Methadone Blockade of Cardiac Inward Rectifier K+ Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study

Background Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K+ current (I Kr), the principal mechanism of drug‐associated arrhythmia. Congenital defects of inward rectifier K+ current (I K1) have been linked to increased U‐wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I K1, contributing to delayed repolarization and manifesting on surface ECGs as augmented U‐wave integrals. Methods and Results Using a whole‐cell voltage clamp, methadone inhibited both recombinant and native I K1 with a half‐maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I Kr block (half‐maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal repolarization at low concentrations. At higher concentrations, action potential duration at 90% repolarization lengthening was abolished, but its effect on terminal repolarization rose steadily and correlated with increased fluctuations of diastolic membrane potential. In parallel, patient ECGs were analyzed before and after methadone initiation, with 68% of patients having a markedly increased U‐wave integral compared with premethadone (lead V3; mean +38%±15%, P=0.016), along with increased QT and TPeak to TEnd intervals, likely reflective of I Kr block. Conclusions Methadone is a potent I K1 inhibitor that causes augmentation of U waves on surface ECG. We propose that increased membrane instability resulting from I K1 block may better explain methadone’s arrhythmia risk beyond I Kr inhibition alone. Drug‐induced augmentation of U waves may represent evidence of blockade of multiple repolarizing ion channels, and evaluation of the effect of that agent on I K1 may be warranted.