Commentary on Foot et al.: Clinical considerations in addressing comorbid stimulant use in opioid use disorder

The opioid overdose crisis has been worsened by the increasing prevalence of comorbid stimulant use together with opioid use disorder. Individuals who also use stimulants are at higher risk of relapse and treatment dropout. Further research is desperately needed to guide clinicians in the treatment of this high-risk population. The United States opioid overdose crisis continues to claim tens of thousands of lives a year [1]. This crisis has been worsened by the introduction of high-potency synthetic opioids into the illicit drug supply, but is further complicated by the increasing prevalence of comorbid stimulant use together with opioid use disorder [2, 3]. In some cases, illicit drug suppliers are adding synthetic opioids to products sold as crystal methamphetamine or other stimulants, and in others, stimulants (usually methamphetamine) are being mixed with opioids to increase the potency of the ‘high’ or to counteract the sedating effects of high-dose opioids [4-6]. Although the increase in overdose deaths is probably fentanyl-associated, there might be a synergistic increase in the toxicity and lethality in individuals combining illicit stimulants with fentanyl [2, 7]. Three effective medications are approved by the US Food and Drug Administration (FDA) for the treatment of opioid use disorder: an opioid agonist (methadone), a partial agonist (buprenorphine) and an antagonist (XR-naltrexone) [8]. Despite these treatments, only a fraction of patients engage in treatment and, among those who initiate the medication, many continue to use illicit opioids and discontinue medication for OUD within the first few months of treatment [9]. The increase in comorbid stimulant use among individuals with opioid use disorder (OUD) only exacerbates these issues, as Foot and colleagues demonstrated in their secondary analysis of a series of large community-based opioid use disorder treatment trials [10]. Our experience in more recent OUD treatment trials echo these findings and has highlighted a clinical challenge for medication-based opioid treatment programs, which primarily have a medical focus. These programs may not be adequately prepared to treat patients presenting with concurrent opioid and stimulant addiction, especially those with major behavioral pathology (e.g. psychosis). Conversely, general addiction treatment programs, which are mainly behaviorally focused, might not be positioned to offer pharmacotherapy for opioid or stimulant use disorder. Unfortunately, decades of pharmacological research trials have yielded no FDA-approved treatments for stimulant use disorders [11], but there are several medications and psychosocial approaches that have proven effective in clinical trials that providers may integrate into treatment of individuals with comorbid opioid and stimulant use disorder. While there might not be an intervention reliably producing abstinence, treatments may be able to facilitate reduction of use. A recent large multi-site trial testing the combination of long-acting injectable naltrexone (XR-naltrexone) and bupropion for methamphetamine use disorder showed that the combination product was more effective than placebo [12]. Although this trial did not specifically recruit individuals with comorbid methamphetamine use disorder and OUD, XR-naltrexone is approved for the treatment of opioid use disorder, and the addition of bupropion for methamphetamine use disorder treatment in individuals maintained on XR-naltrexone for OUD is a straightforward clinical intervention [12]. In individuals maintained on buprenorphine, the addition of bupropion may also be a reasonable intervention, as its partial agonism at the opioid receptor may have some similar benefit to naltrexone on methamphetamine, although no trials have been performed using this combination. Other medication-based options include the noradrenergic and specific serotonergic antidepressant mirtazapine, which has shown some promise for methamphetamine use disorder alone, particularly in low severity users [13]. There is also strong evidence for the use of a prescription stimulant in extended-release formulation to treat methamphetamine use disorder [14]. This approach may be practiced in individuals with comorbid attention deficit hyperactivity disorder (ADHD) for whom treatment with a stimulant is FDA-approved. The use of a stimulant in this population comes with both practical and regulatory concerns due to concern for misuse and diversion, but many clinicians use this approach with appropriate safeguards (small quantities prescribed, frequent callbacks or observed therapy, etc.) with good effect. Clinicians may also consider the addition of further psychosocial interventions in this population, although few trials have been performed. In individuals with methamphetamine use disorder, contingency-based management (CM) therapy has shown the strongest evidence of benefit, although its delivery is challenging in real world clinical settings [15]. Despite the available treatment options, patients with comorbid OUD and methamphetamine use often struggle to remain engaged in treatment, and further research is desperately needed to guide clinicians in the treatment of this high-risk population. Providing a range of services is probably needed, with intensive outreach and provision of food and shelter, with a non-stigmatizing low-barrier, supportive treatment environment. Treatment must also address co-occurring psychiatric and medical problems, medications to help reduce craving and distress and decrease drug use, therapy to retain patients in treatment and teach new skills as well as connecting with peer-support networks and recovery-oriented services, harm reduction and other services [15]. Matisyahu Shulman: Conceptualization (equal); visualization (equal); writing—original draft (lead); writing—review and editing (equal). Miranda Greiner: Conceptualization (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Adam Bisaga: Conceptualization (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). This study was funded by the US Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, National Drug Abuse Treatment Clinical Trials Network UG1 DA013035. The authors acknowledge Kaitlyn Ohrtman for her help editing and formatting this commentary. None to declare. Data sharing is not applicable to this article as no new data were created or analyzed in this study.