Leveraging Real-World Data to Address Potential Methadone Drug–Drug Interactions

Abstract

As the sales of opioids rapidly increased in the United States at the turn of this century, so too did admissions for opioid abuse treatment and deaths due to opioid overdose.¹ The resulting opioid epidemic has devastated innumerable lives as well as strained an already struggling healthcare system. To combat this, a multi-faced approach has been implemented, including strategies to try to prevent inappropriate prescription of opioids in both the acute and chronic pain settings as well as employing pharmacological therapies to mitigate the consequences of opioid use disorders (OUD).² Currently, there are three agents approved as medications for OUD (MOUD), the opioid agonists methadone and buprenorphine as well as the opioid antagonist naltrexone. A retrospective comparative effectiveness study using deidentified claims data demonstrated that only methadone or buprenorphine use, but not other measures such as naltrexone, inpatient treatments, or non-intensive behavioral health initiatives, reduced overdose and opioid-related morbidity.³

Despite the efficacy of MOUD, it was estimated that only 22% of the 2.5 million individuals in the United States who had past-year OUD in 2021 received MOUD.⁴ This degree of undertreatment is in part due to the ongoing stigma associated with OUD as well as lack of sufficient knowledge regarding MOUD on the part of the healthcare enterprise. A recent scoping review focused on understanding healthcare workers’ knowledge and attitudes regarding outpatient use of methadone revealed key knowledge gaps as well as varying degrees of concern regarding the potential for misuse and skepticism regarding efficacy.⁵ OUD is of course not unique to the United States and the stigma associated with OUD impacts management throughout the world. For example, a recent observational study conducted in France involving individuals with OUD revealed that approximately two-thirds of those surveyed had moderate to high levels of self-stigma and nearly one-half had experienced perceived stigma from a healthcare professional with respect to their OUD.⁶ While it is critical that society address the stigma associated with OUD, it is also important that healthcare workers understand how to safely prescribe MOUD agents such as methadone.

One factor that may be contributing to healthcare workers hesitancy to prescribe methadone for OUD is the agent's complex pharmacology, characterized by high inter-individual variability, the potential for numerous drug–drug interactions and prolonged elimination half-life.⁷ In 2006, the FDA issued a public health advisory regarding fatal overdoses involving methadone and noted that some of the overdoses may have been unintentional, possibly linked to prescribers being unfamiliar with methadone's pharmacological properties.⁸ Methadone is considered to be a major substrate of CYP2B6 and to a much lesser extent, CYP3A4 and CYP2D6.⁹ A recent Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline determined that there is insufficient evidence to suggest that CYP2B6 genotype impacts methadone adverse events, dose requirements or analgesia (CPIC level C—no recommendation).¹⁰ Another source of potential drug–drug interactions is P-glycoprotein (P-gp), as preclinical data demonstrated that inhibitors of P-gp can result in increased intestinal absorption of methadone as well as increased brain levels of methadone.¹¹ However, whether concomitant administration of commonly prescribed drugs that are P-gp inhibitors results in clinically meaningful drug–drug interactions that impact methadone safety remains a matter of ongoing investigation.

In the present issue of Clinical Pharmacology & Therapeutics (CPT; Figure 1), Chen and co-workers focus on determining whether the concomitant use of methadone and statins impacts the risk of opioid overdose.¹² In their retrospective cohort analysis using state Medicaid program claims data, the risk of opioid overdose (resulting in hospitalization or emergency department evaluation) in individuals taking both methadone and a P-gp-inhibiting statin (atorvastatin, lovastatin or simvastatin) was compared to that of individuals taking methadone and rosuvastatin (a non-P-gp-inhibiting statin). Notably, no statistically significant differences in opioid overdose were observed between the two groups.¹² Given the widespread use of statins (it is estimated that 92 million individuals in the United States were on a statin in 2018–2019¹³), this particular question of the safety of methadone with statins is highly relevant and the results of the study are practice informing. This analysis also demonstrates how real-world claims data may be used to interrogate whether hypothetical drug–drug interactions translate to clinically significant events. This topic will be further explored in the upcoming CPT-themed issue “Bench to Budget: Streamlining the Full Spectrum of Evidence Integration for Drug-Development and Patient Access.”

It is long past time for the healthcare system to recognize that OUD may be one of several chronic conditions (e.g., hyperlipidemia, diabetes mellitus, hypertension) for which an individual receives medications. In this context, having improved understanding of which of the many potential drug–drug interactions involving methadone are actually clinically significant is critical so that patients can safely receive optimal treatment for not only their OUD but also their other co-morbidities. From a clinical pharmacology perspective, it is essential that the field continue to explore potential pharmacokinetic interactions involving methadone using all of the tools in our armamentarium, including harnessing the power of real-world data, in order to help combat the ongoing opioid epidemic.

No funding was received for this work.

The author declared no competing interests for this work.