Austin Hughes

Introduction. Prolonged QT interval results from genetic or acquired causes, characterized by prolongation of the QT interval, the period from onset of cardiac ventricular depolarization to the end of ventricular repolarization.¹  Drug-induced QT prolongation is common among recovering opioid dependents, particularly in those who are prescribed racemic methadone, the most potent of opioid agonists in regards to cardiac electrophysiology, acting on and inhibiting the hERG potassium channel.²  One third of methadone users experience prolonged QT intervals, putting them at a high risk of torsade de pointes and sudden cardiac death.^1,2  Multiple studies have shown a stereoselective difference in the actions of methadone, where (R)- methadone is responsible for mu-opioid agonist action and (S)-methadone inhibits the hERG potassium channel.³  However, the racemic mixture of methadone is prescribed for pain management and methadone maintenance therapy (MMT).^3,4  Methods. HEK293 cells and cardiomyocytes expressing hERG were analyzed utilizing cryo-EM for determination of channel structure and unique binding properties.⁵  Whole-cell patch-clamp experiments were performed with HEK293 cells that stably expressed hERG, with varying concentrations of the enantiomers and racemic mixture of methadone.³  Studies involving individuals in MMT were also conducted for effects of chronic methadone usage.³  Results. hERG potassium channels contain a small central cavity, with deep extensions, with a preference for hydrophobic molecules and structures similar to that of methadone.⁵  Mechanisms of methadone on the hERG channel are dependent on the involvement of Serum and Glucocorticoid Inducible Kinase-3 (SGK3) and Hsp90, which are involved in hERG gene transcriptional regulation and protein trafficking to the cardiac plasma membrane.⁴  Following five days of treatment with (S)- and racemic methadone and evaluation using real-time PCR, there was significantly reduced levels of SGK3 gene expression, indicating that transcription of hERG in hindered in methadone treated human cardiomyocytes, leading to the potential for generation of prolonged QT intervals.⁴  At the concentration that blocks 50% of hERG channels, hERG mRNA expression in cardiomyocytes was reduced after only 5 days of treatment with racemic form and (S)-methadone, but not (R)-methadone. Conclusions. Given the stereoselectivity of methadone for the hERG channel and the undesirable consequences of sudden cardiac death, the (R)-methadone form, and not the racemic mix or (S)-methadone form should be favored for usage in methadone maintenance therapy and pain management.^3,4  EKG screening and education needs to be more widely implemented and possibly mandated in patients being prescribed methadone, as we face an ongoing and worsening opioid crisis.^6,7

1. Bohnen MS, Peng G, Robey SH, et al. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev. 2017;97(1):89-134. doi:10.1152/physrev.00008.2016
2. Zerdazi EH, Vorspan F, Marees AT, et al. QT length during methadone maintenance treatment: gene × dose interaction. Fundam Clin Pharmacol. 2019;33(1):96-106. doi:10.1111/fcp.12405
3. Eap CB, Crettol S, Rougier JS, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81(5):719-728. doi:10.1038/sj.clpt.6100120
4. Mokhtar, N. and Hussin, M., 2017. Chronic Racemic and (S)-Methadone Treatment Reduces hERG Gene Expression in Human Primary Cardiomyocytes. Cardiology and Cardiovascular Medicine. 2017; 01(06),236-247.
5. Wang W, MacKinnon R. Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. Cell. 2017;169(3):422-430.e10.
6. Zerdazi EH, Vorspan F, Marees AT, et al. QT length during methadone maintenance treatment: gene × dose interaction. Fundam Clin Pharmacol. 2019;33(1):96-106.
7. Martin JA, Campbell A, Killip T, et al. QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel [published correction appears in J Addict Dis. 2012 Jan;31(1):91. Haigney, Mark C P [added]]. J Addict Dis. 2011;30(4):283-306.