Opioids-induced inhibition of HERG ion channels and sudden cardiac death, a systematic review of current literature

It is estimated that over 60 million individuals regularly use opioids globally, with opioid use disorder increasing substantially in the past decade. Several reports have linked sudden cardiac death, QTc prolongation, and other adverse cardiovascular outcomes with opioid use through their inhibitory effect on the human ether-a-go-go-related gene (HERG) ion channel. Therefore, understanding this underlying mechanism may be critical for risk prevention and management in prescribing opioids and treating patients with opioid dependency. The present systematic review summarizes the current literature on the impact of opioids-induced inhibition of HERG channel function and its relationship with sudden cardiac death, QTc prolongation, and other cardiovascular adverse effects. A systematic review was conducted of the databases PubMed, EMBASE, Cochrane, and ClinicalTrials.gov of primary studies that reported the effects of opioids on HERG channel function and associated cardiovascular outcomes. The search identified 1,546 studies, of which 12 were finally included for data extraction. Based on the current literature, methadone, oliceridine, l-α-acetylmethadol (LAAM), and fentanyl were found to inhibit the HERG channel function and were associated with QTc prolongation. However, other opioids such as morphine, codeine, tramadol, and buprenorphine were not associated with inhibition of HERG channels or QTc prolongation. Additional cardiac outcomes associated with opioid related HERG channels dysfunction included sudden cardiac death and Torsade de Pointes. Our findings suggest that certain opioid consumption may result in the inhibition of HERG channels, subsequently prolonging the QTc interval and increasing patient susceptibility to sudden cardiac death.