INTRODUCTION

Cocaine use disorder remains a serious problem in the USA and worldwide. In the USA, 900,000 adults met criteria for cocaine use disorder in 2014 and 40% of visits to emergency departments for drug misuse or abuse involved cocaine.1 Cocaine use is associated with cardiovascular and neurologic effects, and chronic repeated exposure leads to tolerance, adverse psychological and behavioral effects, and complications including infections, stroke, and seizure.2, 3

Psychosocial and behavioral therapies, including cognitive behavioral therapy (CBT) and contingency management (CM) interventions, are the primary treatments for cocaine use disorder. However, they are time-consuming, not universally accessible, and suffer from low treatment retention. Currently, there are no Food and Drug Administration (FDA)-approved medications to treat cocaine use disorder. One challenge in establishing the evidence base for pharmacotherapy of cocaine use disorder is the sheer number of drug classes that have been studied. Prior systematic reviews (SRs) have largely focused on single drugs4 or drug classes (anticonvulsants/carbamazepine,5 dopamine agonists,6 psychostimulants,7 and antipsychotics8). To our knowledge, none have examined the treatment of cocaine use disorder across drug classes. This SR examines the benefits and harms of pharmacological interventions for cocaine use disorder, and was part of a larger report of stimulant use disorders commissioned by the Veterans Health Administration (VHA).

METHODS

Data Sources and Search Strategies

We searched MEDLINE, PsycINFO, and EBM Reviews Cochrane Database of Systematic Reviews through November 2017 (Online Appendix Table 1). We reviewed the bibliographies of relevant articles and contacted experts to identify additional studies. To identify in-progress or unpublished studies, we searched ClinicalTrials.gov, OpenTrials, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The review protocol was registered to PROSPERO before we initiated the study (CRD42018085667). Our methods and reporting follow PRISMA guidelines.9

Study Selection

Study selection was guided by an analytic framework (Online Appendix Figure 1). We included randomized controlled trials (RCTs) of adults with cocaine use disorder that compared pharmacotherapies (head to head), to placebo, usual care, or psychotherapy. We also included RCTs that had been included in existing good quality SRs. We excluded studies examining patients with comorbid psychotic spectrum or bipolar disorders. We excluded studies that did not perform urine drug screens (UDS) at least once per week. PICOTS and study selection criteria are specified in Online Appendix Tables 2 and 3.

We dual reviewed and evaluated titles and abstracts for 18.6% of the search yield to ensure reliability. Two investigators independently reviewed the full text of all potentially relevant articles for inclusion. All discordant results were resolved through consensus or consultation with a third reviewer.

Data Abstraction and Quality Assessment

One investigator abstracted, and a second investigator confirmed details related to study design, setting, population, intervention and follow-up, co-interventions, outcomes, and harms. Two reviewers independently assessed the quality of each RCT using a tool developed by the Cochrane Collaboration10 (Online Appendix Table 8). We directly report the findings from previous SRs as well as their assessments of study quality.

Our outcomes of interest were sustained abstinence (three or more weeks of negative UDS′),11 cocaine use, treatment retention, serious adverse events (SAEs), and treatment dropouts due to adverse events (AEs). For relapse prevention studies of participants abstinent at baseline, we examined lapse (first cocaine positive or missed UDS) and relapse (two consecutive cocaine positive or missed UDS′). For outcomes related to abstinence and use, we excluded studies relying on self-reported drug use, with the exception of findings from previous SRs.

Data Synthesis and Analysis

We qualitatively synthesized the evidence and separately examined the findings in patients with comorbid opioid use disorder. When possible, we combined data from trials as they were reported in previous SRs with data we abstracted directly from newer RCTs identified in our search in random-effects meta-analyses.12 We used RevMan 5.313 to calculate the overall relative risk (RR) and 95% CI of each outcome in the active treatment group compared with placebo. We assessed statistical heterogeneity among the pooled studies using the I2 statistic.14, 15

We assessed the overall strength of evidence (SOE) for each outcome using an established method, and classified SOE as high, moderate, low, or insufficient.16

RESULTS

Our larger search for stimulant use disorders yielded 5564 citations. After reviewing the full text of 354 studies, we included seven systematic reviews and 48 RCTs specific to cocaine use disorder (Fig. 1). The included SRs and RCTs examined 66 different drugs including antidepressants, antipsychotics, anxiolytics, cognitive enhancing drugs, dopamine agonists, muscle relaxants, anticonvulsants, medications approved by the FDA for other substance use disorders, and a wide range of other pharmacotherapies (Online Appendix Table 4).

Figure 1
figure 1

Literature flow diagram. RCT, randomized controlled trial; SR, systematic review.

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Table 1 presents a brief summary of findings for all drug classes. Table 2 provides a more detailed summary of the evidence on all pharmacotherapies for cocaine use disorder, stratified by drug class. The characteristics and findings of individual studies are provided in Online Appendix Tables 5 and 6.

Table 1 Brief Summary of Findings
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Table 2 Summary of the Evidence on Pharmacotherapies for Cocaine Use Disorder, Stratified by Drug Class
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Psychopharmacotherapies

Antidepressants: Bupropion, Desipramine, Fluoxetine, Mirtazapine, Nefazodone, Paroxetine, Sertraline, Venlafaxine

Antidepressants were the most widely studied among the drug classes. We found 34 trials from two previous systematic reviews7, 17 and four subsequent trials18,19,20,21 investigating antidepressants (including bupropion) for cocaine use disorder. The more recent trials examine sertraline,20, 21 venlafaxine,18 and mirtazapine.19 Overall, there were no differences on sustained abstinence, use, retention, or harms outcomes.

In a meta-analysis combining 10 RCTs7, 17, 18 across all antidepressants, abstinence occurred more frequently in the antidepressant groups than placebo (RR 1.27, 95% CI 0.99 to 1.63), but the difference did not reach statistical significance (P = 0.06; Online Appendix Figure 2). We found moderate SOE of no difference on cocaine use between antidepressants as a class and placebo. Findings were consistent across four RCTs reported in a systematic review17 (RR 1.05, 95% CI 0.91 to 1.21) and two additional RCTs.18, 19 We found high SOE that antidepressants as a class are no better than placebo for study retention (33 RCTs; RR 0.95, 95% CI 0.87 to 1.03; Fig. 2). There were no differences in dropouts due to AEs (moderate SOE) or SAEs (low SOE).

Figure 2
figure 2

Treatment retention in RCTs of antidepressants vs placebo for cocaine use disorder.

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Selective Serotonin Reuptake Inhibitors: Fluoxetine, Paroxetine, and Sertraline

We found two low risk of bias (ROB) RCTs20, 21 and seven RCTs in the SR of antidepressants17 that provide moderate SOE that selective serotonin reuptake inhibitors (SSRIs) do not improve study retention (N = 527; RR 0.94, 95% CI 0.68 to 1.29; Fig. 2). However, three RCTs (N = 251) in the SR17 provide low-strength evidence of a higher risk of dropout due to AEs with SSRIs compared with placebo (RR 3.55, 95% CI 1.11 to 11.34).

Relapse Prevention: Sertraline

We found two trials (N = 116) examining sertraline for relapse prevention among subjects who were cocaine-abstinent at baseline.20, 21 These RCTs provided a 2-week residential treatment program during which subjects were required to achieve abstinence in order to continue treatment in a 10-week outpatient program. Patients treated with sertraline were less likely to experience lapse (first cocaine positive or missing UDS samples [combined RR 0.80, 95% CI 0.63 to 1.02]) and relapse (two consecutive cocaine positive or missing UDS [combined RR 0.75, 95% CI 0.58 to 0.98; Online Appendix Figure 3]), although only the latter finding was statistically significant. Retention was also higher versus placebo (combined RR 1.43, 95% CI 0.94 to 2.15; Online Appendix Figure 4), though the difference was not statistically significant (P = 0.09).

Bupropion

There were three trials reported in two existing SRs7, 17 that examined bupropion for cocaine use disorder. There was low SOE that bupropion improved abstinence versus placebo (2 RCTs; combined RR 1.63, 95% CI 1.03 to 2.59).7 Bupropion had no effect on cocaine use (low SOE) or retention (3 RCTs, combined RR 0.94, 95% CI 0.76 to 1.15; moderate SOE; Fig. 2). We found insufficient evidence related to harms.

Antipsychotics: Aripiprazole, Haloperidol, Lamotrigine, Olanzapine, Quetiapine, Risperidone, Reserpine

Fourteen RCTs (N = 719) in an existing SR8 and one additional RCT22 examined antipsychotics as a class for the treatment of cocaine use disorder. The additional RCT22 of recently abstinent subjects found no difference between 15 mg of aripiprazole and placebo for any outcome of interest. Overall, we found low SOE that antipsychotics did not improve abstinence8 or reduce cocaine use,8, 22 and insufficient evidence for lapse and relapse in participants abstinent at baseline.22 We found moderate SOE that antipsychotics improve study retention compared with placebo based on findings from eight RCTs in the SR (RR 0.75, 95% CI 0.57 to 0.97),8 and the additional RCT.22 We found insufficient evidence to form conclusions on harms.

Psychostimulants: Dexamphetamine, Lisdexamfetamine, Mazindol, Methamphetamine, Methylphenidate, Mixed Amphetamine Salts, Modafinil, Selegiline

A SR of 14 RCTs examined psychostimulants for treatment of cocaine use disorder. These trials reported low-strength evidence that psychostimulants improved abstinence versus placebo (RR 1.36, 95% CI 1.05 to 1.77).7 Although one study of bupropion (which we classified as an antidepressant) was included in the combined estimate, its removal does not change the conclusion.23 There were no significant differences between groups for cocaine use during the trial period (SOE low), study retention (moderate SOE), or harms (moderate SOE).

Cognitive Enhancing Drugs: Atomoxetine, Memantine

We found two small RCTs, including one examining memantine (low ROB) and the other examining atomoxetine (unclear ROB), that provide insufficient evidence to draw conclusions about the effects of cognitive enhancing drugs on any outcome of interest.24, 25

Anxiolytics: Buspirone

We identified only one small (N = 62), multi-site, high-ROB RCT that compared 60 mg of buspirone to placebo, along with CM and once weekly optional individual or group psychosocial treatment and relapse prevention.26 This provides insufficient evidence for the use of buspirone for cocaine use disorder.

Other Pharmacotherapies

Anticonvulsants and Muscle Relaxants: Baclofen, Carbamazepine, Gabapentin, Lamotrigine, Phenytoin, Tiagabine, Topiramate, Vigabatrin

We identified 20 RCTs in a prior SR,5 and three additional RCTs27,28,29 examining the effectiveness of anticonvulsants and muscle relaxants. The SR examined anticonvulsants and found moderate SOE that anticonvulsants as a class are no different than placebo for retention (17 RCTs, combined RR 0.95, 95% CI 0.86 to 1.05) or cocaine use (9 RCTs, RR 0.92, 95% CI 0.84 to 1.02). We identified one additional RCT (N = 60) that found improved abstinence and a reduction in cocaine use associated with topiramate, and no difference in retention.29 Two additional RCTs27, 28 compared baclofen (60 mg and 20 mg) to placebo. Neither study reported differences between groups on any of the outcomes of interest. Across all anticonvulsants and muscle relaxants as a class, there is insufficient evidence to form conclusions about the effects on abstinence, moderate SOE of no difference from placebo on cocaine use and study retention, and insufficient evidence on harms.

Topiramate

Five RCTs—four30,31,32,33,34 from an existing SR5 and one additional RCT29—examined topiramate for cocaine use disorder. We found low SOE favoring topiramate over placebo for abstinence (2 RCTs, combined RR 2.56, 95% CI, 1.39 to 4.73; Fig. 3) and moderate SOE that topiramate was no different from placebo for study retention (5 RCTs, combined RR 1.01, 95% CI 0.93 to 1.10; Fig. 3). There was insufficient evidence to form conclusions on AEs.

Figure 3
figure 3

Abstinence and retention in RCTs of topiramate vs placebo for cocaine use disorder.

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Medications FDA-Approved for Other Substance Use Disorders: Acamprosate, Buprenorphine, Buprenorphine and Naloxone, Disulfiram, Methadone, Naltrexone, Varenicline

One SR4 and 18 RCTs35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52 examined FDA-approved pharmacotherapies for other substance use disorders. We found low SOE from six trials43,44,45,46,47,48 that naltrexone was no different than placebo for abstinence or retention. There was insufficient evidence on use reduction and AEs. For studies of acamprosate,50 varenicline,51, 52 buprenorphine plus naloxone,49 and methadone compared directly with buprenorphine,35, 36 there was insufficient evidence to form conclusions on the outcomes of interest.

Disulfiram

Disulfiram for the treatment of cocaine use disorder was examined in a previous SR4 of seven RCTs and in five more recently published RCTs.37,38,39,40,41 There was low SOE that disulfiram does not increase abstinence (3 RCTs, combined RR 0.96, 95% CI 0.63 to 1.45; Figure 7) or increase harms versus placebo. We found moderate SOE that disulfiram worsened rates of retention versus placebo (7 RCTs, combined RR 0.90, 95% CI 0.83 to 0.99; Online Appendix Figure 5). The effects of disulfiram on cocaine use were significantly heterogeneous (I2 = 97%, P < 0.00001) in a meta-analysis of four RCTs (Online Appendix Figure 5), and the evidence was therefore insufficient for drawing conclusions.

Dopamine Agonists: Amantadine, Bromocriptine, Cabergoline Hydergine, l-Dopa/Carbidopa, Pergolide, Pramipexole

A 2015 SR of 24 trials found no difference between dopamine agonists and placebo on retention (moderate SOE), abstinence (low SOE), and a lack of evidence on AEs.6 We identified no additional trials of examining dopamine agonists for cocaine use disorder.

Other Pharmacotherapies

Nineteen trials53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71 examined the effects of other drugs or drug combinations for cocaine use disorder (Table 2). Although there is insufficient evidence to form conclusions due to limited power, positive findings on abstinence and use reduction were reported in studies of doxazosin,59 ondansetron,66 propranolol,70 and topiramate combined with mixed amphetamine salts.64 There were no positive or negative findings on the outcomes of interest for any of the other drugs or drug combinations.

Pharmacotherapies for Comorbid Opioid Use Disorder

Data from 6 SRs4, 5, 7, 8, 17, 72 and 14 additional RCTs22, 35,36,37,38,39,40,41, 49, 51, 54, 61, 62, 69 contribute to the evidence on pharmacotherapy for the treatment of cocaine use disorder in adults with comorbid opioid use disorder. Table 5 summarizes the findings of pharmacotherapies studied in patients with comorbid opioid use disorder, and additional details are provided in an online data supplement (Online Appendix Table 7).

We found low SOE that antidepressants are more effective than placebo for cocaine abstinence,7, 17, 72 and that psychostimulants are more effective than placebo for reducing cocaine use in patients with comorbid opioid use disorder.8, 22 However, we also found moderate SOE that both retention and dropouts due to AEs were higher in subjects receiving antidepressants versus placebo, and moderate SOE of poorer retention associated with disulfiram. There was no difference between placebo and antipsychotics or psychostimulants on retention (low SOE). All other medication/outcomes were insufficient to form conclusions.

DISCUSSION

In this review, we identified seven SRs and 48 RCTs examining a variety of pharmacotherapies for cocaine use disorder. We found no strong evidence that any drug class was effective in increasing abstinence, reducing use, or improving retention rates for cocaine use disorder. However, we found low SOE that bupropion, psychostimulants, and topiramate may improve abstinence, and low SOE that sertraline may reduce relapse rates in abstinent patients. There was moderate SOE that antipsychotics may improve treatment retention. We also found moderate SOE that disulfiram may actually worsen treatment retention, and low SOE that SSRIs were associated with higher dropouts due to AEs (Table 4).

To our knowledge, this is the first report to summarize multiple classes of medications used in treatment of cocaine use disorder, which continues to be a global public health problem with increasing morbidity and mortality.73 One motivation for this review was to find potentially promising treatments and targets for future research for a devastating condition that has been historically difficult to treat with pharmacotherapy. Indeed, we did identify several promising treatments that may be good areas in which to prioritize future research (Table 3). Post hoc analyses in RCTs of bupropion suggest that it may be effective for patients with comorbid depression and in conjunction with CM. We also found that psychostimulants—which serve as a form of agonist replacement therapy—may improve abstinence outcomes. Finally, we found that topiramate, thought to work via GABAergic pathways to regulate dopamine release, was potentially effective for abstinence and warrants continued exploration.74

Our review complements and extends the findings of prior SRs by examining and summarizing data across all drug classes. We defined abstinence as 2 or more weeks of negative UDS—which meant excluding studies using other measures of abstinence. We summarized retention as an outcome, recognizing that improving retention in treatment increases the chances for successful recovery of stimulant use disorders; therefore, we did not consider study retention in our SOE assessment. We were limited in our ability to compare and meta-analyze results across studies because many studies did not report these data, or used different measures, and future research should look to standardize outcome reporting such as 3 or more-week abstinence to compare efficacy across trials and drug classes. It is also possible that the lack of significant findings was due to insufficient power to detect differences.

A lack of engagement in treatment on the part of some study participants who are actively using stimulants may affect the efficacy of pharmacotherapies; retention rates varied widely across studies (24–97%), and overall low rates of retention may have affected the assessment of treatment effectiveness in the majority of studies (attrition was greater than 20% in more than a third of the trials reporting retention rates). Unfortunately, pharmacotherapy alone (aside from antipsychotics) does not appear to be effective in improving treatment retention rates. Two areas of promise that are notable include those in which patients have already demonstrated engagement in treatment, or may have another rationale for ongoing engagement, as is the case for some patients with comorbid opiate use disorder. Indeed, we found low SOE that antidepressants and psychostimulants improved cocaine use outcomes in patients with comorbid opioid use disorder (Table 5). Given that the prevalence of cocaine use among heroin users is between 30 and 80%,75 and concurrent opioid use increases risk of death due to cocaine,76 further investigation on treatments for comorbid opioid use disorder is warranted.

Furthermore, more trials of medications that integrate evidence-based psychosocial and behavioral interventions are necessary to move the field forward. Given the largely disappointing pharmacotherapy results, these interventions (e.g., CM, CBT), alone or in combination, continue to be mainstays of treatment and management of stimulant use disorders.77, 78 A systematic review by Minozzi et al. found that any psychosocial treatment likely reduces dropout rates and may increase the period of abstinence (most of the studies reviewed included CM in addition to treatment as usual).78 The combination of pharmacotherapy with CM is an important area for future research as we do not know how medication may enhance the effectiveness of these interventions.79, 80 When we compared studies with a CM co-intervention to those without, we found that pharmacotherapeutic effects were similar in both.81

Our SR has several limitations. Our scope was broad, and we relied on existing SRs when available. We sought to minimize the disadvantages of using existing SRs by only including those that met key quality criteria; conducting updated searches to identify more recent trials; and combining data in meta-analysis from trials in previous SRs with newer trials from our search. Our definition of abstinence (3 or more weeks) served as a proxy for sustained abstinence, and the effects of treatment on long-term abstinence cannot be directly interpolated. Our search was limited to English language studies; however, the likelihood is low that the exclusion of non-English language studies would alter conclusions.82

CONCLUSIONS

We found no strong or consistent evidence that any drug class was effective in increasing abstinence, reducing use, or improving treatment retention for people with cocaine use disorder. There are several promising classes deserving of further research including psychostimulants, bupropion, topiramate, and treatment of patients with comorbid opioid use disorder.