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. 2023 Jun 13;81(23):2258-2268.
doi: 10.1016/j.jacc.2023.04.009.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids

Mori J Krantz  1 , Todd J Rudo  2 , Mark C P Haigney  3 , Norman Stockbridge  4 , Robert B Kleiman  2 , Michael Klein  3 , David P Kao  5
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Free article

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids

Mori J Krantz et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied.

Objectives: In this study, we sought to explore opioid-associated arrhythmia reporting in North America.

Methods: The U.S. 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) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory.

Results: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS.

Conclusions: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.

Keywords: QTc-prolongation; arrhythmia; kratom; loperamide; methadone; mitragynine.

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Conflict of interest statement

Funding Support and Author Disclosures This publication reflects independent work of the authors and is not a representation of official policies or positions of the American College of Cardiology or any U.S. governmental agency, including the Department of Defense, Veterans Medical Affairs Medical Center, or the Food and Drug Administration. Dr Kao was supported by K08 HL125725. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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