Methadone is a long-acting opioid used primarily as treatment for opioid use disorder (Bell and Strang, 2020). However, methadone maintenance therapy can be complicated by QT interval prolongation in up to 50% of patients (Fanoe et al., 2007; Anchersen et al., 2009; Fareed et al., 2013; Chowdhury et al., 2015; Titus-Lay et al., 2021), with case reports and pharmacovigilance data describing the potential for ensuing Torsade de Pointes and sudden cardiac death (Chugh et al., 2008; Stringer et al., 2009; Kao et al., 2013; Kao et al., 2015). Risk factors for QT interval prolongation and sudden cardiac death are well described, and include older age, female sex, electrolyte abnormalities, and underlying heart disease (Chugh, 2010; Tisdale et al., 2013; Trinkley et al., 2013).

Drug interactions are another important and potentially avoidable risk factor for ventricular dysrhythmias in patients receiving methadone (Stringer et al., 2009). Because co-occurring mental health illness is common in methadone-treated patients and serotonin reuptake inhibitors (SRIs) are the most commonly prescribed class of antidepressants, the likelihood of co-prescription and potential interaction with methadone is high (Callaly et al., 2001; Rosen et al., 2008; Audi et al., 2018; Kane, 2021). However, SRIs differ in their propensity for causing drug interactions because of variable effects on drug metabolizing cytochrome P450 (CYP) isoenzymes as well as the QT interval (Hemeryck and Belpaire, 2002; Beach et al., 2014). This is especially relevant in the case of methadone, which is commercially available as a racemic mixture containing equal amounts of the (R)- and (S)-methadone enantiomers, each of which has distinct clinical and pharmacokinetic properties (Chang et al., 2011). Specifically (R)-methadone is an opioid agonist while (S)-methadone is associated with QT prolongation, increasing the risk of ventricular dysrhythmia and sudden death (Kristensen et al., 1995; Eap et al., 2007; Ansermot et al., 2010). Importantly, each enantiomer is metabolized by different CYP450 enzymes, with the CYP2B6 isoenzyme demonstrating stereoselectivity toward (S)-methadone (Chang et al., 2011; Dobrinas et al., 2013). Concomitantly administered medications that inhibit CYP2B6 may increase (S)-methadone concentrations and therefore increase the risks of dysrhythmia and sudden death. Among SRIs, prior studies have found that fluvoxamine and paroxetine increase concentrations of (S)-methadone by 30–50%, with no such increase observed with fluoxetine (Eap et al., 1997; Begré et al., 2002). In a study of 16 patients receiving methadone, sertraline, which inhibits CYP2B6, was also found to increase methadone levels by 26% (Hamilton et al., 2000). In addition to pharmacokinetic interactions, methadone-related dysrhythmia and sudden death can occur with the concurrent use of additional QT-prolonging drugs. Among SRIs, citalopram and escitalopram are associated with greater QT prolongation and a higher risk of sudden cardiac death than other agents (Castro et al., 2013; Beach et al., 2014; Assimon et al., 2019). The potential for a clinically important interaction between citalopram and methadone was highlighted by a study of forensic toxicological records in the United States, in which a strong signal for drug fatality with combined use was detected (Saad et al., 2018).

However, despite these data, the cardiac safety of combining SRIs with methadone is unknown. We sought to characterize the risk of ventricular dysrhythmias and sudden death in patients receiving these drug combinations in clinical practice. We speculated that, owing to pharmacokinetic and pharmacodynamic interactions, patients treated with methadone and either sertraline, paroxetine, fluvoxamine, citalopram or escitalopram would be at higher risk of these events relative to patients who were not prescribed SRIs.

During the 21-year study period, we identified 960,933 patients who died of sudden cardiac death or were hospitalized with ventricular dysrhythmia. After exclusions, 670 of these individuals had been prescribed methadone within 1 day of death or hospitalization. Of the 670 patients, 626 (93.4%) were matched to at least one control. Overall, baseline characteristics of cases and controls were well balanced, with mean ages of 46.0 years (standard deviation ±11.6) and 45.3 years (standard deviation ±11.3), respectively (Table 1). As expected, case patients exhibited greater co-morbidity, received more prescription drugs in the preceding year, and had more visits with a cardiologist in the preceding year (Table 1).

Following multivariable adjustment, we found that use of sertraline, fluvoxamine or paroxetine (adjusted OR 1.30; 95% CI 0.90–1.86) was associated with a slightly increased risk of cardiac toxicity during methadone therapy (Table 2). The point estimate, representing the value most compatible with the observed data, is displayed at the peak of the corresponding p-value function (Figure 1). Importantly, the point estimate and a considerable portion of the range of effect values consistent with the data exceed 1, supporting an imprecise yet slightly higher risk of cardiac toxicity with these SRIs among methadone-treated patients relative to patients not treated with SRIs. Moreover, the counter-null value is 1.69, demonstrating that a 69% increase in the risk of cardiac toxicity is supported by the same amount of evidence as an odds ratio of 1.0.

Similarly, use of citalopram or escitalopram therapy was associated with a modestly higher risk of cardiac events (adjusted OR 1.26; 95% CI 0.97–1.63) relative to no SRI therapy (Table 2). The point estimate and most of the corresponding p-value function lie above 1, providing support for a slightly higher risk of cardiac toxicity with these SRIs in methadone-treated patients relative to no SRI therapy (Figure 2). The counter-null value is 1.59, demonstrating that a 59% increased risk in cardiac toxicity is supported by the same amount of evidence as a null finding of no risk.

In this population-based study, we found that use of SRIs known to increase levels of (S)-methadone or prolong the QT interval were associated with a slight increase in the risk of dysrhythmias or sudden cardiac death in methadone-treated patients, an assertion supported by the individual point estimates and shapes of the corresponding p-value functions. Although the magnitude of the effect size is small, our findings support the existence of a potentially life-threatening drug interaction between methadone and certain SRIs in clinical practice.

Our findings build upon earlier research exploring interactions between SRIs and methadone. Specifically, past studies have found that fluvoxamine and paroxetine increase concentrations of (S)-methadone (Eap et al., 1997; Begré et al., 2002), and that this enantiomer is 3.5-times more potent than (R)-methadone in blocking the voltage-gated potassium channel of the human ether-a-go-go related gene (hERG) (Eap et al., 2007). Similarly, prior research demonstrating that sertraline inhibits CYP2B6 and that individuals with the slow metabolizer phenotype of CYP2B6 have higher (S)-methadone concentrations and longer QT intervals than individuals with normal CYP2B6 activity supports the notion of a clinically important interaction between methadone and sertraline (Hamilton et al., 2000). Because the QT interval has been found to increase by 19.2 s for every 1,000 ng/ml increase in (S)-methadone concentrations (Csajka et al., 2016), accumulation of this enantiomer following the co-administration of sertraline, fluvoxamine or paroxetine provides a reasonable mechanistic basis for the increased risk of cardiac toxicity with combined use. The finding of a higher risk of methadone-related cardiac toxicity with citalopram and escitalopram aligns with the known QT prolonging effects of these drugs (Castro et al., 2013; Beach et al., 2014). While this effect is likely of minimal significance in patients with no other risk factors for dysrhythmias, it may contribute to life-threatening QT interval prolongation in patients receiving concurrent therapy with proarrhythmic drugs such as methadone. Moreover, the combination of methadone and citalopram was invariably fatal in an exploratory study of drug combinations associated with opioid deaths, lending additional support to the notion of an important pharmacodynamic interaction between these drugs (Saad et al., 2018).

Our findings have important implications for public health. Methadone remains a cornerstone of therapy for the management of opioid use disorder, with the World Health Organization classifying it as an essential medication in 2005 (Herget, 2005). However, methadone-related QT interval prolongation and ventricular dysrhythmia are important contributors to methadone-related morbidity and mortality. Importantly, a community-based study of 22 cases of methadone-related sudden cardiac death at therapeutic doses identified an anatomical cardiac cause in only 23% of cases, with no clear cause identified for the remaining patients (Chugh et al., 2008). In contrast, a cardiac cause could be identified for 60% of non-methadone-related cases of sudden cardiac death. Although the overall risk of torsades de pointes is small and associated with multiple risk factors, our findings highlight an underappreciated drug interaction between methadone and commonly prescribed SRIs as a potential component cause in the occurrence of methadone-related cardiac toxicity, particularly among patients with no pre-existing cardiac risk factors for dysrhythmia. In light of our findings and past research, clinicians should follow standard methadone monitoring practices to mitigate the risk combined methadone-SRI therapy, including identification and management of risk factors for ventricular dysrhythmias, pre-treatment and follow-up electrocardiographic monitoring, and if clinically appropriate, selection of an antidepressant that does not interact with methadone.

Our study has some limitations. First, we used administrative data, and had no access to serum electrolytes, electrocardiograms, treatment adherence, and use of non-prescribed medications. Although we used validated codes for our outcomes, misclassification is possible. However, these limitations apply equally to all SRIs. Second, our study population comprised individuals eligible for public drug coverage in Ontario, which accounts for 70% of all methadone-treated patients in the province. Consequently, our findings may not be generalizable to all methadone-treated patients. Third, we were unable to reliably determine methadone dose. However, a dose-response relationship for methadone-related cardiotoxicity has not been clearly established, with cardiac effects documented at therapeutic doses (Chugh et al., 2008; Roy et al., 2012; Isbister et al., 2017). Fourth, some imbalance in baseline characteristics was apparent between cases and controls despite matching on a disease risk index. However, this is expected in case-control studies when cases are defined by an adverse outcome, and our analysis was adjusted for imbalanced variables. Finally, as with all observational studies, confounding due to unmeasured variables is a potential source of bias.

In conclusion, we found that SRIs expected to increase concentrations of the cardiotoxic (S)-methadone enantiomer or prolong the QT interval were associated with ventricular dysrhythmia and sudden cardiac death in patients receiving methadone. When combined therapy is required, the risks of a drug interaction can be minimized through careful patient selection that considers additional risk factors for QT prolongation and increased patient monitoring.