Loperamide, mitragynine linked to ventricular arrhythmias

Use of nonprescription drugs loperamide and mitragynine appears to contribute to the risk of life-threatening ventricular arrhythmia, reports a study in North America.

A team of investigators searched the databases of the US Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) from 2015 to 2021. They then identified reports involving nonprescription drugs (ie, loperamide, mitragynine) and diphenoxylate/atropine (Lomotil).

The prescription opioid (full agonist) methadone served as a positive control due to its established arrhythmia risk, while buprenorphine (partial agonist) and naltrexone (pure antagonist) served as negative controls.

The investigators classified reports according to the Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting warranted a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. FAERS data were used in the primary analysis, while those of CAERS and CVAR were used to confirm the findings.

Methadone showed a disproportionate association with ventricular arrhythmia reports (PRR, 6.6, 95 percent confidence interval [CI], 6.2‒7.0; n=1,163; chi-square, 5,456), with 852 (73 percent) deaths.

Loperamide also significantly correlated with arrhythmia (PRR, 3.2, 95 percent CI, 3.0‒3.4; n=1,008; chi-square, 1,537), including 371 (37 percent) deaths, while mitragynine exhibited the highest signal (PRR, 8.9, 95 percent CI, 6.7‒11.7; n=46; chi-square, 315), with 42 (91 percent) deaths. On the other hand, buprenorphine, diphenoxylate, and naltrexone showed no association with arrhythmia.

CVAR and CAERS data revealed similar signals.

“Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America,” the investigators said. “Consequently, the over-the-counter opioids loperamide and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria.”