The Risk of Ventricular Dysrhythmia or Sudden Death in Patients Receiving Serotonin Reuptake Inhibitors With Methadone: A Population-Based Study

Abstract

Background: Methadone is associated with ventricular dysrhythmias and sudden death. Serotonin reuptake inhibitors (SRIs) may increase the risk of these events either by inhibiting metabolism of methadone's proarrhythmic (S)-enantiomer, additive QT interval prolongation, or both. We sought to determine whether certain SRIs were associated with a higher risk of methadone-related ventricular dysrhythmias or sudden death. Methods: We conducted a nested case-control study of Ontario residents receiving methadone between April 1, 1996 and December 31, 2017. Cases, defined as patients who died of sudden cardiac death or were hospitalized with a ventricular dysrhythmia while on methadone, were matched with up to four controls who also received methadone on age, sex, and a disease risk score. We determined the odds ratio (OR) and p-value functions for the association between methadone-related cardiotoxicity and treatment with SRIs known to inhibit metabolism of (S)-methadone (paroxetine, fluvoxamine, sertraline) or prolong the QT interval (citalopram and escitalopram). Patients who were not treated with an SRI served as the reference group. Results: During the study period, we identified 626 cases and 2,299 matched controls. Following multivariable adjustment, we found that recent use of sertraline, fluvoxamine or paroxetine (adjusted OR 1.30; 95% confidence intervals [CI] 0.90-1.86) and citalopram and escitalopram (adjusted OR 1.26; 95% CI 0.97-1.63) were associated with small increases in the risk methadone-related cardiac toxicity, an assertion supported by the corresponding p-value functions. Interpretation: Certain SRIs may be associated with a small increase in cardiac toxicity in methadone-treated patients.

Keywords: methadone; nested case control studies; pharmacoepidemiogy; serotonin reuptake inhibitor; sudden cardiac arrest.

FIGURE 1

p-value function for odds ratio for association between fluvoxamine, paroxetine or sertraline and ventricular dysrhythmia or sudden death in methadone-treated patients. The point estimate of 1.30 corresponds to the peak of the p-value function. The vertical continuous line denotes the null value for the odds ratio, and the white point the counter-null value of 1.69, which is the effect size supported by the same amount of evidence as the null value.

FIGURE 2

p-value function for odds ratio for association between citalopram or escitalopram and ventricular dysrhythmia or sudden death in methadone-treated patients.The point estimate of 1.26 corresponds to the peak of the p-value function. The vertical continuous line denotes the null value for the odds ratio, and the white point the counter-null value of 1.59, which is the effect size supported by the same amount of evidence as the null value.