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Reports of Loperamide ODs Reveal a New Cardiotoxic Opioid

Roberts, James R. MD

doi: 10.1097/01.EEM.0000532168.07961.0b

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, PNP, at, and read his past columns at



Never underestimate the ingenuity or resourcefulness of an opioid aficionado. Opioid devotees turned to street heroin after physicians cracked down on opioid prescriptions, limiting the availability of oxycodone and other opioids. Heroin was and still is relatively cheap and easy to obtain, but it's now much stronger than it was 10 years ago. Street heroin now often contains powerful fentanyl and its derivatives. One shot of the extant heroin is more powerful than a handful of Percocet, and deaths from tainted heroin have skyrocketed. Recent reports of severe systemic and cardiac toxicity from abuse of a common OTC antidiarrheal medication, loperamide (Imodium), have also surfaced.

The sagacious and clairvoyant toxicologist, Leon Gussow, MD, informed EMN readers of this news two years ago. (2016;38[7]:8; Since then a variety of case reports have described the respiratory, CNS, and cardiac toxicity of loperamide. Direct cardiac toxicity is highlighted because this effect is not seen from other opioids. The Food and Drug Administration also cautioned clinicians about serious heart problems from high doses of loperamide. It is likely that the FDA will shortly mandate changes in loperamide OTC availability.

A simple ambu bag can save most patients who are still alive after an opioid overdose, but the cardiac toxicity of loperamide may be untreatable and can be fatal. Unfortunately, the emergency clinician has no way to confirm loperamide ingestion, and most will be flummoxed by the ECG findings in the patient who has overdosed on this medication. The only way to suspect loperamide toxicity is via history or finding tablets at the scene. Loperamide has been termed poor man's methadone (strange seeing that methadone treatment is free).

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Loperamide Trends in Abuse and Misuse over 13 Years: 2002-2015

Lasoff DR, Koh CH, et al.



This report from the Department of Medical Toxicology at the University of California, San Diego, and the California Poison Control Center highlights the current information about loperamide abuse. Loperamide is a readily available and rather benign OTC medication used to treat diarrhea. The drug has pharmacological activity at the peripheral mu-opioid receptors in the GI tract. It is relatively safe and effective, with minimal adverse effects when used as directed. The recommended dose of loperamide is initially 4 mg (it comes in 2 mg tablets) followed by 2 mg after each loose stool (maximum use per day is 8-16 mg). Diarrhea generally stops rather quickly. Loperamide does not cause CNS or respiratory depression in therapeutic doses.

The FDA approved loperamide in 1976 and made it OTC in 1988, and it is currently available in generic form. It had been reported that very large doses of loperamide could cause respiratory depression. Recently, loperamide enthusiasts have described opioid-like highs, and it has been used to ameliorate opioid withdrawal, but amazingly large doses are required.

Toxicity has usually been described in individual case reports, but this statewide poison center analysis catalogs loperamide misuse and abuse from 2002 to 2015. It specifically focuses on cardiotoxicity. The California Poison Control Center receives about 300,000 calls annually, and the authors reviewed the records of all who ingested loperamide. Users generally took loperamide to treat opioid withdrawal.

The review identified 224 patients who intentionally misused or abused loperamide ranging in age from 18 to 90 with an equal number of men and women. The number of patients significantly increased after 2014. Moderate to severe effects were noted in 58 cases, and there were three deaths. The major adverse effects were respiratory depression, dysrhythmias, and CNS depression. Doses in symptomatic loperamide users were extremely large, up to an amazing 400 mg per day (200 tablets)!

Methadone and diphenhydramine were also taken in two of the three fatalities. Empiric treatment of cardiotoxicity included sodium bicarbonate, amiodarone, and naloxone. Cardiotoxicity was defined as any arrhythmia, significant ventricular ectopy/VT, Torsades de pointes, QRS duration wider than 120 msec, or a QTc prolongation greater than 500 msec. Note that the risk of severe cardiotoxicity has only been recently recognized. The authors noted that many loperamide exposures did not receive an ECG, so some cardiac effects may have been missed.

Loperamide cardiotoxicity involved chronic daily use of high doses. The dose of loperamide in patients with cardiotoxicity ranged from 200 mg to 400 mg a day. That is an amazing number of the small loperamide tablets—100 to 200—ingested daily. That is clearly a gargantuan overdose.

FDA Caution: The FDA issued its third warning about adverse effects from loperamide on Jan. 30. ( The first in June 2016 warned that higher-than-recommended doses of the common OTC medication could cause serious heart problems that could lead to death. A majority of reported serious heart problems occurred in individuals who were intentionally misusing loperamide, often in attempts to self-treat opioid withdrawal. The loperamide upper limit of dosing is 8 to 16 mg per day. The organization has received reports of 48 cases of serious heart problems since the drug was approved more than 40 years ago. Ten deaths were also logged, but experts speculate that the incidence was likely underreported. The FDA is currently working with manufacturers to limit loperamide toxicity, including the use of blister packs or single-dose packaging to limit the number of drugs per sale.

Comment: Loperamide is safe when used as directed. Those abusing the drug have been reported to take hundreds of tablets per day, clearly not a therapeutic intent. I have great difficulty believing the regular use of hundreds of pills per day, and history is often unreliable, so smaller doses may be toxic. One wonders where such hefty amounts of loperamide are scored (probably the internet). The pharmacology of loperamide mimics that of opioids, and it is only reasonable that those skilled in pharmacology would assume that it would be able to treat withdrawal or to obtain an opioid-like high. The drug is not found by any toxicology screen, so clinicians may not suspect its use. Direct cardiotoxic effects are not seen with opioids, but sodium channel blockade is with loperamide. It also mimics TCA cardiotoxicity with a wide QRS, prolonged QT interval, and ventricular ectopy.

Naloxone does not offer specific cardiac protection, although it has been described as possibly effective for loperamide-induced respiratory depression. Its actual benefit for cardiac toxicity is unknown, however. There are no dosing recommendations. Theoretically, withdrawal could be precipitated with naloxone, but there are no such reports. It seems reasonable to use 2-4 mg of naloxone in patients suspected of loperamide overdose. Whether naloxone should be routine in a TCA cardiotoxic setting, possibly from loperamide, is unclear. The value of amiodarone is unknown, but it has been used in a few cases. I would try IV lipid emulsion in those with severe cardiac toxicity from loperamide (as well as TCA), but that is speculative.

Loperamide has poor penetration into the CNS with standard doses. P-glycoprotein in the blood-brain barrier keeps loperamide out of the CNS, except with very high blood concentrations. Some crafty opioid users have found that some prescription meds, as well as OTC ranitidine and cimetidine, will inhibit p-glycoprotein and may increase loperamide CNS effects.

Eggleston, et al., reported on two patients who died after using loperamide. (Ann Emerg Med 2017;69[1]:83.) Loperamide levels in these cases were 77 ng/ml and 140 ng/ml (therapeutic level: 0.2-1.4 ng/ml). A 24-year-old man was found in cardiac arrest with six boxes of loperamide. CPR and naloxone were given without benefit, and the patient was pronounced dead in the ED. The patient had been seen in the ED the day before his cardiac arrest for urinary retention, a common side effect of loperamide. Autopsy findings were consistent with opioid overdose, including pulmonary and cerebral edema.



The second death was a 39-year-old man with a history of opioid addiction, previously on buprenorphine, suddenly passed out at home and was found to be asystolic by EMS. He had been treated with buprenorphine for opioid addiction, but he apparently stopped using the drug and was self-treating his opioid addiction with OTC loperamide. In this case, the patient suddenly gasped for breath and then experienced abrupt cardiac collapse, which is consistent with a sudden cardiac dysrhythmia as opposed to respiratory depression. Toxicology analysis found only high levels of loperamide.

Loperamide has low cost and wide availability, and its legal status is intriguing to opioid enthusiasts. Abuse has only recently been reported in the medical literature, and it may not be suspected because it is not found on any drug screen and looks like other sodium channel cardiotoxic agents. It is likely that abuse will increase because of decreased availability of opioid prescription medications. A perusal of the internet and multiple drug information websites revealed loperamide as a way to get high or lessen withdrawal. Poison centers have also reported a remarkable increase in calls concerning loperamide toxicity. A small number of patients with GI symptoms also ingest large amounts of loperamide on a regular basis to treat their chronic bowel issues.

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Cardiotoxicity Associated with Loperamide Overdose*

  • Cardiac arrest
  • Ventricular fibrillation
  • Ventricular tachycardia/multiple PVCs
  • Prolonged QTc interval
  • Wide QRS duration
  • Torsades de pointes

* Cardiotoxicity is likely from sodium channel blockade and is similar to TCA ECG changes. It is reasonable to use IV bicarbonate as an antidote for cardiotoxicity, but specific treatment has not been clarified.

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