While cases have declined, use of loperamide as an opioid substitute still poses serious risks

Loperamide, the active ingredient in Imodium, is readily available in over-the-counter (OTC) anti-diarrheal agents that are safe when used as directed. Sources have reported cases of people misusing extreme high doses of loperamide to act as an opioid substitute or to self-manage their opioid withdrawal, which can come with serious health risks.

Through my work as the assistant clinical director at the Upstate New York Poison Center, I was involved in 2012 in the second-known reported caseopens in a new tab or window of loperamide-induced cardiac toxicity and published the first case series of patients with ventricular arrhythmias in connection with loperamide misuse. In the years following, poison control centers and medical examiners saw an increased number of cases with toxicity and death due to high doses of loperamide; however, recent poison center data shows a slight decrease in the number of casesopens in a new tab or window.

It is promising that the number of loperamide cases have declined, however, deaths from opioids remain a public health crisis. The CDC reported a 31% increaseopens in a new tab or window in drug overdose mortality from 2019 through 2020 with these numbers expected to continue to rise. Tragically, in the 12 months ending in April 2021, more than 100,000 people diedopens in a new tab or window from drug overdoses, with more than 70,000 deaths due to synthetic opioids, specifically fentanyl. Despite increased efforts towards harm reduction, resources are still unavailable for many. With that, some may turn to alternative opioid substitutes — and clinicians need to be aware of these agents.

Let’s discuss why healthcare providers need to be aware of cardiac toxicity from loperamide misuse and current initiatives designed to help mitigate misuse and abuse.

Pharmacology of Loperamide

First made available in the U.S. as an OTC product in the late 1980s, loperamide was considered to be free of abuse potentialopens in a new tab or window despite being a mu opioid receptor agonist. At therapeutic doses, loperamide has limited oral bioavailability (<1%) and does not cross the blood-brain barrier. Loperamide is structurally similar to haloperidol (Haldol) and methadone. Although it is an opioid agonist, doses of up to 16 mg do not cause central opioid effects in adults. If taken concurrently with a P-glycoprotein inhibitor or in excessive dosing, opioid effects do occur.

A reviewopens in a new tab or window of the FDA MedWatch system from 1976 through December 2015 described 48 casesopens in a new tab or window of loperamide abuse with serious cardiac events and 10 deaths with a median daily dose of 250 mg (range: 70 mg–1,600 mg). The cardiac toxicity typically occurs with chronic dosing rather than acute overdose.

At high plasma concentrations, loperamide and its metabolite, n-desmethyl-loperamide, interfere with cardiac conduction by blocking both sodium and potassium channels, resulting in widening of the QRS complex and the QT interval and subsequent ventricular arrhythmias. There also have been reports of bradycardiaopens in a new tab or window that suggest a direct myocardial depressant effect.

Efforts to Mitigate Loperamide Misuse

In 2016, the FDA released a warningopens in a new tab or window about the risks of cardiac toxicity and death after supratherapeutic dosing. In addition, in 2018, FDA and the OTC medicine industry announced packaging limits on solid forms of OTC loperamide. The products can only be sold in unit-dose blister packages and in no more than a maximum of 24 tablets (48 mg). Liquid products are still sold in 4- and 8-oz sizes, with no more than 32 mg of loperamide in 8 oz.

The Consumer Healthcare Products Association (CHPA) formed a national advisory board with multiple experts, including myself and other healthcare providers, FDA, pharmaceutical companies, patients, and advocates. Through this work, CHPA developed a national campaign to educateopens in a new tab or window healthcare providers and at-risk patients about loperamide abuse and misuse.

The exact incidence of ongoing loperamide misuse is impossible to quantify. Fortunately, cases of loperamide toxicity in the literature appear to have declined since 2020 and the National Poison Data Center has reported declines in intentional loperamide exposures every year since 2017. Anecdotally, calls to my poison center have decreased since 2020.

The Role of Clinicians and Health Systems

There is no specific antidote for patients with loperamide-induced cardiac toxicity, and the mainstay of care is supportive care. For patients with life-threatening arrhythmias, standard advanced cardiac life support management should be employedopens in a new tab or window. Sodium bicarbonate at doses of 1-2 meq/kg IV bolus may be considered. However, close monitoring of serum potassium is needed because hypokalemia may worsen QT prolongation.

Deaths from drug overdose, the majority of which involve opioids, is a public health crisis. Harm reduction measures, including access to medications for opioid use disorder, need to be readily available and accessible. Clinicians should consider loperamide in the differential diagnosis in patients with opioid use disorder and unexplained syncope or an abnormal electrocardiogram. Clinicians should share the dangers of loperamide misuse and abuse with vulnerable patients, their families, and all members of the healthcare team. For any potential case of loperamide toxicity, call the regional poison center at 1-800-222-1222.