Opioid and stimulant co-prescribing does not equate to a co-epidemic

We read, with interest, the study by Lee and colleagues,¹ who used the Merative MarketScan claims data to evaluate the relationship between stimulant and opioid prescribing between 2010 and 2021. The authors report that receipt of a stimulant medication before prescription opioid initiation is associated with more than a 7-fold increase in odds of escalating opioid dose. While these findings are intriguing, we have several concerns that limit our confidence in the conclusions drawn from this study.

In a highlighted analysis, the authors defined stimulant exposure based on whether enrollees “were prescribed stimulants at any time between the start and end dates of their opioid prescription.” This exposure definition may cause selection bias: enrollees with longer opioid exposure periods would have more opportunity to receive stimulants than peers with shorter periods of opioid exposure. Consequently, stimulant exposure may be artefactually associated with more opioid prescriptions and higher cumulative morphine milligram equivalents (MMEs). Differential follow-up time compounds these problems, as enrollees with longer follow-up periods are expected to accumulate more opioid prescriptions than peers with shorter follow-up periods and may, therefore, be more likely to be classified as stimulant-exposed. Notably, when comparing average daily MMEs—a measure not directly dependent on follow-up time—the standardized mean difference between stimulant and non-stimulant groups was only 0.06. While the authors’ trajectory models account for time-varying stimulant receipt and baseline comorbidities, the increased likelihood of stimulant-exposed enrollees to follow an escalating opioid dose trajectory could potentially be explained by greater opioid exposure and increased opioid tolerance resulting from longer follow-up time. Moreover, the authors acknowledge that their study design precludes casual inferences. Indeed, it is widely understood that studies of prescribed medications must account for bias due to confounding by indication. The extent to which any differences in opioid prescribing observed here may be due to stimulants themselves versus attention-deficit hyperactivity disorder (ADHD), other indications for stimulants, or associated mental health processes would need to be determined in future research.

Beyond the study's methodological issues, it is important to weigh the potential risks of stimulant prescribing alongside potential therapeutic benefits. While there exist valid concerns about nonmedical prescription stimulant use on the rise (especially in the youth), prescription stimulants have substantial benefits for many people with ADHD. Moreover, when taken as prescribed, they have consistently not been associated with increased risk for substance-related problems.² On the contrary, ADHD, particularly when untreated, is a well-established risk factor for the development of substance use disorders, including opioid use disorder (OUD).³ While the literature has suggested a possible association between prescription stimulant exposure and nonfatal overdose in the OUD population, analyses also show that pharmacologic treatment of ADHD, via stimulants, may be associated with improved retention in life-saving medication to treat OUD (MOUD).^4,5 A recent analysis by Park and colleagues illustrates that co-occurring stimulant use disorders were uncommon (<5%) in people receiving MOUD receiving ADHD medication.⁶

Finally, we want to add nuance to the authors’ framing of opioid and stimulant prescribing being a determinant of the current overdose epidemic, which is increasingly driven by non-prescribed synthetic drugs (fentanyl, methamphetamine), rather than prescription opioids and stimulants. For prescribing trends to be considered an epidemic, we would expect to see evidence of a disease or harmful health-related behaviors occurring at rates significantly above the expected baseline in the U.S. Yet, from a population perspective, if only 1–7% people with OUD in the U.S. are being co-prescribed stimulants,⁶ are we really seeing evidence of an “epidemic”? Amid widespread efforts to curb opioid prescribing in the U.S., we underscore that use of prescribed opioids and stimulants should not necessarily be conflated with problematic substance use behaviors. In contrast to rising non-prescribed fentanyl and methamphetamine use, national-level data suggest that most people receiving prescription opioids and/or stimulants in the U.S. do not meet formal diagnostic criteria for substance use disorder (nor engage in illicit drug use or misuse of their opioid and/or stimulant medication).7, 8, 9 While stimulant prescribing is associated with an increased risk for long-term opioid therapy, analyses show that stimulant use among patients with long-term opioid therapy was not associated with the development of opioid use disorder after adjustment for confounding.¹⁰

Lee and colleagues appropriately note that there is a lack of guidelines for prescribing stimulants to patients with comorbid ADHD and pain who are receiving opioids. While we agree that more research is needed in this area, we think that it may be an overstatement to conclude that there exists a twin prescription opioid and stimulant epidemic.

Contributors

All authors contributed equally to conceptualization, data interpretation, and revision and approval of manuscript. JFS, KYX, and RAG wrote the initial draft. JFS had final responsibility for the decision to submit for publication.

Declaration of interests

The authors have no conflicts of interest. Dr. Xu and Grucza have conducted reviews for NIH study sections outside of the submitted work, which encompasses fees for grant review.