Paracelsus, the Swiss-German physician credited as the father of toxicology, wrote in the early 1500s, “All things are poison, and nothing is without poison: the dose alone makes a thing not poison.” Centuries later, after many of his once-radical ideas found wide acceptance, Paracelsus’ pronouncement would be distilled into a pithy phrase that became foundational dogma for the modern science of toxicology: “The dose makes the poison.”

The over-the-counter antidiarrheal medication Imodium, or its key ingredient, loperamide, is increasingly being abused by people attempting to self-treat their opioid addiction, sometimes with fatal results. These patients are ending up in the emergency department and must be appropriately treated (see Table 1).
Table 1. Treatment of Imodium (lopermide HCL) Overdose

Eggleston et al describe two case studies of patients with histories of substance abuse who attempted to self-treat opioid addictions with massive doses of loperamide.¹ Both patients overdosed on massive amounts of the drug. The patients were treated with cardiopulmonary resuscitation, naloxone, and standard advanced cardiac life support. Both patients died. The first patient was found with six empty boxes of loperamide, and postmortem toxicology analysis of cardiac blood demonstrated a loperamide concentration of 77 ng/mL. (The therapeutic range is 0.24–3.1 ng/mL.) The second patient had been self-treating his opioid addiction with the over-the-counter antidiarrheal medication after discontinuing buprenorphine. A complete autopsy revealed cardiomegaly and severe pulmonary edema. Comprehensive postmortem toxicology revealed a femoral blood loperamide concentration of 140 ng/mL.

In the approximately 40 years since loperamide was first approved as an antidiarrheal in 1976, 48 cases of serious heart problems associated with its use have been reported to the U.S. Food and Drug Administration (FDA). Thirty-one of these cases resulted in hospitalization, and 10 patients died. More than half of the 48 cases were reported after 2010. The serious cardiac problems occurred mostly in patients who were taking doses that were much higher than recommended. In other cases, patients were taking the recommended dose of loperamide, but they were also taking interacting medicines, causing an increase in loperamide levels.² Additional cases of serious heart problems associated with the use of loperamide were reported in the medical literature.

Cases reported to the FDA and in the medical literature indicate that individuals are taking significantly high doses of loperamide in situations of both misuse and abuse, often attempting to achieve euphoria or self-treat opioid withdrawal. They are also combining loperamide with interacting drugs in attempts to increase these effects. The most severe cases involved doses ranging from 70 mg to 1,600 mg daily, which is four to 100 times the recommended dose. (It should be noted some of these case reports may be as short as one sentence, and up to half are submitted by non-physicians, most commonly malpractice attorneys. Many patients were reported to have died of dysrhythmias, yet no electrocardiographs are available. Also, the doses are often self-reported or not known, as noted by Eggleston.¹)

Oral loperamide abuse postings to web-based forums increased tenfold between 2010 and 2011. A majority of user-generated content pertaining to loperamide reported using the medication to self-treat opioid withdrawal (70 percent).³ Users also cited abusing the medication for its euphoric properties (25 percent). The Upstate New York Poison Center experienced a sevenfold increase in calls related to loperamide abuse or misuse from 2011 through 2015. That is consistent with national poison data, which reported a 71 percent increase in calls related to intentional loperamide exposure from 2011 through 2014.

If the dose does make the poison, then it won’t come as a surprise to most clinicians that 100 times the therapeutic dose of almost anything, including loperamide, would cause toxicity.

Dr. LoVecchio is vice-chairman and research director for Maricopa Medical Center and co-medical director for Banner Poison and Drug Information Center, both in Phoenix, and professor of emergency medicine at The University of Arizona in Tucson.

References

1. Eggleston W, Clark KH, Marraffa JM. Loperamide abuse associated with cardiac dysrhythmia and death (published online ahead of print April 26, 2016). Ann Emerg Med. doi:10.1016/j.annemergmed.2016.03.047.
2. FAERS Reporting by Healthcare Providers and Consumers by Year. U.S. Food and Drug Administration website. Accessed July 11, 2016.
3. Dierksen J, Gonsoulin M, Walterscheid JP. Poor man’s methadone: a case report of loperamide toxicity. Am J Forensic Med Pathol. 2015;36(4):268-270.