Rethinking Methadone and QTc prolongation in the Fentanyl Era: A Decision Analysis for Medically Ill Patients

Abstract: Background/Significance:

The opioid crisis in the United States continues to be an urgent public health issue with more than 80,000 opioid overdoses in the past year—the majority involving fentanyl and other high potency synthetic opioids.¹ Medications for opioid use disorder (MOUD) including the opioid agonists methadone and buprenorphine are effective treatments and reduce all-cause mortality.^{2, 3} However, only 13% of individuals with opioid use disorder (OUD) are receiving treatment.⁴ One clinical challenge with methadone is an association with QT prolongation and increased risk for torsades de pointes (TdP), a potentially fatal cardiac arrthymia.⁵ Though QT prolongation is dose-dependent, there is no formal guidance to inform clinician decision-making on methadone dose adjustment nor when to switch to alternative therapies (i.e., buprenorphine).

Methods:

A decision analysis was performed to inform development of a decision aid tool for clinicians providing methadone therapy in individuals with QT prolongation. Outcomes included continuing, decreasing, or stopping methadone along with switching to buprenorphine.

Results:

The decision analysis estimated a 1-year mortality rate of 0.3% in switching to buprenorphine, 0.3% in continuing methadone, 1% decreasing the methadone dose, and 3.6% in stopping methadone. The analysis suggests the optimal strategy in patients with a prolonged QTc receiving methadone is to continue methadone or switch to buprenorphine.



Discussion:

This decision analysis suggests that the 1-year mortality rate is extremely low for continuing methadone in the setting of prolonged QTc, likely due to the low probability of TdP. Given the higher probability of overdose death without MOUD and the possible challenges of cross-tapering to buprenorphine while a patient is acutely or critically ill, maintenance of methadone without dose adjustment may be a preferred strategy.

Conclusions:

This decision aid tool has the potential to inform clinicians’ decision-making regarding the management of methadone in individuals with OUD and QTc prolongation. Sensitivity analyses and validity testing is needed to establish whether the optimal treatment decision is maintained under different probabilistic assumptions.