Management of overdoses of loperamide, gabapentin, and modafinil: a literature review.

Introduction: The current emphasis on combatting the opioid epidemic in the United States and across the globe is well warranted, but rates and variations of other drugs and substances of abuse may be inadvertently increasing as well. These drugs and substances deserve equal attention in the literature to equip healthcare practitioners with the knowledge to provide optimal care in overdose patients. Areas covered: This evaluation includes loperamide, gabapentin, and modafinil and was accomplished through a comprehensive literature review of PubMed, MEDLINE, SCOPUS, ProQuest Central, ProQuest Dissertations, and CINAHL. The results of forty-four pieces of literature are included in this evaluation. The objective of this review is to provide a repository of standard and emerging treatment modalities for loperamide, gabapentin and modafinil for the emergency medicine team. Expert opinion: Loperamide, gabapentin, and modafinil are becoming drugs of abuse, and as such, should be on the radar of healthcare providers. Recognizing their unique toxicity profiles is imperative in providing optimal resuscitative care.

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina.

Loperamide is an over-the-counter, µ-opioid receptor agonist commonly used as an antidiarrheal agent. Loperamide was thought to have minimal abuse potential due to its low bioavailability and limited central nervous system activity; however, there have been increasing reports of loperamide misuse in supratherapeutic doses to achieve euphoria and/or avoid opioid withdrawal. A literature review suggests a rise in loperamide abuse was inevitable, with substantial increases in reported cases over the last decade. Five fatal cases of toxic medication use where loperamide was listed as a primary or contributory cause of death were identified at the Medical University of South Carolina. The characteristic autopsy demographics and findings are described, and the mechanisms of abuse and toxicity of loperamide are reviewed. Loperamide overdoses are a growing concern from both a forensic and clinical standpoint, and the frequency of reported cases will likely increase as awareness grows within the medical and toxicological communities.

Loperamide-Induced Torsades de Pointes: A Case Series.

BACKGROUND: Loperamide is an over-the-counter, inexpensive, antidiarrheal opioid that can produce life-threatening toxicity at high concentrations. CASE REPORT 1: A 28-year-old man with a history of depression and substance abuse disorder (SUD) presented to the emergency department (ED) with shortness of breath and lightheadedness. He ingested large amounts of loperamide daily. The patient's initial electrocardiogram (ECG) demonstrated sinus rhythm, right axis deviation, undetectable PR interval, QRS 168 ms, and QTc 693 ms. He was administered intravenous sodium bicarbonate and magnesium sulfate and admitted to the intensive care unit, eventually developing Torsades de Pointes (TdP). He was given lidocaine and isoproterenol infusions, and an external pacemaker was placed. He was discharged in stable condition on hospital day (HD) 16. CASE REPORT 2: A 39-year-old woman with a history of hepatitis C, depression, and SUD was transported to the ED after reported seizure-like activity. The patient experienced TdP in the ED and admitted to ingesting large amount of loperamide daily. An ECG demonstrated sinus rhythm, right axis deviation, PR interval 208 ms, QRS interval 142 ms, and QTc 687 ms. She was administered intravenous magnesium, sodium bicarbonate, and isoproterenol. After intensive care unit admission, the patient experienced no further TdP and was discharged on HD 6. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should proceed with caution when treating patients with loperamide toxicity. Even in asymptomatic patients and drug discontinuance, obtain consultation with a medical toxicologist, promptly treat ECG abnormalities aggressively, and admit all patients for further monitoring.

Unexpected Serious Cardiac Arrhythmias in the Setting of Loperamide Abuse.

Loperamide (Imodium) is a non-prescription opioid receptor agonist available over-the-counter for the treatment of diarrhea. When ingested in excessive doses, loperamide can penetrate the blood-brain barrier and is reported to produce euphoria, central nervous system and respiratory depression, and cardiotoxicity. There is an emerging trend in its use among drug abusers for its euphoric effects or for self-treatment of opioid withdrawal. We report a case of ventricular dysrhythmias associated with loperamide abuse in a 28-year-old man who substituted loperamide for the opioids that he used to abuse. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp].

Loperamide metabolite-induced cardiomyopathy and QTc prolongation.

Loperamide is an over-the-counter, peripherally acting, µ-opioid receptor agonist used for the treatment of diarrhea. In recent times users have found that at higher doses, loperamide crosses the blood-brain barrier and reaches central µ-receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report a case of a 37-year-old female who attempted suicide with over 200 loperamide tablets. During her overdose, her QTc was significantly prolonged at >600 ms. Our case aims to add to the growing body of literature describing life-threatening ventricular arrhythmias associated with loperamide toxicity and further suggests that a metabolite of loperamide, desmethylloperamide, may play a role in the pathogenesis.

Loperamide misuse and abuse.

OBJECTIVE: The epidemic of opioid prescription deaths in recent years resulted in the recent rescheduling of hydrocodone-containing products to restrict access to them. Opioid users have recognized that loperamide can ameliorate withdrawal symptoms and also produce euphoria in very high doses. This article discusses the potential for loperamide misuse and abuse and examines trends in the increasing number of published cases of loperamide toxicity. DESIGN: PubMed was used to search MEDLINE for case reports of loperamide abuse. SETTING: United States. MAIN OUTCOME MEASURES: Numbers of cases of loperamide misuse, characteristics of patients, reported toxicities. RESULTS: From 1985 to 2016, 54 case reports of loperamide toxicity were published, with 21 cases between 1985 and 2013 and 33 cases between 2014 and 2016. In addition, 179 cases of intentional loperamide misuse were reported to the National Poison Database System between 2008 and 2016, with more than half reported after January 1, 2014. CONCLUSION: Loperamide misuse and abuse is increasing in the United States, and pharmacists are encouraged to monitor and restrict their sales.

Epidemiologic Trends in Loperamide Abuse and Misuse.

STUDY OBJECTIVE: Loperamide abuse has been increasing in the United States as a potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use. In June 2016, the Food and Drug Administration warned health care providers and the general public about potential serious adverse outcomes, including cardiac dysrhythmias and death. The purpose of this study is to determine recent trends in intentional loperamide abuse and misuse, reported clinical effects and management, and medical outcomes as reported to poison centers across the United States. METHODS: Loperamide exposures reported to the National Poison Data System indicating intentional misuse, abuse, and suspected suicide between January 1, 2010, and December 31, 2015, were assessed. Demographic and temporal trends, as well as reported clinical effects, medical management, and health outcomes, were analyzed. RESULTS: There was a 91% increase in reported exposures from 2010 to 2015, of which half were single-agent loperamide use only. Loperamide exposures reported to the National Poison Data System increased at approximately 38 cases per year (95% confidence interval [CI] 32.5 to 42.9; P<0.0001). Fifteen deaths were reported during this time frame, of which 8 involved single-agent loperamide abuse. CONCLUSION: Loperamide abuse and misuse are projected to increase in the absence of any methods to reduce exposure or curb abuse. Health care providers should consider the potential for loperamide toxicity when managing patients with opioidlike toxicity.

Loperamide-Related Deaths in North Carolina.

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.

Not your regular high: cardiac dysrhythmias caused by loperamide.

OBJECTIVE: Loperamide, a non-prescription anti-diarrheal agent, is a peripheral mu-opioid receptor agonist that is excluded from the blood-brain barrier by p-glycoprotein at therapeutic doses. Overdoses of loperamide penetrate the central nervous system (CNS), leading to abuse. We report cardiac conduction abnormalities and dysrhythmias after ingestion of a recreational supra-therapeutic dose of loperamide confirmed with an elevated blood loperamide concentration. CASE DETAILS: A 48-year-old woman with a history of alcohol and benzodiazepine abuse presented to the emergency department (ED) with somnolence, weakness and slurred speech. She was taking 20 to 40 tablets of 2 mg loperamide 1-2 times/day for weeks along with clonazepam and whiskey. Vital signs were: blood pressure (BP), 124/90 mmHg; heart rate (HR), 88/min; respiratory rate(RR), 20/min; T, 36.9 °C; O2 saturation 100% on room air (RA). Glucose was 6.4 mmol/L. Electrocardiogram (ECG) had a ventricular rate of 58/min, QRS 164 ms, QT 582 ms with no discernable p-waves. Lactate was 3.5 mmol/L and potassium was 6.2 mEq/L. Labs were notable for an anion gap of 20 mEq/L, ethanol of 3.9 mmol/L, creatinine of 2.3 mg/dL and loperamide concentration of 210 ng/mL (average therapeutic plasma concentration 1.2 ng/mL). She became hypotensive, but responded to fluids. Following treatment for hyperkalemia with calcium, insulin, dextrose, and hypertonic sodium bicarbonate a repeat ECG had a ventricular rate of 66/min, QRS 156 ms, and QT 576 ms. Magnesium was given and pacer pads were placed. During the infusion of magnesium, her BP fell to 92/58 mmHg with a HR of 54/min, RR 14/min, O2 saturation of 97% on RA so the infusion was stopped. The ECG after the magnesium infusion had a ventricular rate of 51/min, QRS of 134 ms, and QT 614 ms. In the ICU she had multiple runs of non-sustained ventricular tachycardia that did not require therapy. Over the next 48 h she improved and was transferred to a floor bed. On day four of hospitalization the patient left against medical advice. At that time, her ECG showed sinus tachycardia with a heart rate 114/min, QRS 82 ms, QT 334 ms. DISCUSSION: Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing. A blood loperamide concentration of 210 ng/mL is among the highest concentrations reported. Supra-therapeutic dosing of loperamide is promoted on multiple drug-use websites and online forums as a treatment for opioid withdrawal, as well as for euphoric effects. With the current epidemic of prescription opioid abuse, toxicity related to loperamide, an opioid agonist that is readily available without a prescription is occurring more frequently. It is important for clinicians to be aware of the potentially life-threatening toxicity related to loperamide abuse in order to provide proper diagnosis, management and patient education.

Poor Man's Methadone: A Case Report of Loperamide Toxicity.

Loperamide, a common over-the-counter antidiarrheal drug and opioid derivative, is formulated to act upon intestinal opioid receptors. However, at high doses, loperamide crosses the blood-brain barrier and reaches central opioid receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report the case of a young man found dead in his residence with a known history of drug abuse. At autopsy, the only significant findings were a distended bladder and bloody oral purge. Drug screening found nontoxic levels of alprazolam, fluoxetine, and marijuana metabolites. Liquid chromatography time-of-flight mass spectrometry found an unusual set of split isotope peaks consistent with chlorine. On the basis of autopsy and toxicological findings, loperamide toxicity was suspected because of its opioid properties and molecular formula containing chlorine. A sample of loperamide was analyzed by liquid chromatography time-of-flight mass spectrometry, resulting in a matching mass and retention time to the decedent's sample. Subsequently, quantitative testing detected 63 ng/mL of loperamide or more than 6 times of therapeutic peak concentration. Cause of death was determined as "toxic effects of loperamide with fluoxetine and alprazolam." Because of its opioid effects and easy accessibility, loperamide is known as "poor man's methadone" and may go undetected at medical and forensic drug screening.

Loperamide dependence and abuse.

Loperamide is a common over-the-counter antidiarrheal considered safe in a broad range of dosages and thought devoid of abuse potential. We describe the first case of a patient with loperamide dependence due to misuse of its opiate-like effects achieved by chronic massive oral ingestions. A 26-year-old man who was taking 800 mg of loperamide per day presented requesting detoxification referral. Loperamide has potential for euphoric effects and information on how to facilitate such effects is easily available. It is important for physicians to be aware of the potential for misuse of and dependence on loperamide, with symptoms mimicking opiate use.

Cardiac conduction disturbance after loperamide abuse.

CONTEXT: Prescription opioid abuse is a major public health concern and an ongoing epidemic in the United States. Loperamide is a widely available and inexpensive over-the-counter antidiarrheal with peripheral mu-opioid receptor activity. Online resources discuss the use of loperamide for the amelioration of withdrawal symptoms or recreational abuse. We describe the clinical course of 5 patients abusing loperamide, 3 of whom had life-threatening cardiac arrhythmias. METHODS: In this observational case series, patients with cardiac arrhythmias or history of loperamide abuse with cardiac arrhythmias were identified; 5 patients were identified and 4 of the 5 patients were seen directly at the bedside. Clinical profile and outcome of patients is reported. RESULTS: We report 5 patients with history of loperamide abuse; 3 of the 5 patients had life-threatening cardiac arrhythmias. One of the patients experienced a second life-threatening arrhythmia after he resumed loperamide abuse. Loperamide levels were obtained in 4 of the 5 patients and were at least one order of magnitude greater than therapeutic concentrations. Discontinuation of loperamide resulted in complete resolution of cardiac conduction disturbances. CONCLUSION: This case series describes several patients with cardiac conduction abnormalities and life-threatening ventricular arrhythmias temporally related to loperamide abuse. With the recent efforts to restrict the diversion of prescription opioids, increasing abuse of loperamide as an opioid substitute may be seen. Toxicologists should be aware of these risks and we urge all clinicians to report such cases to FDA Medwatch(®).

Tissue distribution of loperamide and N-desmethylloperamide following a fatal overdose.

We report a case involving a fatal intoxication with loperamide (Imodium). Loperamide is a synthetic opioid of the phenyl piperidine class used as an over-the-counter antidiarrheal. It exerts its effects through interaction with micro-opiate receptors in the intestine to reduce peristalsis. Loperamide lacks the typical euphoric opiate effects when administered at recommended doses. Both loperamide and its major metabolite, N-desmethylloperamide, were isolated by liquid-liquid extraction into n-butyl chloride from alkalinized samples. Extracts were analyzed by liquid chromatography-electrospray-mass spectrometry in selected-ion-monitoring mode. Rapid separation of the drug, metabolite, and internal standard (diphenoxylate) was achieved using a high-resolution C18 column with 1.8-microm particle diameter. The mobile phase consisted of 0.1% formic acid in deionized water (60%) and acetonitrile (40%) at a flow rate of 0.5 mL/min. Heart blood concentrations for loperamide and its metabolite were 1.2 mg/L and 3.3 mg/L, respectively. In contrast, reported peak plasma concentrations of loperamide after administration of recommended daily doses of 16 mg did not exceed 0.012 mg/L in controlled trials. Because the heart blood ethanol concentration was 0.08 g/dL, the medical examiner ruled that the cause of death was loperamide and ethanol intoxication, and the manner of death as undetermined.