Loperamide, a common antidiarrheal available at pharmacies across the country, has unexpectedly become one of the latest in a growing trend of over-the-counter medications being repurposed for recreational use. Over the past 10 years, the broader public has discovered that supratherapeutic doses of loperamide can result in opioid-like euphoric effects. This information has been widely reported in internet forums that tout its use as a cheap “legal high.” Unfortunately, in addition to euphoria, large doses of loperamide have been associated with cardiotoxicity, respiratory depression, and even death.

Indication and mechanism
Commonly known by the brand name Imodium, loperamide can easily be purchased without a prescription. We prescribe or recommend it for patients with ostomies, GI distress related to opioid withdrawal, some forms of chronic diarrhea, or run-of-the-mill occasional diarrhea. Many clinicians don’t realize that loperamide is in fact a synthetic opioid. It slows down the gut by inhibiting intestinal peristalsis and allowing increased water absorption through its action as a mu-opioid receptor agonist in the intestinal tract, just like common opioids of abuse. Loperamide has historically been considered safe due to limited blood-brain permeability at its maximum recommended dose of 16 mg daily (Baker DE, Rev Gastroenterol Disord 2007;7:S11–S18). In other words, at therapeutic doses, loperamide does not act as an opioid agonist in the central nervous system, only in the gut, and therefore does not cause any of the analgesic or euphoric effects that we commonly associate with opioids.

Misuse
The significant GI distress that is experienced by patients in opioid withdrawal, characterized by diarrhea, nausea, and vomiting, can be treated appropriately with loperamide. Along with clonidine, ibuprofen, acetaminophen, and dicyclomine, loperamide is often a component of a symptom-based opioid detoxification protocol. In fact, it is thought that loperamide abuse first became widespread when patients taking it over the counter as a self-treatment for opioid withdrawal discovered that it could be taken regularly to keep withdrawal symptoms at bay. Given the inconvenience of daily methadone clinic visits, more and more posts on internet substance use message boards now recommend loperamide as a cheap and accessible alternative to methadone (Daniulaityte R et al, Drug Alcohol Depend 2013;130(1–3):241–244). Online users tout that supratherapeutic doses of loperamide (70–100 mg per day) result in central nervous system effects similar to methadone and can improve symptoms of opioid withdrawal. In fact, loperamide has recently come to be known as the “poor man’s methadone.”

Illicit drug websites discuss the use of “lope” at single doses of up to 400 mg to achieve an opioid high (the maximum recommended single dose is 4 mg). Once doses get above 25 times the recommended maximum daily dose, loperamide does cross the blood-brain barrier to achieve central nervous system effects, such as euphoria and analgesia. To further enhance these effects, users take loperamide in combination with P450 inhibitors that slow its metabolism and excretion, like quinine, quinidine, and cimetidine.

Studies looking at the number of calls to poison centers reporting loperamide overdoses, as well as analyses of Google search trends, have revealed the growing concern of loperamide’s abuse potential (Borron SW et al, J Emerg Med 2017;53(1):73–84). From 2010 to 2015, there was a 91% increase in intentional loperamide exposures reported to the National Poison Data System—a worrying trend given the potentially lethal effects of loperamide taken at such high doses (Vakkalanka JP et al, Ann Emerg Med 2017;69(1):73–78). Loperamide manufacturers have gotten wary and capped the dose of a single pill at 2 mg. Packages typically contain loperamide exclusively in blister packs, and some pharmacies limit the number of packages that an individual can buy.

Side effects and toxicity
At recommended doses, the side effects of loperamide are mild and the medication is generally acknowledged to be safe. However, at the high supratherapeutic doses taken to achieve euphoria, frank opioid intoxication occurs with characteristic respiratory depression, pinpoint pupils, and sedation. Furthermore, like methadone, high-dose loperamide interferes with cardiac conduction and can cause dangerous arrhythmias. Many case studies have detailed QRS widening and QT prolongation, resulting in an increased risk of torsades de pointes (Marraffa JM et al, Clin Toxicol (Phila) 2014;52(9):952–957; Katz KD et al, J Emerg Med 2017;53(3):339–344).

Why is this important?
There is clear evidence of the rising popularity of loperamide abuse. As a result, in 2016 the FDA released a warning that high doses of loperamide can cause abnormal heart rhythms and serious cardiac events. Loperamide is not tested on the standard urine drug screen, so it is important for us to recognize and consider loperamide toxicity. In the case of acute toxicity, naloxone can be given for respiratory depression. Given the high risk of arrhythmias, these patients should be transferred to an inpatient unit with telemetry and receive a cardiology consultation (Eggleston W et al, Clin Toxicol (Phila) 2020;58(5):355–359). Unfortunately, we don’t have any research about how best to treat patients with loperamide use disorder. It is unclear whether these patients require detoxification or whether buprenorphine, methadone, or naltrexone are helpful.

CATR Verdict: Remain wary of loperamide abuse, particularly in patients with signs of opioid toxicity but a negative urine drug screen. Patients intoxicated on loperamide need inpatient admission and a cardiology consultation.