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Electrocardiographic Abnormalities, Malignant VentricularArrhythmias, and Cardiomyopathy Associated With

Loperamide AbusePATRICIA VAUGHN, A.C.N.P., MICHELLE M. K. SOLIK, M.D., SHIV BAGGA, M.D., and

BENZY J. PADANILAM, M.D.

From the St. Vincent Medical Group, Indianapolis, Indiana, USA

Electrocardiographic Abnormalities Associated With Loperamide Abuse. A 20-year-oldman presented with recurrent syncope and abnormal electrocardiogram (ECG). His evaluation revealed aprolonged QT interval >600 milliseconds, witnessed torsades de pointes (TdP), and dilated cardiomyopathy.At his initial admission, an ICD was implanted and atrial pacing at 80 beats per minute suppressedventricular arrhythmias. The patient was readmitted with device infection and recurrent TdP leading tointubation. This led to the discovery of a hitherto unrevealed loperamide abuse and his cardiac arrhythmiasand LV dysfunction were determined to be related to large doses of loperamide. Following abstinence, hisejection fraction and ECG returned to normal. (J Cardiovasc Electrophysiol, Vol. 27, pp. 1230-1233, October2016)

Implantable Cardioverter Defibrillator (ICD), Loperamide, Narcotic withdrawal, QT prolongation, Torsades dePointes (TdP)

Introduction

Loperamide is a widely available over-the-counter antidiar-rheal agent that acts as a peripheral µ-opioid receptor agonist.Over the last decade an online movement has emerged us-ing the drug for opioid withdrawal symptoms or recreationalabuse.1 We report the case of a young man presenting withrecurrent syncope, abnormal electrocardiogram (ECG), andlife-threatening ventricular arrhythmias due to loperamideabuse.

Case Presentation

A 20-year-old male with a remote history of intra-venous drug use presented to our emergency department after2 episodes of syncope while ambulating at home. Over theprevious 4 months, the patient reported multiple episodesof palpitations, shortness of breath, and near syncope. Hisfamily history was negative for sudden death. The physicalexamination was normal, but the admission 12-lead ECGwas grossly abnormal with broad QRS complexes and QTprolongation (Fig. 1). A standard urine drug screen was neg-ative. On day 2 of admission, he had syncope with teleme-try revealing torsades de pointes (TdP) that degenerated toventricular fibrillation (VF) (Fig. 2). Telemetry recordingsshowed spontaneous conversion of VF after 45 seconds,sinus bradycardia with a heart rate in the low 50 beats

This manuscript was processed by a guest editor.

Disclosures: None.

Address for correspondence: Benzy J. Padanilam, M.D., St. Vincent MedicalGroup, 8333 Naab Road, #400, Indianapolis, IN 46260, USA. Fax: 317-338-6066; E-mail: bjpadani@stvincent.org

Manuscript received 7 June 2016; Revised manuscript received 12 July2016; Accepted for publication 20 July 2016.

doi: 10.1111/jce.13052

per minute (bpm) range, frequent premature ventricularcontractions (PVCs) and postpause QT prolongation. Intra-venous isoproterenol infusion was initiated resulting in anincreased sinus rate to about 80 bpm and suppression ofventricular ectopy. A cardiac magnetic resonance imaging(MRI) revealed dilated cardiomyopathy with a left ventric-ular ejection fraction (EF) of 45%. The right ventricle wasnormal. The 2D echocardiogram also revealed mild globalhypokinesis of the left ventricle and an estimated EF of40–45%. The patient was suspected to have a genetic defectaccounting for his abnormal ECG and VF episode. A dualchamber ICD was implanted with the lower atrial pacingrate of 80 bpm per minute, which shortened the QT intervalto 500 milliseconds, and completely suppressed ventriculararrhythmias (Fig. 3). He was released home on metoprololsuccinate 12.5 mg daily with the recommendation for genetictesting as an outpatient.

Three weeks later the patient was readmitted with a devicepocket infection and underwent ICD system removal and an-tibiotic treatment. There were no arrhythmias detected on theICD interrogation. With discontinuation of atrial pacing, thesinus rate was observed to be in the mid 50 bpm range andQTc 600 milliseconds. On day 4 of admission, the patienthad multiple episodes of sustained TdP events that required5 external defibrillations. He was intubated and sedated. Anisoproterenol infusion was started with control of VF eventsand reimplantation of a dual chamber ICD from the rightinfraclavicular region was performed on day 7 of admis-sion. Atrial pacing at 80 bpm again suppressed ventriculararrhythmias and isoproterenol was discontinued.

Upon extubation on day 9, the patient developed opioidwithdrawal symptoms and admitted to use of high doses ofloperamide daily over the last year. He started this habit toprevent withdrawal symptoms when he quit heroin. He tookup to 288 mg loperamide daily (2 bottles of 2-mg tablets) andcontinued the habit in-hospital assisted by a friend withoutthe knowledge of the staff. The last loperamide tablet takenwas reported to be on the morning of the day of intubation

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Figure 1. Presenting ECG. Grossly ab-normal ECG with PR interval prolongedto 320 milliseconds, QRS duration of 200milliseconds, and QTc of 600 millisec-onds. For a high quality, full color versionof this figure, please see Journal of Car-diovascular Electrophysiology’s website:www.wileyonlinelibrary.com/journal/jce

Figure 2. Torsade de pointes. Telemetryrecording showing onset of torsade depointes.

Figure 3. Atrial pacing at 80 bpm. QRSduration is prolonged to 160 millisec-onds and QTc is 500 milliseconds. Fora high quality, full color version ofthis figure, please see Journal of Car-diovascular Electrophysiology’s website:www.wileyonlinelibrary.com/journal/jce

1232 Journal of Cardiovascular Electrophysiology Vol. 27, No. 10, October 2016

Figure 4. ECG 6 weeks after discon-tinuation of loperamide showing nor-malization of intervals. The rhythm isatrial paced at 80 bpm, PR interval160 milliseconds, QRS duration 90 mil-liseconds, and QTc 440 milliseconds.For a high quality, full color version ofthis figure, please see Journal of Car-diovascular Electrophysiology’s website:www.wileyonlinelibrary.com/journal/jce

(day 4) and a loperamide level on day 10 was 1.3. (Thera-peutic loperamide levels are 0.24–1.2 ng/mL.)2 The patientunderwent inpatient and outpatient drug rehabilitation. At6 weeks, the follow-up ECG revealed atrial pacing at 80 bpmand normal intervals (Fig. 4), and repeat 2D-echocardiogramshowed normalization of EF to 55%.

Discussion

The temporal relationship of ECG changes and ventriculararrhythmias to loperamide use in our patient’s case suggeststhis to be the likely etiology of his prolonged QTc, QRSprolongation, and episodes of TdP. This became evident dur-ing the second hospitalization when the patient no longerhad access to loperamide while intubated. There was nearnormalization of ECG changes and resolution of ventriculararrhythmias a few days after discontinuation of loperamide.The half-life of loperamide is approximately 9–13 hours.3

The patient continued to have a detectable loperamide levelin the therapeutic range 6 days after his known last ingestion,suggesting very high drug levels during the abuse. Levelswere not evaluated earlier since there was no reason to sus-pect this etiology. We could not identify any other potentialetiology, including inpatient medications that could accountfor the patient’s presentation.

Loperamide is a peripherally acting µ-opioid receptor ag-onist that acts on sites in the large intestine in an effort toslow intestinal peristalsis, decrease fluid and electrolyte loss,and inhibit secretion.2,3 FDA-approved in 1976, clinicianshave long used it as an over-the-counter means of alleviat-ing diarrhea. At the recommended maximum daily dose of16 mg/day, loperamide’s effects appear to be limited to thegut with minimal penetration of the blood-brain barrier.1 Itis thought to be devoid of abuse potential owing to consid-erable first-pass metabolism and poor blood–brain barrierpenetration because of P-glycoprotein efflux pump.2,4 Satu-ration of P-glycoprotein efflux transporters explains the eu-phoric effects seen at high doses and the consequent abusepotential.5,6

With a potential for euphoric effects at high doses, easyaccessibility and low expense, the use of loperamide as aremedy for opioid withdrawal and its recreational use as anopioid substitute is widely discussed in online drug forums.7

Indeed, in 1 observational study of web-based trends of the

use of loperamide beyond therapeutic purposes, loperamidehas been described as the “poor man’s methadone” in man-aging symptoms of opioid withdrawal. In January 2014, ourpatient decided to stop heroin abuse and researched methodsof suppressing the withdrawal symptoms on the Internet. Hestarted taking 48 mg (24 pills) of loperamide each morning.He gradually built up a tolerance and escalated his loperamideuse to a peak of 288 mg (144 pills) each morning by July2015. He began to have infrequent episodes of near-syncopein August 2015 and started weaning the loperamide; he hadweaned himself to a dose of 144 mg (72 pills) daily, but wasstill having brief near-syncopal episodes 2–3 times per weekat the time of his admission. Unbeknownst to the medicalstaff, he was being supplied with the loperamide by a friendduring both hospitalizations. Intubation ended the patient’saccess to loperamide, leading to a complete resolution ofthe ECG changes seen on admission. At his 6-week follow-up with abstinence from loperamide, the patient’s ECG re-mained normal and his left ventricular dysfunction resolvedcompletely.

There is a paucity of electrophysiology literature describ-ing the cardiac toxicity associated with loperamide abuse.A few case reports available are primarily in the toxicol-ogy literature.1,8-11 Marraffa et al. were among the firstto report the association observed between loperamideabuse and cardiac conduction disturbances8: they described5 individual cases observed at various institutions in whichpatients presented with a life-threatening cardiac arrhythmiatemporally related to loperamide abuse. One of the patientsexperienced a second life-threatening arrhythmia afterresuming loperamide abuse following discharge from thehospital. Loperamide levels were obtained in most of thesepatients and found to be at least 1 order of magnitudegreater than therapeutic concentrations. Furthermore,discontinuation of this medication resulted in a completeresolution of cardiac conduction disturbances observed oninitial presentation. Similarly, Eggleston et al.,3 Enakpeneet al.,9 Spinner et al.,1 and Marzec et al.11 have publishedindividual cases of patients with loperamide toxicity and car-diac arrhythmias. To the best of our knowledge, a reversiblecardiomyopathy as seen in this case has not been describedbefore with loperamide abuse. Although loperamide hasbeen generally considered devoid of cardiac electrophys-iological properties, these reports are changing this view.

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A dynamic public registry for long QT drugs (http://www.crediblemeds.org/everyone/composite-list-allqtdrugs) hasrecently categorized loperamide as a QT prolonging drugwith a conditional risk of TdP. In comparison, methadone,a central-acting µ-opioid receptor agonist with structuralsimilarities to loperamide, is classified as high risk for TdP.Methadone has been associated with dose-dependent QTinterval prolongation and TdP.12 In addition, the UnitedStates Food and Drug Administration has recently releaseda warning about serious cardiac arrhythmias, includingcardiac arrest, associated with loperamide abuse.13

The frequency with which cardiac electrophysiologicalabnormalities occur in patients abusing loperamide is un-known. It could be patient specific and it is possible thatsusceptible patients may have underlying genetic variationsthat become manifest when exposed to high doses of the drug.The exact mechanism whereby loperamide leads to thesecardiac conduction disturbances at supratherapeutic doses isunclear. Marraffa et al. propose that high drug concentrationsof loperamide block IKr channels and INa channels, leadingto QT prolongation and QRS prolongation, respectively.8

Spinner et al. recognize the structural similarity that existsbetween loperamide and another piperidine derivative knownto cause cardiac arrhythmia: haloperidol.1 QTc prolongationrelated to other synthetic opioids such as methadone hasbeen recognized to be due to blockade of the cardiac IKrchannels,11 and due to structural homology with methadoneit is speculated that loperamide also blocks IKr.

Conclusion

This case illustrates the evolving cardiac risks related toroutinely used over-the-counter medications. Patients oftendo not reveal such information during encounters and clini-cians need awareness to be specific in interviewing for etiol-ogy of unusual presentations.

References

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12. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS: Dose relatedeffects of methadone on QT prolongation in a series of patients withtorsade de pointes. Pharmacotherapy 2003;23:802-805.

13. FDA Drug Safety Communication: FDA warns about serious heartproblems with high doses of the antidiarrheal medicine loperamide(Imodium), including from abuse and misuse. June 7, 2016. Availableat: http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm. AccessedJuly 11, 2016.