Methadone, synthetic opioids and torsades de pointes

Opioids are the most potent of all analgesics. Currently available agents are classified as natural, semisynthetic, and synthetic. Opioids have traditionally been used solely for acute self-limited conditions such as fracture or postoperatively, as well as for chronic palliation of cancer-associated pain. However, within the United States, a movement to promote subjective pain (scale, 0 to 10) to the status of a fifth vital-sign led to widespread prescribing of extended-release opioids for managing chronic, noncancer pain. This, coupled with rising opioid misuse, initiated a surge in unintentional deaths. Natural opioids via “on-target” μ-receptor agonism result in cardiovascular and respiratory consequences including hypotension and ventilatory depression but are devoid of electrophysiologic properties. By contrast, synthetic agents can be proarrhythmic via “off-target” effects. Herein, we explore conduction and repolarization effects of opioids using methadone as a prototype. We also examine the potential contribution of these electrophysiologic properties to opioid-associated mortality and provide practical cardiac safety recommendations for clinicians.