The report is a product of the VA/HSR Evidence Synthesis Program.

Pharmacotherapy for Stimulant Use Disorders: A Systematic Review

Stimulant use disorders, specifically cocaine and methamphetamine use disorders, present ongoing public health problems in the United States, with major medical, psychiatric, cognitive, socioeconomic, and legal consequences. There are more emergency department visits associated with cocaine compared with other illicit substances, and several US cities consider methamphetamine as the drug of abuse associated with the "most serious consequences." To date, there are no FDA-approved pharmacotherapies for cocaine or methamphetamine use disorders. However, several have been proposed as possible experimental interventions to promote reduction in use or cessation. Currently, psychotherapy (e.g., cognitive behavioral therapy, drug counseling, relapse prevention, etc.) is offered as the primary treatment for stimulant addiction. Contingency management strategies employing incentives to increase engagement in treatment and reduce drug use are often commonly used.

In order to guide future VA research and policy decisions, VA's Office of Mental Health, Addictions Program Office and the Seattle and Philadelphia Centers of Excellence in Substance Abuse Treatment and Education (CESATE) asked HSR&D's Evidence-based Synthesis Program (ESP) to provide an up-to-date examination of the benefits and risks of various pharmacologic treatments for stimulant use disorder. Specifically, this review examined the:

• Benefits and harms of pharmacotherapy for cocaine use disorder;
• Sub-populations for whom different forms of pharmacotherapy are most or least effective for cocaine use disorder,
• Benefits and harms of pharmacotherapy for amphetamine/methamphetamine use disorder, and
• Sub-populations for whom different forms of pharmacotherapy are most or least effective for amphetamine/methamphetamine use disorder.

Investigators with VA's ESP Center in Portland, OR worked with a research librarian to search multiple data sources (i.e., Ovid MEDLINE and the Cochrane Database of Systematic reviews) from database inception through November 2017 for systematic reviews and randomized controlled trials (RCTs) directly comparing pharmacological interventions against each other, placebo, usual care, or psychotherapy in adults with cocaine or amphetamine/methamphetamine use disorders. After reviewing more than 5,500 titles and abstracts, investigators identified 8 systematic reviews and 61 RCTs that were included in this review.

Summary of Findings
Investigators found no strong, consistent evidence that any drug class was effective in increasing abstinence, reducing use, or improving retention rates for study participants with cocaine use disorders. Many of the trials were small with limited power to detect differences, methodologic deficiencies, and high enough attrition rates to further limit the assessment of treatment effectiveness. Across studies there also was significant variability in population, setting, co-interventions, and the outcomes reported. Given these limitations, findings show:

• Psychostimulants, bupropion, and topiramate may improve cocaine abstinence (low strength of evidence or SOE).
• Sertraline may be useful to prevent relapse in detoxed/abstinent patients (low SOE).
• Antipsychotics may improve treatment retention (moderate SOE).
• In populations with comorbid opioid use, psychostimulants and antidepressants may increase cocaine abstinence (low SOE).
• There was moderate- to high-strength evidence that antidepressants, disulfiram, and anticonvulsants (apart from topiramate) are unlikely to be effective in non-abstinent patients.

For methamphetamine use disorder, investigators found less promising results. Similar to the body of research examining pharmacotherapy for cocaine use disorder, studies evaluating pharmacotherapy for amphetamine/methamphetamine use disorders were largely of low or unclear quality, and were underpowered. Co-interventions differed widely, and rates of retention varied greatly. Moreover, for nearly all of the pharmacotherapies and almost all of the outcomes, findings were either null or insufficient to form conclusions. With low strength of evidence, investigators did find that methylphenidate and topiramate may be effective at reducing amphetamine/methamphetamine use.

Future Research
There are several promising areas deserving of further research including the use of bupropion, the use of topiramate, treatment of abstinent patients to prevent relapse, and treatment of patients with comorbid opioid use disorder. It is possible that the lack of significant findings was due to insufficient power to detect differences. Investigators suggest that future studies be larger and assess clinically relevant and uniform outcomes, including the reduction in use and defined periods of abstinence outcomes. Contingency management and behavioral interventions, along with pharmacotherapy, should continue to be explored.

Implications for VA Policy/Practice
Given the absence of strong, consistent evidence that any drug class was effective in increasing abstinence, reducing use, or improving retention rates for study participants with stimulant use disorders, providers are strongly encouraged to make evidence-based psychosocial treatments (EBTs) available to such patients. Off-label prescribing of the medications evaluated in this ESP is permitted, but is NOT acceptable as stand-alone treatment for stimulant use disorder. Therefore, the medications may be offered as an adjunct to the EBTs, or may be prescribed when the EBTs have been either declined by the patient or applied without successful outcome. Of EBTs for stimulant use disorder, contingency management (CM) has the largest effect size and is mandated by VA policy to be available to Veterans in intensive outpatient programs for SUD.

For assistance with implementation of CM for stimulant use disorders, providers and programs are encouraged to contact the Philadelphia CESATE (Dominick.DePhilippis@va.gov or Kendall.Browne@va.gov). The Philadelphia CESATE can provide implementation guidance and coaching, material support for motivational incentives, and guidance in implementing point-of-care (POC) testing to support CM.

Reference
Chan B, Kondo K, Ayers C, Freeman M, Montgomery J, Paynter R, and Kansagara D. Pharmacotherapy for Stimulant Use Disorders: A Systematic Review of the Evidence. VA ESP Project #05-225; 2018.

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This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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