Loperamide-Related Deaths in North Carolina

Journal of Analytical Toxicology, 2016;40:677–686 doi: 10.1093/jat/bkw069 Advance Access Publication Date: 29 August 2016 Article Article Loperamide-Related Deaths in North Carolina Sandra C. Bishop-Freeman*, Marc S. Feaster, Jennifer Beal, Alison Miller, Robert L. Hargrove, Justin O. Brower, and Ruth E. Winecker North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA *Author to whom correspondence should be addressed. Email: Abstract Loperamide (Imodium®) has been accepted as a safe, effective, over-the-counter anti-diarrheal drug with low potential for abuse. It is a synthetic opioid that lacks central nervous system activity at prescribed doses, rendering it ineffective for abuse. Since 2012, however, the North Carolina Office of the Chief Medical Examiner has seen cases involving loperamide at supratherapeutic levels that indicate abuse. The recommended dose associated with loperamide should not exceed 16 mg per day, although users seeking an opioid-like high reportedly take it in excess of 100 mg per dose. When taken as directed, the laboratory organic base extraction screening method with gas chromatography-mass spectrometry/nitrogen phosphorus detector lacks the sensitivity to detect loperamide. When taken in excess, the screening method identifies loperamide followed by a separate technique to confirm and quantify the drug by liquid chromatography-tandem mass spectrometry. Of the 21 cases involving loperamide, the pathologist implicated the drug as either additive or primary to the cause of death in 19 cases. The mean and median peripheral blood concentrations for the drug overdose cases were 0.27 and 0.23 mg/L, respectively. Furthermore, an extensive review of the pharmacology associated with loperamide and its interaction with P-glycoprotein will be examined as it relates to the mechanism of toxicity. Introduction Loperamide (Imodium®) is a synthetic opioid of the phenylpiperidinetype (Figure 1), originally identified as a drug with low potential for abuse because of its inability to access the brain (1–3). Although loperamide is a potent µ-opioid receptor agonist, the drug has limited central nervous system (CNS) activity and will not readily cross the blood–brain barrier (BBB) when taken as advised (3, 4). The drug is absorbed and concentrated in the gut and acts to reduce peristalsis in the intestines, thus controlling symptoms of acute and chronic diarrhea (2). At the recommended daily adult dose of 4–16 mg, loperamide does not cause euphoria or analgesia to help relieve pain associated with abdominal discomfort (2, 5). After a single 4 mg oral dose (n = 12), peak plasma concentrations of loperamide and its major inactive metabolite, N-desmethylloperamide, were 0.00062 mg/L at 5 h and 0.013 mg/L at 11 h, respectively (1, 5). The elimination half-life is ~12 h. Adverse side effects of loperamide include dizziness, drowsiness and dry mouth. In 1977, loperamide was first classified as a Schedule V drug under the Controlled Substances Act based on animal data that suggested opioid-like effects associated with the drug (6). The FDA Advisory Committee re-evaluated the scheduling and recommended decontrolling loperamide in the 1980s in response to human studies performed using low doses of the drug and epidemiologic data that supported its overall safety (6, 7). It is important to consider, however, that conclusions made regarding the safety of loperamide were based on therapeutic doses of the drug. Recent data suggest that users are taking supratherapeutic doses of loperamide to self-medicate for symptoms of opioid withdrawal (8–10) or abusing the drug to replace illicit opioids, causing new safety concerns. Despite previous evidence demonstrating the safety of loperamide, self-reporting by opioid users on internet forums indicates that the effects of the drug at high doses are similar to centrally acting opioids (8, 9, 11). While 16 mg per day is the maximum recommended dose, users seeking an opioid-like high from loperamide reportedly take 100 mg or more (11, 12). Daniulaityte et al. (8) studied loperamide abuse from a webbased standpoint and described patterns of extra-medical drug use of loperamide and self-treatment behaviors among illicit opioid © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: 677 678 Bishop-Freeman et al. users. The authors found that increased interest in loperamide coincided with the introduction of abuse-deterrent OxyContin® in 2010. In other web-based forums, users suggest taking loperamide in combination with other substances (10, 13–15). Some of the suggested supplements, such as vitamin C, may counteract the side effects associated with over-consuming an anti-diarrheal medication. Omeprazole, quinidine, tonic water, grapefruit juice, cimetidine and other complementary substances may cause drug–drug (or food-drug) interactions, which will be addressed in the discussion section. A summary of therapeutic (5), toxic and fatal (7, 16) loperamide concentrations from the literature is displayed in Table I. The North Carolina Office of the Chief Medical Examiner (NC OCME) has quantified loperamide in 21 cases since 2012. Since loperamide is not detected at therapeutic levels in our laboratory, it quickly became evident based on concentrations and case histories that self-medication and recreational use resulted in supratherapetic post-mortem concentrations. Experimental At the NC OCME, cases are routinely screened for over-thecounter, prescription and illicit drugs using an organic base extraction with gas chromatography-mass spectrometry/nitrogen phosphorus detector (GC-MS/NPD). When taken as prescribed, loperamide will not be detected in the routine GC-MS/NPD organic base screen performed in our laboratory. When taken in excess, loperamide and its metabolite will be detected late in the GC-MS chromatogram after trazodone. Based on our GC-NPD conditions, Figure 1. Loperamide (Imodium®). Table I. Loperamide concentrations previously reported in the literature Matrix Concentration Additional (mg/L or information mg/kg) Therapeutic Plasma studies 0.00024 0.00062 0.00120 0.00310 Fatalities Blood 1.2 Liver Blood Liver 12.5 0.084 0.87 2 mg oral dose (n = 8) 4 mg oral dose (n = 12) 8 mg oral dose (n = 8) 16 mg oral dose (n = 1) Ethanol 0.08 g/dL, pseudoephedrine 2.6 mg/L None Reference (5) loperamide will elute in the next sample. Loperamide was then confirmed and quantitated using liquid chromatography-tandem mass spectrometry (LC–MS-MS). Screening method Extraction procedure The organic base screen uses a liquid–liquid extraction method that has been described previously (17). Two milliliters blood or 1 g of tissue homogenate (1:4 dilution in water) was fortified with alphaprodine internal standard (IS) purchased from Grace Discovery Sciences (Columbia, MD, USA). Next, 0.5 mL concentrated ammonium hydroxide was added to the fortified aliquot, fol (...truncated)