Loperamide: A Readily Available but Dangerous Opioid Substitute

Abstract

The antidiarrheal over‐the‐counter drug loperamide is increasingly being used to control opioid withdrawal or for opioid abuse. Taking many times above the normally recommended dose is dangerous with cardiovascular, respiratory, and neurological adverse events. Cytochrome P‐450 (CYP)2C8, CYP3A, and P‐glycoprotein inhibitors can increase the plasma and central nervous system concentrations and radically alter the risk profile of loperamide. Online forums suggest using over‐the‐counter metabolic enzyme blockers to enhance the effects. Public health options include switching over‐the‐counter loperamide to blister packs (the FDA‐preferred method), making loperamide only available by prescription, or moving the product behind the pharmacy counter. Although naloxone may ameliorate the neurological and respiratory adverse events, it is ineffective at reversing loperamide‐induced arrhythmias. Even magnesium might provide less efficacy in loperamide‐induced Torsade de Pointes necessitating the use of cardiac pacing and electrical cardioversion.

Ensuring Patient Protections When Tapering Opioids: Consensus Panel Recommendations

“…73 Gastrointestinal discomfort may respond to loperamide; however, clinicians should know that it can be abused and, in high doses, can cause dangerous arrhythmias. 74 The Role of Buprenorphine Buprenorphine, a partial mu-receptor agonist, is approved in sublingual form for treatment of OUD in combination with naloxone. As noted at a 2018 National Academies of Sciences, Engineering, and Medicine workshop on MAT of OUD, "Medications are irrefutably the most effective way to treat OUDdreducing the likelihood of overdose death by up to threefold."…”

Discovery and Characterization of the Biflavones From Ginkgo biloba as Highly Specific and Potent Inhibitors Against Human Carboxylesterase 2

“…Currently, loperamide (LPA, a marketed anti-diarrhea agent) has been used for alleviating irinotecan-induced intestinal toxicity in clinical settings ( Tobin et al, 2005 ; Baker, 2007 ). However, the moderate CES2 inhibition potency, as well as the potential adverse effects of LPA (such as headache, dizziness, constipation, nausea and flatulence), strongly limited the long-term administration of this anti-diarrhea agent ( Hanauer, 2008 ; Eggleston et al, 2017 ; Miller et al, 2017 ; White, 2019 ). Therefore, it is urgent and necessary to find more efficacious CES2 inhibitors to reduce the excessive hydrolysis of CPT-11 into its toxic product SN-38 in the intestinal tract.…”

A life threatening ventricular arrhythmia secondary to loperamide abuse, “a poor man’s methadone”

“…Acquired long QT syndrome has been related to the intake of some drugs, although some are antiarrhythmic, this effect has also been reported in relation to drugs used in digestive pathology, antiepileptic drugs, antibiotics, and antidepressants that prolong ventricular repolarization (1). In these cases, the risk of arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation are increased, which could cause sudden death as the only manifestation (2,3).…”

“…Loperamide is an over-the-counter medication used to treat diarrhea, however, there are reports from the United States where the drug has been used as a recreational drug; initially was acquired to control diarrhea as a symptom of heroin withdrawal in the rehabilitation clinics and subsequently consumed in search of its opioid properties (1,4).There are case reports of overdose of loperamide from 100 to 400 tablets per day and in these patients cardiotoxicity manifested as syncope due to tachyarrhythmias such as VT, torsade de pointes, long QT, Brugada pattern and sudden death; improving completely as soon as the use of the drug is abandoned around 14 to 48 hours (5).…”