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Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?
YAJEM-57529; No of Pages 3 American Journal of Emergency Medicine xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication? Amr Idris, MD a,b,⁎, Kenji Kaye, MD b a b
University of Central Florida College of Medicine HCA GME Consortium North Florida Regional Medical Center, Internal Medicine, Gainesville, Florida, USA
a r t i c l e
i n f o
Article history: Received 3 May 2018 Accepted 13 May 2018 Available online xxxx Keywords: Loperamide Cardiotoxicity QTc prolongation
a b s t r a c t Loperamide is an over-the-counter anti-diarrheal medication that is inexpensive, easily accessible, and widely used. It is generally thought to be safe and effective without the potential for abuse. However, recent discovery of its ability to treat opioid withdrawal symptoms at high doses has led to not only its abuse, but also the need to recognize its cardiotoxicity due to the ability to prolong the QTc interval. We report a case of a 33 year old female with a history of opioid dependence who presented to the emergency department with acute onset shortness of breath and generalized weakness who was subsequently found to be in ventricular tachycardia. Electrocardiogram showed prolongation of the QTc and the patient later admitted to ingestion of 70 loperamide pills daily for the past year in order to alleviate her opioid withdrawal symptoms. Due to increased loperamide abuse and toxicity displayed within the last several years, public and health provider awareness should be optimized to fully understand its lethality, and stricter regulations on its availability to the general population should be considered. Even in asymptomatic patients with ECG abnormalities, emergency medicine physicians should admit them for further monitoring and aggressive medical therapy. © 2018 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Loperamide is a readily accessible over-the-counter (OTC) antidiarrheal medication that has historically been regarded for its safety, efficacy, lack of significant adverse side effects, and absence of significant potential for abuse [1]. Loperamide works by binding to the muopioid receptors in the circular and longitudinal intestinal muscles that slow peristalsis and increase gastrointestinal transit time [2]. Loperamide has low oral bioavailability, is almost entirely extracted and metabolized by the liver cytochrome P450, has low solubility, and does not readily cross the blood brain barrier at the recommended dosage. However, recent discovery of its ability to treat the symptoms of opioid withdrawal at doses 40–100 times the recommended antidiarrheal dosages has led to loperamide abuse and toxicity. At such mega-doses, loperamide has been shown to cause QTc prolongation, oftentimes leading to Torsades de Pointes, and in some cases, patient demise [3]. The mechanism of loperamide cardiotoxicity is currently not well understood.
A 33 year old Caucasian female with a history of prior opioid dependence presented to the emergency department (ED) with a chief complaint of acute onset of shortness of breath (SOB), generalized weakness, and tingling over her entire body. The SOB started one day prior to presenting to the ED, but the symptom quickly resolved. Later, the SOB began again and was associated with generalized weakness, tingling all over the entire body, dizziness, and diaphoresis. The patient called the Emergency Medical Services who subsequently found the patient in ventricular tachycardia (VT), which spontaneously converted back to sinus rhythm en route. The patient admitted that for the past year, she had been taking 70 pills of loperamide daily to prevent opioid withdrawal symptoms secondary to stopping Lortab a few years prior to admission. The patient denied taking other medications or other medical problems.
Abbreviations: ED, emergency department; EKG, electrocardiogram; OTC, over-thecounter; SOB, shortness of breath; VT, ventricular tachycardia. ⁎ Corresponding author at: University of Central Florida College of Medicine HCA GME Consortium, North Florida Regional Medical Center, Suite 101-B Medical Arts Bldg 6400, W Newberry Road, Gainesville, FL 32605, USA. E-mail address: [email protected] (A. Idris).
2.1. Physical exam Upon arrival to the ED, the patient's vital signs were as follows; blood pressure of 118/75 mmHg, heart rate of 86 beats/min, respiratory rate of 18 breaths/min, O2 saturation 100% on room air and a temperature of 98.4 °F. The patient was lethargic, oriented, and in no acute distress. The patient's pupils were symmetrical, equal, round, and reactive to light and accommodation. The patient had normal neuromuscular,
https://doi.org/10.1016/j.ajem.2018.05.027 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027
2
A. Idris, K. Kaye / American Journal of Emergency Medicine xxx (2018) xxx–xxx
Table 1 Laboratory data upon presenting to the emergency room Complete blood count
RBC: 4.6 (×106 cells/ml): WBC: 8.7 (×103 cells/ml). Hgb: 13.1 g/dl. HCT: 39.6%. Platelets: 255 (×103 cells/ml).
Comprehensive metabolic panel
Sodium: 138 mEq/l. Potassium: 3.7 mEq/l. Chloride: 102 mmol/l. CO2: 26 mEq/l. BUN: 17 mg/dl. Creatinine: 1.16 mg/dl. Glucose: 188 mg/dl. Calcium: 8.2 mg/dl. Magnesium: 2 mg/dl. Phosphorus: 2.5 mg/dl. Albumin: 3.5 g/dl. AST: 131 U/l. ALT: 115 U/l. Bilirubin: 0.6 mg/dl. Alkaline phosphatase: 8.4 U/l. Negative. Troponin I: 0.055 ng/ml, CK: 224 U/L, CK-MB: 4.1 ng/ml. b3 mg/d
Serum B-HCG: Cardiac enzymes Blood alcohol level
cardiac, respiratory, gastrointestinal and psychological exam with no suicidal or homicidal ideations. 2.2. Laboratory data Summarized in Table 1. 2.3. Chest x-ray No abnormalities were noted on chest x-ray.
3. Discussion What was originally formulated to be used solely as an antidiarrheal medication, loperamide is being abused as an opioid alternative at an alarming rate [4]. Mortality rates due to antidiarrheal drug misuse have been reported to be between 3% and 21% with patients presented to the hospital with symptoms of loperamide misuse [4,5]. Since 2005, loperamide has appeared in the literature describing its use to treat opioid withdrawal symptoms, to produce feelings of euphoria, and as its use as an analgesic. To produce these effect, the use of dosages well exceeding the recommended maximum dose for adults of 8 mg/day for OTC use and 16 mg/day for prescription use [5]. Reported dosages ranged anywhere from 100 to 200 mg daily, which equates to 50–100 2 mg pills daily [6]. More recent studies have shown dosages reaching levels of 1600 mg daily [5]. In 2010 and 2011, the number of such web-based forums promoting the use of loperamide to treat opioid withdrawal symptoms skyrocketed [6]. Since discovery as its effectiveness in treating opioid withdrawal symptoms, numerous cases have been reported of patients presenting to the ED with nonspecific symptoms and prolonged QTc intervals due to loperamide abuse. Presenting symptoms have included abdominal discomfort, syncopal episodes, shortness of breath, nausea and vomiting, lethargy, lower extremity edema, seizure-like activity, syncope and even cardiac arrest [2,3,7,8]. Upon discovering elongation of QTc in these patients, intravenous infusion of sodium bicarbonate is routinely administered. Despite administration of sodium bicarbonate, many patients nevertheless progress to ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
2.4. Electrocardiogram (EKG) 4. Conclusion EKG showed sinus rhythm with first degree AV block, normal QRS, but prolonged QT/QTc intervals 586/724 ms (Fig. 1). 2.5. Echocardiogram Bedside trans-thoracic echocardiogram was performed and was completely normal except for mild tricuspid valve regurgitation. Sodium bicarbonate drip was started in the ED and patient was admitted to the cardiac intensive care unit due to the high risk of torsades de pointes. Serial EKGs were obtained. EKG after starting sodium bicarbonate showed improvement with QT/QTc intervals 510/595 ms, 538/ 550, 466/531 ms at 2, 4 and 24 h intervals, respectively. (Fig. 1b) The patient remained asymptomatic and was discharged home to follow up with her primary care physician. The patient presented to the ED 10 days after discharge, for a different reason, and her EKG showed QT/QTc intervals 426/460 ms. (Fig. 2).
The potential for loperamide abuse to treat the symptoms of opioid withdrawal has proven to be dangerous and life-threatening. Its availability as an inexpensive over-the-counter medication makes it widely accessible to the general population. In addition to its wide accessibility, the web-based promotion of its use to treat opioid withdrawal, and lessso for its ability to produce euphoria and analgesia, further intensifies its potential for misuse. Based on the rising levels of loperamide abuse displayed within the last several years, healthcare providers need to start considering loperamide toxicity when evaluating patients with nonspecific symptoms and QTc prolongation. More strict regulations on its availability to the general population should also be considered. Conflict of interest The authors have no conflicts of interest to declare.
Fig. 1. The patient's 12 lead ECG a: 12 lead ECG upon presenting to the emergency room showing sinus rhythm with first degree AV block, normal QRS and prolonged QT/QTc intervals 586/ 724 ms b: 12 lead ECG 24 h after presenting to the emergency room and starting sodium bicarbonate showing sinus rhythm with first degree AV block, normal QRS and improvement in QT/QTc intervals 466/531 ms.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027
A. Idris, K. Kaye / American Journal of Emergency Medicine xxx (2018) xxx–xxx
3
Fig. 2. The patient's 12 lead ECG 1 week after the initial presentation to the emergency room showing QT/QTc intervals 426/460 ms.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Ericsson CD, Johnson PC. Safety and efficacy of loperamide. Am J Med 1990;88:S10–4. [2] Katz KD, Cannon RD, Cook MD, et al. Loperamide-induced Torsades de Pointes: a case series. J Emerg Med 2017;53:339–44. [3] Enakpene EO, Riaz IB, Shirazi FM, et al. The long QT teaser: loperamide abuse. Am J Med 2015;128:1083–6.
[4] Lasoff DR, Koh CH, Corbett B, et al. Loperamide trends in abuse and misuse over 13 years: 2002–2015. Pharmacotherapy 2017;37:249–53. [5] FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse. Safety Announcement. [cited 2016 Jul 6]. [6] 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;130:241–4. [7] Smith NA, Sehring M, Chambers J. Loperamide abuse and cardiotoxicity. J Community Hosp Intern Med Perspect 2017;7:275. [8] Salama A, Levin Y, Jha P, et al. Ventricular fibrillation due to overdose of loperamide, the "poor man's methadone". J Community Hosp Intern Med Perspect 2017 Sep 19;7 (4):222–6.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication? Amr Idris, MD a,b,⁎, Kenji Kaye, MD b a b
University of Central Florida College of Medicine HCA GME Consortium North Florida Regional Medical Center, Internal Medicine, Gainesville, Florida, USA
a r t i c l e
i n f o
Article history: Received 3 May 2018 Accepted 13 May 2018 Available online xxxx Keywords: Loperamide Cardiotoxicity QTc prolongation
a b s t r a c t Loperamide is an over-the-counter anti-diarrheal medication that is inexpensive, easily accessible, and widely used. It is generally thought to be safe and effective without the potential for abuse. However, recent discovery of its ability to treat opioid withdrawal symptoms at high doses has led to not only its abuse, but also the need to recognize its cardiotoxicity due to the ability to prolong the QTc interval. We report a case of a 33 year old female with a history of opioid dependence who presented to the emergency department with acute onset shortness of breath and generalized weakness who was subsequently found to be in ventricular tachycardia. Electrocardiogram showed prolongation of the QTc and the patient later admitted to ingestion of 70 loperamide pills daily for the past year in order to alleviate her opioid withdrawal symptoms. Due to increased loperamide abuse and toxicity displayed within the last several years, public and health provider awareness should be optimized to fully understand its lethality, and stricter regulations on its availability to the general population should be considered. Even in asymptomatic patients with ECG abnormalities, emergency medicine physicians should admit them for further monitoring and aggressive medical therapy. © 2018 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Loperamide is a readily accessible over-the-counter (OTC) antidiarrheal medication that has historically been regarded for its safety, efficacy, lack of significant adverse side effects, and absence of significant potential for abuse [1]. Loperamide works by binding to the muopioid receptors in the circular and longitudinal intestinal muscles that slow peristalsis and increase gastrointestinal transit time [2]. Loperamide has low oral bioavailability, is almost entirely extracted and metabolized by the liver cytochrome P450, has low solubility, and does not readily cross the blood brain barrier at the recommended dosage. However, recent discovery of its ability to treat the symptoms of opioid withdrawal at doses 40–100 times the recommended antidiarrheal dosages has led to loperamide abuse and toxicity. At such mega-doses, loperamide has been shown to cause QTc prolongation, oftentimes leading to Torsades de Pointes, and in some cases, patient demise [3]. The mechanism of loperamide cardiotoxicity is currently not well understood.
A 33 year old Caucasian female with a history of prior opioid dependence presented to the emergency department (ED) with a chief complaint of acute onset of shortness of breath (SOB), generalized weakness, and tingling over her entire body. The SOB started one day prior to presenting to the ED, but the symptom quickly resolved. Later, the SOB began again and was associated with generalized weakness, tingling all over the entire body, dizziness, and diaphoresis. The patient called the Emergency Medical Services who subsequently found the patient in ventricular tachycardia (VT), which spontaneously converted back to sinus rhythm en route. The patient admitted that for the past year, she had been taking 70 pills of loperamide daily to prevent opioid withdrawal symptoms secondary to stopping Lortab a few years prior to admission. The patient denied taking other medications or other medical problems.
Abbreviations: ED, emergency department; EKG, electrocardiogram; OTC, over-thecounter; SOB, shortness of breath; VT, ventricular tachycardia. ⁎ Corresponding author at: University of Central Florida College of Medicine HCA GME Consortium, North Florida Regional Medical Center, Suite 101-B Medical Arts Bldg 6400, W Newberry Road, Gainesville, FL 32605, USA. E-mail address: [email protected] (A. Idris).
2.1. Physical exam Upon arrival to the ED, the patient's vital signs were as follows; blood pressure of 118/75 mmHg, heart rate of 86 beats/min, respiratory rate of 18 breaths/min, O2 saturation 100% on room air and a temperature of 98.4 °F. The patient was lethargic, oriented, and in no acute distress. The patient's pupils were symmetrical, equal, round, and reactive to light and accommodation. The patient had normal neuromuscular,
https://doi.org/10.1016/j.ajem.2018.05.027 0735-6757/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027
2
A. Idris, K. Kaye / American Journal of Emergency Medicine xxx (2018) xxx–xxx
Table 1 Laboratory data upon presenting to the emergency room Complete blood count
RBC: 4.6 (×106 cells/ml): WBC: 8.7 (×103 cells/ml). Hgb: 13.1 g/dl. HCT: 39.6%. Platelets: 255 (×103 cells/ml).
Comprehensive metabolic panel
Sodium: 138 mEq/l. Potassium: 3.7 mEq/l. Chloride: 102 mmol/l. CO2: 26 mEq/l. BUN: 17 mg/dl. Creatinine: 1.16 mg/dl. Glucose: 188 mg/dl. Calcium: 8.2 mg/dl. Magnesium: 2 mg/dl. Phosphorus: 2.5 mg/dl. Albumin: 3.5 g/dl. AST: 131 U/l. ALT: 115 U/l. Bilirubin: 0.6 mg/dl. Alkaline phosphatase: 8.4 U/l. Negative. Troponin I: 0.055 ng/ml, CK: 224 U/L, CK-MB: 4.1 ng/ml. b3 mg/d
Serum B-HCG: Cardiac enzymes Blood alcohol level
cardiac, respiratory, gastrointestinal and psychological exam with no suicidal or homicidal ideations. 2.2. Laboratory data Summarized in Table 1. 2.3. Chest x-ray No abnormalities were noted on chest x-ray.
3. Discussion What was originally formulated to be used solely as an antidiarrheal medication, loperamide is being abused as an opioid alternative at an alarming rate [4]. Mortality rates due to antidiarrheal drug misuse have been reported to be between 3% and 21% with patients presented to the hospital with symptoms of loperamide misuse [4,5]. Since 2005, loperamide has appeared in the literature describing its use to treat opioid withdrawal symptoms, to produce feelings of euphoria, and as its use as an analgesic. To produce these effect, the use of dosages well exceeding the recommended maximum dose for adults of 8 mg/day for OTC use and 16 mg/day for prescription use [5]. Reported dosages ranged anywhere from 100 to 200 mg daily, which equates to 50–100 2 mg pills daily [6]. More recent studies have shown dosages reaching levels of 1600 mg daily [5]. In 2010 and 2011, the number of such web-based forums promoting the use of loperamide to treat opioid withdrawal symptoms skyrocketed [6]. Since discovery as its effectiveness in treating opioid withdrawal symptoms, numerous cases have been reported of patients presenting to the ED with nonspecific symptoms and prolonged QTc intervals due to loperamide abuse. Presenting symptoms have included abdominal discomfort, syncopal episodes, shortness of breath, nausea and vomiting, lethargy, lower extremity edema, seizure-like activity, syncope and even cardiac arrest [2,3,7,8]. Upon discovering elongation of QTc in these patients, intravenous infusion of sodium bicarbonate is routinely administered. Despite administration of sodium bicarbonate, many patients nevertheless progress to ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
2.4. Electrocardiogram (EKG) 4. Conclusion EKG showed sinus rhythm with first degree AV block, normal QRS, but prolonged QT/QTc intervals 586/724 ms (Fig. 1). 2.5. Echocardiogram Bedside trans-thoracic echocardiogram was performed and was completely normal except for mild tricuspid valve regurgitation. Sodium bicarbonate drip was started in the ED and patient was admitted to the cardiac intensive care unit due to the high risk of torsades de pointes. Serial EKGs were obtained. EKG after starting sodium bicarbonate showed improvement with QT/QTc intervals 510/595 ms, 538/ 550, 466/531 ms at 2, 4 and 24 h intervals, respectively. (Fig. 1b) The patient remained asymptomatic and was discharged home to follow up with her primary care physician. The patient presented to the ED 10 days after discharge, for a different reason, and her EKG showed QT/QTc intervals 426/460 ms. (Fig. 2).
The potential for loperamide abuse to treat the symptoms of opioid withdrawal has proven to be dangerous and life-threatening. Its availability as an inexpensive over-the-counter medication makes it widely accessible to the general population. In addition to its wide accessibility, the web-based promotion of its use to treat opioid withdrawal, and lessso for its ability to produce euphoria and analgesia, further intensifies its potential for misuse. Based on the rising levels of loperamide abuse displayed within the last several years, healthcare providers need to start considering loperamide toxicity when evaluating patients with nonspecific symptoms and QTc prolongation. More strict regulations on its availability to the general population should also be considered. Conflict of interest The authors have no conflicts of interest to declare.
Fig. 1. The patient's 12 lead ECG a: 12 lead ECG upon presenting to the emergency room showing sinus rhythm with first degree AV block, normal QRS and prolonged QT/QTc intervals 586/ 724 ms b: 12 lead ECG 24 h after presenting to the emergency room and starting sodium bicarbonate showing sinus rhythm with first degree AV block, normal QRS and improvement in QT/QTc intervals 466/531 ms.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027
A. Idris, K. Kaye / American Journal of Emergency Medicine xxx (2018) xxx–xxx
3
Fig. 2. The patient's 12 lead ECG 1 week after the initial presentation to the emergency room showing QT/QTc intervals 426/460 ms.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Ericsson CD, Johnson PC. Safety and efficacy of loperamide. Am J Med 1990;88:S10–4. [2] Katz KD, Cannon RD, Cook MD, et al. Loperamide-induced Torsades de Pointes: a case series. J Emerg Med 2017;53:339–44. [3] Enakpene EO, Riaz IB, Shirazi FM, et al. The long QT teaser: loperamide abuse. Am J Med 2015;128:1083–6.
[4] Lasoff DR, Koh CH, Corbett B, et al. Loperamide trends in abuse and misuse over 13 years: 2002–2015. Pharmacotherapy 2017;37:249–53. [5] FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse. Safety Announcement. [cited 2016 Jul 6]. [6] 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;130:241–4. [7] Smith NA, Sehring M, Chambers J. Loperamide abuse and cardiotoxicity. J Community Hosp Intern Med Perspect 2017;7:275. [8] Salama A, Levin Y, Jha P, et al. Ventricular fibrillation due to overdose of loperamide, the "poor man's methadone". J Community Hosp Intern Med Perspect 2017 Sep 19;7 (4):222–6.
Please cite this article as: Idris A, Kaye K, Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?, American Journal of Emergency Medicine (2018), https://doi.org/10.1016/j.ajem.2018.05.027