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Over-the-counter agents misused to curb opioid withdrawal or induce euphoria at high doses were linked to a disproportionate number of lethal arrhythmias reported to national pharmacovigilance systems, researchers found.

Antidiarrheal drug loperamide, a weak synthetic opioid, was significantly associated with ventricular arrhythmia (proportional reporting ratio [PRR] 3.2, 95% CI 3.0-3.4), with 37% of the 1,008 FDA Adverse Event Reporting System (FAERS) reports involving death.

The arrhythmic signal was worse -- an 8.9 PRR (95% CI 6.7-11.7) -- for mitragynine, the primary active ingredient in the herbal supplement kratom. Fully 91% of its 46 FAERS reports resulted in death.

"This suggests that a shift toward over-the-counter and recreational opioids poses novel cardiovascular hazards," according to a group led by Mori Krantz, MD, medical officer of the FDA and president/governor of the Colorado chapter of the American College of Cardiology, reporting in the .

As both readily available drugs have come to be used to curb opioid cravings at large doses, their hazards have taken on urgency amid the crackdown on prescription opioid access.

The shift in illicit drug use that crackdowns have prompted -- increasing IV heroin use, for example -- has sharply increased infective endocarditis, "with incidence rates now exceeding 1 million per year in the United States, which is the highest burden worldwide," Krantz and colleagues wrote. "In contrast, the potential cardiac arrhythmic sequelae of this shift in opioid utilization patterns have not been well studied."

"Although a convincing mechanistic link between mitragynine and ventricular arrhythmia is lacking, our pharmacovigilance findings suggest that additional in vitro and clinical research, quantifying the arrhythmia liability of this novel compound, is needed. This is essential to inform regulatory decisions in the ever-changing landscape of opioid use and abuse," the authors stressed.

Much remains unknown regarding the proarrhythmic and fatal effects of these unconventional opioids, agreed electrophysiologist Lee Eckhardt, MD, and cardiology fellow Andrew Nickel, MD, both of the University of Wisconsin-Madison.

Kratom has even been touted as a safe alternative to prescription opioids because of an observed lack of QT prolongation related to human ether-a-go-go (hERG) potassium channel blockade.

"Ascription of the arrhythmia vulnerability as related to hERG blockade is clearly barking up the wrong (kratom) tree. We think that instead of touting the lack of QT prolongation from kratom as justification for its safety, efforts should be directed to increase access to safer alternatives (i.e., buprenorphine) for OUD," Eckhardt and Nickel wrote in .

For their study, Krantz and colleagues analyzed voluntary FAERS reports capturing arrhythmic events from 2015-2017. For the quantification of arrhythmic risk, events involving ventricular arrhythmia and cardiac arrest were ranked higher than QTc-prolongation and torsade de pointes.

Prescription opioid methadone served as positive control with established arrhythmia risk. Indeed, methadone was disproportionately associated with ventricular arrhythmia reports (PRR 6.6, 95% CI 6.2-7.0), with death reported in 73% of the 1,163 cases.

As expected, negative controls buprenorphine (partial μ-opioid agonist) and naltrexone (pure antagonist) had no associations with arrhythmia. Neither did another the antidiarrheal agent diphenoxylate.

Study findings were similar in the Center for Food Safety and Applied Nutrition Adverse Event Reporting System and the Canada Vigilance Adverse Reaction databases, according to Krantz's group.

"Given this landscape of addiction-driven experimentation, ongoing pharmacovigilance is needed to identify newly emerging threats," the investigators urged. "These efforts must be coupled with methodologically robust prospective, dose-controlled, clinical studies assessing the impact of these over-the-counter and recreational opioids on both cardiac repolarization and cardiac rhythm."

Study authors and editorialists alike cautioned that the available pharmacovigilance data cannot provide an accurate count of arrhythmic incidents due to the voluntary reporting of cases. Confounding from co-ingestion of other potentially lethal agents may not be excluded, either.

Furthermore, findings regarding mitragynine in particular may merit lower confidence due to the low absolute number of adverse events associated with that agent.

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