Opioid abuse is a major problem in the United States. In 2014, 4.3 million Americans aged 12 and older admitted to current, nonmedical use of prescription pain relievers. [1] Opioid abuse can lead to accidental overdose death, increased healthcare, crime involvement, and additional addiction (i.e. heroin).2,3 Several medications (i.e. methadone, buprenorphine, naltrexone) are available to help wean patients off of opioids; however, costs and/or enrollment in specialized monitoring programs may deter patients from obtaining these prescription medications. Additionally, opioid medications are becoming harder to obtain, likely due to prescriber education and abuse-deterrent formulations.4 As a result, individuals addicted to opioid medications may seek alternative remedies to ease withdrawal symptoms despite potential health repercussions. [2], [3] 

Loperamide (Imodium®) is an antidiarrheal and peripheral µ-opioid receptor agonist available over the counter. After its approval, loperamide was classified as a Schedule V controlled substance due to its mechanism action. This restriction was later removed because it was considered to have "extremely low abuse potential" due to its poor central nervous system (CNS) penetration and low bioavailability.5 Major side effects reported are constipation, dizziness, abdominal cramps and nausea. At therapeutic doses, this drug is considered safe and well tolerated. At supratherapeutic doses, however, loperamide is able to cross the blood by way of P-glycoprotein (Pgp) saturation and/or inhibition.6 Higher than normal loperamide levels may also result due to interactions with the cytochrome P450 isozymes, CYP3A4 and CYP2C8, because these isozymes play an important role in its metabolism.5 Because loperamide is easy to obtain, cheap, and unregulated, it has been referred to as the "poor man's methadone."7 Online posts discussing loperamide's use to alleviate opioid withdrawal symptoms has been evaluated in a web-based review of the extra-medical use of loperamide. This review highlights the increased discussions relating to the illicit use of loperamide by the often hard-to-reach population of drug abusers.7 The national poison control center reported a 71% increase in the number of calls related to intentional loperamide overdose between the years of 2011 and 2014.8,9 These calls involved case reports which led to serious cardiac issues. The mechanism behind this cardiotoxicity is not yet completely understood, however there are some theories. One proposed mechanism deals with the chemical structure of the compound. Loperamide is a piperidine derivative. These drugs have been shown to increase the action potential duration and the effective refractory period in animal studies.10 At large doses, piperidines can act as sodium channel blockers. Additionally, the ability of loperamide to block L-type Ca2+ channels at high doses has been shown in previous studies.10 Supratherapeutic concentrations are required for these hypothetical mechanism to result in cardiotoxicity.

Several cases have been reported in the literature detailing the potential risks of supratherapeutic doses of loperamide. A 25-year-old woman with a prior history of substance abuse first visited the emergency department due to abdominal pain and was admitted to the hospital on two separate occasion weeks later, first due to a syncope episode while driving and later due to nausea and vomiting.10 Electrocardiograms (ECGs) taken during the patient's hospital visits showed abnormalities at each visit. During the second admission, the patient experienced multiple episodes of ventricular tachycardia. The patient denied use of over-the-counter medications or illicit substances and her toxicology report was negative for drugs of abuse. Upon investigation, multiple empty bottles of loperamide were found at her house, and her blood level of loperamide was found to be markedly elevated. The physicians reported this patient case was a classic example of substitutive behavior in which the loperamide was abused in place of stronger opioids. 10 Two months after her second discharge, the patient was readmitted for cardiopulmonary arrest attributed to continued loperamide abuse, from which she died 18 hours post admission.Another case involved a 54-year-old woman who reported taking loperamide for diarrhea.11 The patient reported two episodes of syncope prior to hospital admission. Upon arrival to the hospital, she presented with multiple episodes of sinus pauses up to 5 seconds and intermittent ventricular tachycardia. Her past medical history was significant for a cholecystectomy resulting in severe chronic diarrhea. The patient reported self-medicating her diarrhea with loperamide since her surgery 8 years prior. Over the course of a couple years, the patient titrated herself from the recommended maximum dose of loperamide (16 mg/day) to 72 capsules (144 mg) per day in two divided doses and maintained the regimen for around 2 years. During this time, the patient took nine times the maximum recommended dosage. 5 The patient received an implantable cardioverter-defibrillator and was discharged after six days. The patient was instructed to avoid loperamide and was placed on cholestyramine for her symptoms. Two months post discharge the patient had no ventricular tachycardia or bradycardia requiring intervention.11

As a result of multiple case reports, the FDA announced the potential of loperamide to cause serious heart problems in individuals misusing and/or abusing high doses of loperamide.12 These problems may manifest in the form of unexplained QT prolongation, Torsades de Pointes, ventricular tachycardia, cardiac arrest, or syncope. Since this is a relatively new discovery and because loperamide testing is not included in routine toxicology testing, the suspected loperamide death toll is higher than reported. Healthcare professionals should be aware of the potential serious cardiac adverse events involving loperamide. Patients should be advised of the signs and symptoms associated with cardiotoxicity including fainting, irregular heartbeats, or faster than normal heartbeat. Pharmacists can educate other healthcare practitioners about this new warning and review medications for potential drug-drug interactions involving CYP3A4, CYP2C8, and Pgp substrates.5 It is important that healthcare providers are aware of potential issues involving medications, especially common ones patients consider safe.

References:

1. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from the 2014 National Surveyon Drug Use and Health. Rockville, MD: Substance Abuse and Mental Health Services Administration.

2. Stotts AL, Dodrill CL, Kosten TR. Opioid dependence treatment: options in pharmacotherapy. Expert Opin Pharmacother. 2009;10(11):1727-40.

3. Cameron D, Smith GA, Daniulaityte R, Sheth AP, Dave D, Chen L, Anand G, Carlson R, Watkins KZ, Falck R. PREDOSE: a semantic web platform for drug abuse epidemiology using social media. J Biomed Inform. 2013 Dec;46(6):985-997. doi: 10.1016/j.jbi.2013.07.007.

4. Ensuring Appropriate Opioid Management in a Community Pharmacy Setting. Pharmacist's Letter. Vol. 2016 Course No. 214. Self-study Course #160214.  

5. Loperamide [Package Insert]. Morgantown, WV: Mylan Pharmaceuticals Inc, 2006.

6. Crowe A, Wong P. Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport. Toxicol Appl Pharmacol. 2003;193(1):127-37.

7. Daniulaityte R, Carlson R, Falck R, et al. "I just wanted to tell you that loperamide WILL WORK": a web-based study of extra-medical use of loperamide. Drug Alcohol Depend. 2013;130(1-3):241-4.

8. Bronstein AC, Spyker DA, Cantilena LR, et al. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila). 2012;50:911-1164.

9. Mowry JB, Spyker DA, Brooks DE, et al. 2014 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd annual report.  Clin Toxicol (Phila). 2015;53: 962-1147.

10. Enakpene EO, Riaz IB, Shirazi FM, Raz Y, Indik JH. The long QT teaser: loperamide abuse. Am J Med. 2015;128(10):1083-6.

11. Spinner HL, Lonardo NW, Mulamalla R, Stehlik J. Ventricular tachycardia associated with high-dose chronic loperamide use. Pharmacotherapy 2015;35:234-8.

12. FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse. http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm  . Accessed July 20, 2016. 

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