
| 526 per 1000 | 784 per 1000 | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1Most were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | |||||
| Amantidine versus antidepressants for the treatment of cocaine dependence | |||||
| Patient or population: patients with the treatment of cocaine dependence | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Amantidine versus antidepressants | ||||
| Dropouts | Study population | RR 0.86 | 153 | ⊕⊕⊕⊝ | |
| 329 per 1000 | 283 per 1000 | ||||
| Moderate | |||||
| 267 per 1000 | 230 per 1000 | ||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 0.56 | 44 | ⊕⊕⊝⊝ | |
| 320 per 1000 | 179 per 1000 | ||||
| Moderate | |||||
| 335 per 1000 | 188 per 1000 | ||||
| Abstinence (objective) | Study population | RR 0.25 | 68 | ⊕⊕⊝⊝ | |
| 775 per 1000 | 194 per 1000 | ||||
| Moderate | |||||
| 859 per 1000 | 215 per 1000 | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1Most studies were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | |||||
Background
Description of the condition
Cocaine is an alkaloid derived from the leaf of erythroxylon coca. People commonly use it as a 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 (UNODC 2014). There is a wide and well documented range of consequences associated with 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.
The annual prevalence of cocaine use on a global estimate is 0.4% (0.3 to 0.4%), with a higher annual prevalence in Oceania (1.5%) and North America (1.8%), and a lower annual prevalence in Asia (0.05%). The number of first‐time users has declined in recent years due to a decrease in the global availability of cocaine, related to a one‐quarter reduction in the cultivation of coca bush (UNODC 2014)
Although cocaine prevalence figures are much lower than comparable figures for cannabis, the prevalence of use among young adults can be higher than the population average.
In Europe, lifetime prevalence for cocaine among 15‐ to 64‐year‐olds is 4.2% and ranges from 0.4% to 9.0%, with the highest levels being found in Spain (8.8%) and in United Kingdom (UK) (9.0%); recent use among 15‐ to 34‐year‐olds is 1.7% with Spain and UK having rates over 3% (EMCDDA 2014).
In the USA, 0.6% of the population (1.5 million) currently uses cocaine and the lifetime prevalence for cocaine use is about 13.7% (SAMHSA 2014).
Description of the intervention
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. The effect of this drug seems to rely on its ability to increase the availability of monoamines (dopamine, serotonin and noradrenaline) in the brain. An increase in dopamine levels in specific areas of the meso‐limbic system, such as the nucleus accumbens, has been associated with the rewarding effect of drugs and self‐administration behaviour in animal and human (Di Chiara 1988; Drevets 1999; Drevets 2001; Volkow 2003a). Specifically, the speed with which addictive drugs enter the brain and elevates dopamine levels in the nucleus accumbens seems to be positively correlated with addictive potential (Volkow 1995; Volkow 2003b; Kimmel 2007). Among addictive drugs, cocaine is the most directly involved in the activation of dopaminergic system, since acute cocaine‐induced increase of extracellular dopamine is due to the inhibition of its presynaptic reuptake through the blockade of its transporter (Self 1995; Gold 1997; Wise 2005). On the contrary, chronic cocaine abuse leads to down‐regulation of dopaminergic systems (Volkow 1997; Gardner 1999; Volkow 1999a; Volkow 2006; Martinez 2009; Volkow 2010). Depression following post‐cocaine use and cocaine craving may be linked to this down‐regulation.
How the intervention might work
These pre‐clinical findings are the theoretical foundations on which the use of dopamine agonists for the treatment of cocaine dependence is based. Given this knowledge, manipulation of dopamine transmission in the reward circuitry of the brain has been looked as the mainstay of the development of new medications for the treatment of cocaine addiction. More specifically, dopamine agonists or antagonists, acting on brain dopamine transporter or brain dopamine receptors, have been tested.
Use of dopamine agonists is based primarily on two reasons:
-
Slow‐onset long acting dopamine agonists will have less addictive potential (Volkow 1999b; Volkow 2003b);
-
Dopamine agonists will ameliorate dopaminergic dysfunction, counter‐acting mesolimbic dopaminergic down regulation consequent to chronic use of cocaine, thereby reducing craving and the risk of relapse (Gardner 1999; Volkow 1999a; Volkow 2006; Volkow 2010).
Under this assumption, dopamine agonists may alleviate cocaine abstinence symptomatology, reduce craving and the risk of relapse.
Why it is important to do this review
Although effective pharmacotherapy is available for people who are heroin (Faggiano 2003; Mattick 2008; Mattick 2009) or alcohol dependent (Amato 2010; Rösner 2010a; Rösner 2010b), none currently exists for people who are cocaine dependent. This is despite three decades of clinical trials on the efficacy of pharmacological and psychosocial interventions to treat this syndrome.
Four Cochrane Reviews have been published on the efficacy of antipsychotics (Amato 2007), anticonvulsants (Minozzi 2015), antidepressants (Pani 2011) and psychostimulants (Castells 2010) for people with cocaine dependence but none found support for the efficacy of these treatments. Moreover, a Cochrane Review assessing the efficacy and safety of disulphiram (Pani 2010) has shown low evidence supporting its clinical use for the treatment of cocaine dependence.
One Cochrane Review has been published on the efficacy of psychosocial treatments for psychostimulants dependence (Knapp 2007). It shows that existing treatments demonstrate modest outcomes at best. Therefore, there is still a need to develop and test different formats of existing treatment models and newer psychosocial interventions should be undertaken.
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.
The former Cochrane Review on dopamine agonists for cocaine dependence was published in 2003 (Soares 2003) and updated in 2011 (Amato 2011). Moreover, the review on psychostimulants, which actually are dopamine agonists (Castells 2010), did not consider medications devoid of psychostimulant effect. Therefore, a review update is required to examine the effect of dopamine agonists that do not have psychostimulant effects..
Objectives
To investigate the efficacy and acceptability of dopamine agonists alone or in combination with any psychosocial intervention for the treatment of of people who misuse cocaine.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) which focused on the use of dopamine agonists for people who misuse cocaine.
Types of participants
Cocaine misusing as diagnosed by the Diagnostic and Statistical Manual of Mental Disorder (DSM IIIR; DSM IV; DSM‐IV‐R, DSM V) or by specialists. Trials including participants with additional diagnoses of substance dependence were also eligible. We excluded people under 18 years of age and pregnant women for the substantially different approach and clinical management of these people. We included people with comorbid mental health conditions and considered them in subgroup analyses.
Types of interventions
Experimental
-
Any dopamine agonist alone or in combination with any psychosocial intervention. We excluded psychostimulants.
Control
-
Placebo;
-
Other pharmacological interventions;
-
Any psychosocial intervention.
Furthermore, we considered different factors as confounders and accounted for them in the analyses 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 consumption);
-
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
-
Dropouts as number of participants who did not complete the treatment;
-
Acceptability of the treatment as number of participants experiencing adverse effect;
-
Dropouts due to adverse effects;
-
Abstinence self reported or number of participants with urine samples negative for cocaine, or both;
-
Results at follow‐up as number of participants abstinent at follow‐up.
Secondary outcomes
-
Craving as measured by validated scales e.g. Brief Substance Craving Scale (BSCS) or Visual Analog Scale (VAS);
-
Severity of dependence as measured by validated scales e.g. Addiction Severity Index (ASI);
-
Clinical Global valuation as measured by validated scales e.g. Clinical Global Impression Subjective ‐Scale (CGI‐S) or Clinical Global Impression ‐Observer Scale (CGI‐O), Severity of Dependence Scale (SDS);
-
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), or Positive and Negative Syndrome Scale (PANSS).
Search methods for identification of studies
Electronic searches
In Appendix 1 we have detailed the search methods used in the previous version of this review (Amato 2011). Amato 2011 included searches up to June 2011.
For this update, we searched the following electronic databases up to 13 January 2015:
-
CDAG Specialized Register (January 2015);
-
CENTRAL (the Cochrane Library, Issue 1, January 2015);
-
MEDLINE (PubMed) (June 2011 to 12 January 2015);
-
EMBASE (Elsevier, EMBASE.com) (June 2011 to 12 January 2015);
-
CINAHL (EBSCO Host) (June 2011 to 12 January 2015);
-
Web of Science (June 2011 to 12 January 2015).
In addition, we searched for ongoing clinical trials and unpublished studies via internet searches on the following websites on 12 January 2015:
-
ClinicalTrials.gov: www.clinicaltrials.gov;
-
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) www.who.int/ictrp/en/.
See Appendix 2 for the search terms we used in this Cochrane Review update.
Searching other resources
We also searched:
-
Reference lists of all relevant papers to identify further studies;
-
Conference proceedings likely to contain trials relevant to the review;
-
We contacted investigators seeking information about unpublished or incomplete trials.
All searches included non‐English language literature and we assessed studies with English abstracts for inclusion. When considered likely to meet inclusion criteria, studies were translated.
Data collection and analysis
Selection of studies
For the previous update of this review, two review authors (SV, RS) independently screened the titles and abstracts of all publications obtained through the search strategy. We obtained all potentially eligible studies as full text articles. Three review authors (SV, RS, SM) independently assessed these for inclusion. In doubtful or controversial cases, we discussed all identified discrepancies and reached consensus on all items.
For this update, two review authors (SM, FDC) independently screened the titles and abstracts and assessed the full text of potentially eligible studies. In doubtful or controversial cases, we discussed all identified discrepancies and reached consensus on all items.
Data extraction and management
Two review authors (LA, SM) assessed study quality according to the criteria indicated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and extracted data.
Assessment of risk of bias in included studies
We performed 'Risk of bias' assessments for included RCTs and CCTs using the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The recommended approach for 'Risk of bias' assessment in studies included in a Cochrane Review is a two‐part tool, addressing specific domains, namely sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias) and selective outcome reporting (reporting bias). The first part of the tool involves describing what was reported to have happened in the included study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry, in terms of 'low', 'high' or 'unclear' risk. We used the criteria indicated by Higgins 2011 and adapted to the addiction field (see Table 1 for details).
| Item | Judgment | Description |
| 1. Random sequence generation (selection bias)
| Low risk | The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; or minimization. |
| High risk | The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; or availability of the intervention. | |
| Unclear risk | Insufficient information about the sequence generation process to permit judgement of low or high risk. | |
| 2. Allocation concealment (selection bias)
| Low risk | Investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled, randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes. |
| High risk | Investigators enrolling participants could possibly foresee assignments because one of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure. | |
| Unclear risk | Insufficient information to permit judgement of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement. | |
| 3. Blinding of participants and providers (performance bias) subjective outcomes
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 4. Blinding of participants and providers (performance bias) objective outcomes | Low risk |
|
| High risk |
| |
| Unclear risk |
| |
| 5. Blinding of outcome assessor (detection bias) Subjective outcomes
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 6. Blinding of outcome assessor (detection bias) objective outcomes | Low risk |
|
| High risk |
| |
| Unclear risk |
| |
| 7. Incomplete outcome data (attrition bias) For all outcomes except retention in treatment or dropout
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 8. Selective reporting (reporting bias)
| Low risk |
|
| High risk |
| |
| Unclear risk |
|
We addressed the domains of sequence generation and allocation concealment (avoidance of selection bias) in the tool by a single entry for each study.
We considered blinding of participants and outcome assessor (avoidance of detection bias) separately for objective outcomes (e.g. dropout, abstinence measured by urine‐analysis, subjects relapsed at the end of follow‐up) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, craving, patient self‐reported use of substance, side effects, psychiatric symptoms, clinical global valuation).
Incomplete outcome data (avoidance of attrition bias) was considered for all outcomes except for dropout from the treatment, which is very often the primary outcome measure in trials on addiction (see Table 1 for a detailed description on how we assessed the risk of bias in this review).
Grading of evidence
We assessed the overall quality of the evidence for the primary outcome using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. The GRADE Working Group developed a system for grading the quality of evidence (Atkins 2004; Schünemann 2006; Guyatt 2008; Guyatt 2011) which takes into account issues not only related to internal validity but also to external validity, such as directness of results. The 'Summary of findings' tables present the main findings of a review in a transparent and simple tabular format. In particular, they provide key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the main outcomes.
The GRADE system uses the following criteria for assigning grades of evidence:
-
High: further research is very unlikely to change our confidence in the estimate of effect;
-
Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;
-
Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
-
Very low: any estimate of effect is very uncertain.
Quality of the evidence may be downgraded for the following reasons:
-
Serious (‐1) or very serious (‐2) limitation to study quality;
-
Important inconsistency (‐1);
-
Some (‐1) or major (‐2) uncertainty about directness;
-
Imprecise or sparse data (‐1);
-
High probability of reporting bias (‐1).
Quality of the evidence may be upgraded for the following reasons:
-
Strong evidence of association ‐ significant relative risk of > 2 (< 0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1);
-
Very strong evidence of association ‐ significant relative risk of > 5 (< 0.2) based on direct evidence with no major threats to validity (+2);
-
Evidence of a dose response gradient (+1);
-
All plausible confounders would have reduced the effect (+1).
Measures of treatment effect
We analysed dichotomous outcomes (dropouts, abstinence, abstinence at follow‐up, side effects) by calculating the relative risk (RR) for each trial, with the uncertainty in each result being expressed by their confidence intervals (CIs). Continuous outcomes (craving, severity of dependence, clinical valuation, psychiatric symptoms) were analysed by calculating the standardised mean difference (SMD) with 95% CIs. We did not use 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. We made this decision because using the number of tests instead of the number of subjects as the 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. All but adverse events were computed using intention‐to‐treat (ITT) principles.
Unit of analysis issues
If all arms in a multi‐arm trial were included in the meta‐analysis and one treatment arm was included more than once in some comparisons, then we divided the number of events and the number of participants in that arm by the number of treatment comparisons made. This method avoids the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. It compromises the precision of the pooled estimate slightly.
Assessment of heterogeneity
We tested the presence of heterogeneity between trials using the I² statistic and with Chi² test. A P value < 0.1 and an I2 statistic value > 50% indicated significant heterogeneity.
Assessment of reporting biases
We used funnel plots (plot of the effect estimate from each study against the sample size or effect standard error) to assess the potential for bias related to the size of included trials.
Data synthesis
We combined the outcomes from the individual trials through meta‐analysis where possible (comparability of intervention and outcomes between trials) using a random‐effect models because we expected a certain degree of heterogeneity among trials. For the abstinence rate we used the number of randomised patients as the denominator, assuming that people who dropped out continued to use cocaine.
Sensitivity analysis
To incorporate the '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 studies at high risk of bias from the analysis.
Results
Description of studies
For substantive descriptions of studies see the 'Characteristics of included studies' and 'Characteristics of excluded studies' tables.
Results of the search
This is an update of a Cochrane Review first published in 2001 (Soares 2003). In the first edition of this review we identified 442 reports. We excluded 392 on basis of title and abstract. We retrieved50 articles for more detailed evaluation, 27 of which we excluded after reading the full text. The remaining 23 studies satisfied all the inclusion criteria (see Figure 1).
Study flow diagram present update.
In this update, we identified 220 records after bibliographic searches and removal of duplicates. We excluded 213 records on the basis of title and article. We retrieved the full text of seven articles for more detailed evaluation. We excluded five articles after full text evaluation. Two articles, related to one study, met the inclusion criteria (see Figure 2).
Included studies
Twenty‐four studies, 2147 participants, met the inclusion criteria for this Cochrane Review (for details see the 'Characteristics of included studies' tables.
Trial duration
The mean duration of the trials was seven weeks (range 1.5 to 16 weeks).
Treatment regimes and setting
The included studies considered the dopamine agonists of amantadine, bromocriptine, cabergoline, hydergine, L dopa/carbidopa, pergolide and pramipexole:
-
Amantadine: 10 studies compared amantadine with placebo (Giannini 1989; Weddington 1991; Alterman 1992; Kolar 1992; Kosten 1992; Handelsman 1995; Kampman 1996; Pérez de los Cobos 2001; Shoptaw 2002; Kampman 2006 ), four studies with the antidepressant desipramine (Weddington 1991; Kolar 1992; Kosten 1992; Oliveto 1995), one study with the antidepressant fluoxetine (Oliveto 1995), one with the beta‐adrenergic antagonist propanolol (Kampman 2006). The mean dosage of amantadine was 267 mg/day (range 100 to 400 mg/day);
-
Bromocriptine: bromocriptine was considered in five studies compared with placebo (Giannini 1989; Moscovitz 1993; Eiler 1995; Handelsman 1997; Gorelick 2006), the mean dosage of bromocriptine was 6.2 mg/day (range 2.5 to 10 mg/day);
-
L‐dopa/carbidopa: six studies compared L‐dopa/Carbidopa with placebo (Shoptaw 2005; Mooney 2007a; Mooney 2007b; Schmitz 2008; Schmitz 2010; Schmitz 2014), the mean dosages of these drug were respectively 545 mg/183 mg/day (range 75 mg/100 mg to 800 mg/200 mg/day). Schmitz 2014 also compared L‐dopa/carbidopa with naltrexone and modafinil;
-
Pergolide: two studies (Malcolm 2000; Focchi 2005) compared pergolide with placebo and the mean dosage was 0.2 mg/day (range 0.1 to 0.5 mg/day);
-
Single studies considered the other three dopamine agonists: cabergoline (0.5 mg/week) and hydergine (3 mg) were considered in Shoptaw 2005, a study with four arms that also compared L‐dopa/carbidopa and placebo. Ciraulo 2005 considered pramipexole and compared it at a dosage of 1.5 mg with placebo and the antidepressant venlafaxine.
In 16 studies, psychosocial interventions were added to the pharmacological one: cognitive behavioural therapy (Handelsman 1997; Kampman 2006; Schmitz 2008; Schmitz 2014), counselling sessions (Kolar 1992; Kampman 1996; Shoptaw 2002; Shoptaw 2005; Mooney 2007a; Mooney 2007b), contingency management (Schmitz 2008; Schmitz 2010; Schmitz 2014), group relapse prevention therapy (Kosten 1992; Oliveto 1995) and interpersonal psychotherapy (Weddington 1991).
Twenty‐one studies were conducted in outpatient settings and four were performed in inpatient settings.
Participants
All participants were addicted to cocaine according to DSM criteria (DSM IIIR; DSM IV; DSM‐IV‐R; five studies (Kosten 1992; Handelsman 1995; Oliveto 1995; Handelsman 1997; Pérez de los Cobos 2001) enrolled patients with also opioid dependence in methadone maintenance therapy. Most participants were male (82%), with a mean age of 37 years.
Trial location (country)
Twenty‐two studies were conducted in the USA, one in Brazil and one in Spain.
Comparisons
-
Any dopamine agonist versus placebo;
-
Amantadine versus placebo;
-
Bromocriptine versus placebo;
-
L dopa/carbidopa versus placebo;
-
Amantadine versus antidepressants.
Excluded studies
We excluded 32 studies from this review for the following reasons: inappropriate outcome measures (13 studies); inappropriate study design (six studies); inappropriate type of intervention considered (nine studies), comparisons considered not in the inclusion criteria (two studies), study design and outcomes not in the inclusion criteria (two studies). See the 'Characteristics of excluded studies' table for further details.
Risk of bias in included studies
We have presented judgements for each 'Risk of bias' item for each included study (Figure 2) and as percentages across all included studies (Figure 3).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Random sequence generation
Only five included studies (20.8%) used an adequate method of sequence generation. We classifed all other included studies at unclear risk of bias because the trial authors gave no information about the method used.
Allocation concealment
Only four included studies (16.6%) used an adequate method of allocation concealment. The remaining studies were classified at unclear risk of bias because no information was given about the method used.
Blinding
Performance bias
All but two trials adopted a double‐blind design. Weddington 1991 and Focchi 2005 were both single‐blinded and judged at high risk of bias for subjective outcomes. Ten trials (41.6%) gave detailed information about the way to maintain blinding and were judged at low risk of bias. We considered the remaining trials at unclear risk for subjective outcomes. We judged all included studies at low risk of performance bias for objective outcomes.
Detection bias
Two studies were single blinded and were judged at high risk of detection bias (Weddington 1991; Focchi 2005). Seven trials (29.1%) stated that outcome assessors were blinded. We judged all other included studies at unclear risk of detection bias.
Incomplete outcome data
Seventeen included studies (70.8%) were judged at low risk of attrition bias or because the ITT principle was used or because there were few lost at follow‐up, balanced between groups and reason for dropout were reported. We judged six studies at high risk of attrition bias (Weddington 1991; Moscovitz 1993; Eiler 1995; Kampman 1996; Malcolm 2000; Gorelick 2006) and one at unclear risk (Focchi 2005).
Selective reporting
We considered 20/24 (83.3%) of the included studies at low risk of reporting bias. Two were judged at high risk (Kosten 1992; Schmitz 2014) and two at unclear risk (Kolar 1992; Oliveto 1995).
Effects of interventions
See: Summary of findings for the main comparison Any dopamine agonist versus placebo for the treatment of cocaine dependence; Summary of findings 2 Amantadine versus placebo for the treatment of cocaine dependence; Summary of findings 3 Amantidine versus antidepressants for the treatment of cocaine dependence
1. Dopamine agonist versus placebo
See summary of findings Table for the main comparison
1.1 Dropouts
Twenty trials, 1656 participants, examined this outcome (Giannini 1989; Weddington 1991; Kolar 1992; Kosten 1992; Moscovitz 1993; Eiler 1995; Handelsman 1995; Kampman 1996; Handelsman 1997; Malcolm 2000; Pérez de los Cobos 2001; Shoptaw 2002; Ciraulo 2005; Shoptaw 2005; Gorelick 2006; Kampman 2006; Mooney 2007a; Mooney 2007b; Schmitz 2008; Schmitz 2014) showing no difference between the two treatments, RR 1.04, (95% CI 0.94 to 1.14); moderate quality of evidence. Analysis 1.1; Figure 4. Sensitivity analysis excluding studies at high risk of attrition bias did not change results.
Forest plot of comparison: 1 Any dopamine agonist versus placebo, outcome: 1.1 Dropouts.
1.2 Adverse events as number of participants with at least one adverse event
Seven studies, 252 participants, reported on this outcome (Weddington 1991; Kolar 1992; Moscovitz 1993; Pérez de los Cobos 2001; Gorelick 2006; Kampman 2006; Schmitz 2014) we detected no difference between the two treatments, RR 1.27 (95% CI 0.66 to 2.44); moderate quality of evidence ; Analysis 1.2; Figure 5.
Forest plot of comparison: 1 Any dopamine agonist versus placebo, outcome: 1.2 Adverse events as number of participants with at least one adverse event.
1.3 Abstinence (objective)
Eleven trials, 731 participants, reported this outcome (Weddington 1991; Alterman 1992; Kosten 1992; Moscovitz 1993; Kampman 1996; Shoptaw 2002; Focchi 2005; Shoptaw 2005; Mooney 2007a; Mooney 2007b; Schmitz 2008; ) and we detected no difference between the two treatments, RR 1.12 (95% CI 0.85 to 1.47); low quality of evidence; Analysis 1.3. Sensitivity analysis excluding studies at high risk of attrition bias did not affect the results.
1.4 Abstinence at follow‐up (objective)
We detected no difference between the two treatments after analysis of the results of four included studies, 136 participants, that reported on this outcome (Alterman 1992; Kolar 1992; Shoptaw 2002; Shoptaw 2005): RR 1.10 (95% CI 0.61 to 1.98); low quality of evidence; Analysis 1.4.
1.5 Severity of dependence (measured as difference before and after treatment)
Based on four included studies, 202 participants, (Alterman 1992; Ciraulo 2005; Shoptaw 2005; Kampman 2006), there was a statistically significant result in favour of placebo treatment: SMD 1.69 (95% CI 0.17 to 3.20); low quality of evidence; Analysis 1.5.
1.6 Dropouts due to adverse effects
Based on the results of four studies, 368 participants (Mooney 2007a; Mooney 2007b; Schmitz 2008; Schmitz 2014), we did not detect no difference between the two treatments, RR 1.21 (95% CI 0.27 to 5.38); Analysis 1.6.
1.7 Craving at the end of treatment
Three studies, 151 participants, reported on this outcome (Shoptaw 2002; Ciraulo 2005; Focchi 2005). We detected no differences between treatments: SMD 0.20 (95% CI ‐0.35 to 0.74); Analysis 1.7.
1.8 Clinical global evaluation at the end of the treatment
Two studies, 70 participants, reported this outcome (Ciraulo 2005; Shoptaw 2005) and we detected no difference between treatments: SMD ‐0.04 (95% CI ‐0.50 to 0.43); Analysis 1.8.
1.9 Depression (measured as difference before and after treatment)
We included five studies, 292 participants in this analysis (Alterman 1992; Handelsman 1995; Kampman 1996; Focchi 2005; Shoptaw 2005) and detected no difference between treatments: SMD 0.47 (95% CI ‐0.35 to 1.28); Analysis 1.9.
2. Amantadine versus placebo
See summary of findings Table 2
2.1 Dropouts
Nine studies, 484 participants, reported on this outcome (Giannini 1989; Weddington 1991; Kolar 1992; Kosten 1992; Handelsman 1995; Kampman 1996; Pérez de los Cobos 2001; Shoptaw 2002; Kampman 2006). We detected no difference between treatments, RR 0.98 (95% CI 0.77 to 1.26); moderate quality of evidence; Analysis 2.1; Figure 6).
Forest plot of comparison: 2 Amantadine versus placebo, outcome: 2.2 Adverse events as number of participants with at least one adverse event.
2.2 Adverse events as number of participants with at least one adverse event
Four studies, 275 participants, were included in this analysis (Weddington 1991; Kolar 1992; Kampman 1996; Pérez de los Cobos 2001). We detected no difference between treatments, RR 1.19 (95% CI 0.69 to 2.06); moderate quality of evidence; Analysis 2.2.
2.3 Abstinence (objective)
Five studies, 275 participants, reported on this outcome (Weddington 1991; Alterman 1992; Kosten 1992; Kampman 1996; Shoptaw 2002) and we detected no difference between treatments,RR 1.13, (95% CI 0.59 to 2.13); low quality of evidence; Analysis 2.3.
2.4 Abstinence at follow‐up (objective)
We included three studies , 76 participants, in this analysis (Alterman 1992; Kolar 1992; Shoptaw 2002) and detected no difference between treatments, RR 1.49 (95% CI 1.03 to 2.15); moderate quality of evidence; Analysis 2.4.
2.5 Severity of dependence (measured as difference before and after the treatment)
Two studies, 102 participants, reported on this outcome (Alterman 1992; Kampman 2006). No difference was detected between treatments, SMD 0.39 (95% CI ‐0.00 to 0.79); Analysis 2.5.
2.6 Depression (measured as difference before and after the treatment)
We included two studies, 109 participants, in this analysis (Alterman 1992; Handelsman 1995). There was no difference between treatments, SMD ‐0.30 (95% CI ‐1.33 to 0.74); Analysis 2.6.
3. Bromocriptine versus placebo
3.1 Dropouts
Five studies, 242 participants, (Giannini 1989; Moscovitz 1993; Eiler 1995; Handelsman 1997; Gorelick 2006) and there was no difference between treatments, RR 1.00 (95% CI 0.73 to 1.38); Analysis 3.1.
3.2 Adverse events as number of participants with at least one adverse event
We included two studies, 89 participants, in this analysis (Moscovitz 1993; Gorelick 2006) and detected no difference between treatments, RR 0.92 (95% CI 0.38 to 2.22); Analysis 3.2.
4. L dopa/carbidopa versus placebo
4.1 Dropouts
Four studies, 262 participants, reported this outcome (Mooney 2007a; Mooney 2007b; Shoptaw 2005; Schmitz 2014) and there was no difference between treatments, RR 0.95 (95% CI 0.78 to 1.17); Analysis 4.1.
4.2 Dropouts due to adverse effects
We included four studies, 368 participants, in this analysis (Mooney 2007a; Mooney 2007b; Schmitz 2008; Schmitz 2014). We did not detect any difference between treatments, RR 1.21 (95% CI 0.27 to 5.38); Analysis 4.2.
4.3 Abstinence (objective)
Four studies, 355 participants, reported on this outcome (Mooney 2007a; Mooney 2007b; Shoptaw 2005; Schmitz 2008) and we detected no difference between treatments, RR 1.11 (95% CI 0.80 to 1.52); Analysis 4.3.
5. Amantadine versus antidepressants
See summary of findings Table 3.
The antidepressants considered in the studies were desipramine (four trials: Kolar 1992; Kosten 1992; Oliveto 1995; Weddington 1991) and fluoxetine (one trial: Oliveto 1995).
5.1 Dropouts
We included four studies, 153 participants, in this analysis (Weddington 1991; Kolar 1992; Kosten 1992; Oliveto 1995) and detected no difference between treatments, RR 0.86 (95% CI 0.48 to 1.53); moderate quality of evidence; Analysis 5.1.
5.2 Adverse events as number of participants with at least one adverse event
Two studies, 44 participants, reported this outcome (Weddington 1991; Kolar 1992) and we did not detect any difference between treatments, RR 0.56 (95% CI 0.18 to 1.77); low quality of evidence; Analysis 5.2.
5.3 Abstinence (objective)
Based on two studies, 68 participants, (Weddington 1991; Kolar 1992), the result was in favour of antidepressants, RR 0.25 (95% CI 0.12 to 0.53); low quality of evidence; Analysis 5.3.
6. L‐dopa/carbidopa versus naltrexone or modafinil
One study (Schmitz 2014) reported that there were no difference in retention between L‐dopa and modafinil (14/25 and 9/22 respectively) and between L‐dopa and naltrexone (14/25 and 9/16 respectively).
Discussion
Summary of main results
Twenty‐four studies, including a total of 2147 participants, met the inclusion criteria for this review. However, the large variety of outcomes and rating scales considerably limited a quantitative synthesis of data. We could not synthesize a large amount of information.
Comparing any dopamine agonist versus placebo, we found moderate to low quality of evidence that there were no significant differences for any of the outcomes considered (dropout, abstinence, craving, severity of dependence depression adverse events). This also occurred when single dopamine agonists were compared against placebo.
Comparing amantadine versus antidepressants (desipramine in four comparisons and fluoxetine in one comparison), we found low quality of evidence that antidepressants performed better for abstinence, but results were from only two studies with 44 participants. The other two outcomes considered did not show statistically significant differences, although dropouts and adverse events tended to be more common in the antidepressant group.
Overall completeness and applicability of evidence
As seen for other treatments, the trials included in this review had important differences in psychiatric and substance use diagnoses, definitions of outcomes variables and varying amounts of psychotherapy provided in conjunction with medications. These discrepancies have two consequences: data are more generalizable, but there is a clear limitation for pooling data.
Besides the limits in external validity due to the general requirement of RCTs in terms of strict inclusion criteria, highly homogenous study groups, limitations in dose adjustment, etc., the types of participants (adults abusers/dependents on cocaine or on cocaine and opioids) are quite representative of the general population of cocaine addicts. Moreover, the interventions and the outcomes investigated (dropouts, abstinence, adverse events) are important to populations, practitioners and decision makers, and relevant for the context of current practice. However, an important limitation to the generalization of the evidence is trial location. Despite our systematic bibliographical search, only two out of 23 included studies were conducted outside of the USA. It should be considered that different social contexts can influence the severity of dependence and the availability to enter an experimental design. Also different clinical contests can differentially influence participant selection 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
Regarding risk of bias of the included trials, only 20.8% used an adequate method of sequence generation and the 17% an adequate method of allocation concealment. We judged the other studies were at unclear risk because the trial authors did not provide details. Only 41% of included trials described an adequate method to maintain blinding. Only 21% of included trials declared that outcome assessors were blinded. We judged all but two of the other at unclear risk of bias for subjective outcomes. We considered 83.3% of the included studies at low risk of reporting bias. We judged 70.8% at low risk of attrition bias or because the ITT principle was used or there were few participants lost at follow‐up, balanced between groups and reason for dropout were reported.
Finally, the great heterogeneity of the scales used in the primary studies and the way in which results were reported meant it was not possible at times to undertake a cumulative analysis.
The quality of evidence using GRADE was judged from moderate to low, see summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3
Study flow diagram present update.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 Any dopamine agonist versus placebo, outcome: 1.1 Dropouts.
Forest plot of comparison: 1 Any dopamine agonist versus placebo, outcome: 1.2 Adverse events as number of participants with at least one adverse event.
Forest plot of comparison: 2 Amantadine versus placebo, outcome: 2.2 Adverse events as number of participants with at least one adverse event.
Comparison 1 Any dopamine agonist versus placebo, Outcome 1 Dropouts.
Comparison 1 Any dopamine agonist versus placebo, Outcome 2 Adverse events as N of participants with at least one adverse event.
Comparison 1 Any dopamine agonist versus placebo, Outcome 3 Abstinence (objective).
Comparison 1 Any dopamine agonist versus placebo, Outcome 4 Abstinence at follow‐up (objective).
Comparison 1 Any dopamine agonist versus placebo, Outcome 5 Severity of dependence (difference before and after).
Comparison 1 Any dopamine agonist versus placebo, Outcome 6 Dropouts due to adverse events.
Comparison 1 Any dopamine agonist versus placebo, Outcome 7 Craving at the end of treatment.
Comparison 1 Any dopamine agonist versus placebo, Outcome 8 Clinical global evaluation (end of treatment).
Comparison 1 Any dopamine agonist versus placebo, Outcome 9 Depression (difference before and after).
Comparison 2 Amantadine versus placebo, Outcome 1 Dropouts.
Comparison 2 Amantadine versus placebo, Outcome 2 Adverse events as N of participants with at least one adverse event.
Comparison 2 Amantadine versus placebo, Outcome 3 Abstinence (objective).
Comparison 2 Amantadine versus placebo, Outcome 4 Abstinence at follow‐up (objective).
Comparison 2 Amantadine versus placebo, Outcome 5 Severity of dependence (difference before and after).
Comparison 2 Amantadine versus placebo, Outcome 6 Depression (difference before and after).
Comparison 3 Bromocriptine versus placebo, Outcome 1 Dropouts.
Comparison 3 Bromocriptine versus placebo, Outcome 2 Adverse events as N of participants with at least one adverse event.
Comparison 4 L dopa/carbidopa versus placebo, Outcome 1 Dropouts.
Comparison 4 L dopa/carbidopa versus placebo, Outcome 2 Dropouts due to adverse events.
Comparison 4 L dopa/carbidopa versus placebo, Outcome 3 Abstinence (objective).
Comparison 5 Amantidine versus antidepressants, Outcome 1 Dropouts.
Comparison 5 Amantidine versus antidepressants, Outcome 2 Adverse events as N of participants with at least one adverse event.
Comparison 5 Amantidine versus antidepressants, Outcome 3 Abstinence (objective).
| Any dopamine agonist versus placebo for the treatment of cocaine dependence | ||||||
| Patient or population: patients with the treatment of cocaine dependence | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Any dopamine agonist versus placebo | |||||
| Dropouts | Study population | RR 1.04 | 1656 | ⊕⊕⊕⊝ | ||
| 456 per 1000 | 474 per 1000 | |||||
| Moderate | ||||||
| 400 per 1000 | 416 per 1000 | |||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 1.27 | 252 | ⊕⊕⊕⊝ | ||
| 272 per 1000 | 345 per 1000 | |||||
| Moderate | ||||||
| 200 per 1000 | 254 per 1000 | |||||
| Abstinence (objective) | Study population | RR 1.12 | 731 | ⊕⊕⊝⊝ | ||
| 308 per 1000 | 345 per 1000 | |||||
| Moderate | ||||||
| 355 per 1000 | 398 per 1000 | |||||
| Abstinence at follow‐up (objective) | Study population | RR 1.1 | 136 | ⊕⊕⊝⊝ | ||
| 625 per 1000 | 688 per 1000 | |||||
| Moderate | ||||||
| 541 per 1000 | 595 per 1000 | |||||
| Severity of dependence (difference before and after) | The mean severity of dependence (difference before and after) in the intervention groups was | 202 | ⊕⊕⊝⊝ | SMD 1.69 (0.17 to 3.2) | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Most studies were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | ||||||
| Amantadine versus placebo for the treatment of cocaine dependence | |||||
| Patient or population: patients with the treatment of cocaine dependence | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Amantadine versus placebo | ||||
| Dropouts | Study population | RR 0.98 | 484 | ⊕⊕⊕⊝ | |
| 378 per 1000 | 371 per 1000 | ||||
| Moderate | |||||
| 286 per 1000 | 280 per 1000 | ||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 1.19 | 128 | ⊕⊕⊕⊝ | |
| 329 per 1000 | 391 per 1000 | ||||
| Moderate | |||||
| 300 per 1000 | 357 per 1000 | ||||
| Abstinence (objective) | Study population | RR 1.13 | 275 | ⊕⊕⊝⊝ | |
| 307 per 1000 | 347 per 1000 | ||||
| Moderate | |||||
| 355 per 1000 | 401 per 1000 | ||||
| Abstinence at follow‐up (objective) | Study population | RR 1.49 | 76 | ⊕⊕⊕⊝ | |
| 512 per 1000 | 763 per 1000 | ||||
| Moderate | |||||
| 526 per 1000 | 784 per 1000 | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1Most were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | |||||
| Amantidine versus antidepressants for the treatment of cocaine dependence | |||||
| Patient or population: patients with the treatment of cocaine dependence | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Amantidine versus antidepressants | ||||
| Dropouts | Study population | RR 0.86 | 153 | ⊕⊕⊕⊝ | |
| 329 per 1000 | 283 per 1000 | ||||
| Moderate | |||||
| 267 per 1000 | 230 per 1000 | ||||
| Adverse events as N of participants with at least one adverse event | Study population | RR 0.56 | 44 | ⊕⊕⊝⊝ | |
| 320 per 1000 | 179 per 1000 | ||||
| Moderate | |||||
| 335 per 1000 | 188 per 1000 | ||||
| Abstinence (objective) | Study population | RR 0.25 | 68 | ⊕⊕⊝⊝ | |
| 775 per 1000 | 194 per 1000 | ||||
| Moderate | |||||
| 859 per 1000 | 215 per 1000 | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1Most studies were classified as at unclear risk of bias for sequence generation and method of allocation concealment. | |||||
| Item | Judgment | Description |
| 1. Random sequence generation (selection bias)
| Low risk | The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; or minimization. |
| High risk | The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; or availability of the intervention. | |
| Unclear risk | Insufficient information about the sequence generation process to permit judgement of low or high risk. | |
| 2. Allocation concealment (selection bias)
| Low risk | Investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled, randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes. |
| High risk | Investigators enrolling participants could possibly foresee assignments because one of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure. | |
| Unclear risk | Insufficient information to permit judgement of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement. | |
| 3. Blinding of participants and providers (performance bias) subjective outcomes
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 4. Blinding of participants and providers (performance bias) objective outcomes | Low risk |
|
| High risk |
| |
| Unclear risk |
| |
| 5. Blinding of outcome assessor (detection bias) Subjective outcomes
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 6. Blinding of outcome assessor (detection bias) objective outcomes | Low risk |
|
| High risk |
| |
| Unclear risk |
| |
| 7. Incomplete outcome data (attrition bias) For all outcomes except retention in treatment or dropout
| Low risk
|
|
| High risk |
| |
| Unclear risk |
| |
| 8. Selective reporting (reporting bias)
| Low risk |
|
| High risk |
| |
| Unclear risk |
|
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Dropouts Show forest plot | 20 | 1656 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.94, 1.14] |
| 2 Adverse events as N of participants with at least one adverse event Show forest plot | 7 | 252 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.66, 2.44] |
| 3 Abstinence (objective) Show forest plot | 11 | 731 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.85, 1.47] |
| 4 Abstinence at follow‐up (objective) Show forest plot | 4 | 136 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.61, 1.98] |
| 5 Severity of dependence (difference before and after) Show forest plot | 4 | 202 | Std. Mean Difference (IV, Random, 95% CI) | 1.69 [0.17, 3.20] |
| 6 Dropouts due to adverse events Show forest plot | 4 | 368 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.27, 5.38] |
| 7 Craving at the end of treatment Show forest plot | 3 | 151 | Std. Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.35, 0.74] |
| 8 Clinical global evaluation (end of treatment) Show forest plot | 2 | 70 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.04 [‐0.50, 0.43] |
| 9 Depression (difference before and after) Show forest plot | 5 | 292 | Std. Mean Difference (IV, Random, 95% CI) | 0.47 [‐0.35, 1.28] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Dropouts Show forest plot | 9 | 484 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.77, 1.26] |
| 2 Adverse events as N of participants with at least one adverse event Show forest plot | 4 | 128 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.69, 2.06] |
| 3 Abstinence (objective) Show forest plot | 5 | 275 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.59, 2.13] |
| 4 Abstinence at follow‐up (objective) Show forest plot | 3 | 76 | Risk Ratio (M‐H, Random, 95% CI) | 1.49 [1.03, 2.15] |
| 5 Severity of dependence (difference before and after) Show forest plot | 2 | 102 | Std. Mean Difference (IV, Random, 95% CI) | 0.39 [‐0.00, 0.79] |
| 6 Depression (difference before and after) Show forest plot | 2 | 109 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐1.33, 0.74] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Dropouts Show forest plot | 5 | 242 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.73, 1.38] |
| 2 Adverse events as N of participants with at least one adverse event Show forest plot | 2 | 89 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.38, 2.22] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Dropouts Show forest plot | 4 | 262 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.78, 1.17] |
| 2 Dropouts due to adverse events Show forest plot | 4 | 368 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.27, 5.38] |
| 3 Abstinence (objective) Show forest plot | 4 | 355 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.80, 1.52] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Dropouts Show forest plot | 4 | 153 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.48, 1.53] |
| 2 Adverse events as N of participants with at least one adverse event Show forest plot | 2 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.18, 1.77] |
| 3 Abstinence (objective) Show forest plot | 2 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 0.25 [0.12, 0.53] |
