Cardiotoxicity of Opioids

Background:

Loperamide, sold over-the-counter as Imodium among others, is a medication to decrease the frequency of diarrhea. The medication was first synthesized in 1969, first used medically after FDA approval in 1976, and first sold OTC in 1988. Loperamide was recently listed on the WHO’s List of Essential Medicines, due to its affordability and widespread use for patients with inflammatory bowel disease, gastroenteritis, irritable bowel syndrome, and traveler’s diarrhea.

Mechanism:

Loperamide is an opioid-receptor agonist, decreasing the tone of intestinal smooth muscles, and subsequently allowing more water to be absorbed from fecal matter. The effects of loperamide are limited by the actions of P-glycoprotein (P-gp), a cell membrane protein that pumps xenobiotics back into the intestinal lumen, preventing further absorption. This effect is also noticed in the blood-brain barrier where P-gp prevents loperamide from affecting the central nervous system.

Misuse/abuse: 

Appropriate dosing is 4 mg initially, followed by 2 mg after each subsequent loose stool, with a recommended daily maximum of 16 mg. When taken in large quantities, the levels of P-gp in the CNS and gut are overwhelmed, and the medication is able to cross the blood-brain barrier, eliciting opiate-like effects. A report from the National Poison Data System showed a 91% increase in loperamide exposures from 2010-2015, notable for 23 ingestion deaths, with 8 being solely attributed to loperamide. During this timeframe, on-line drug forums with user-generated content noted significant opportunity for misuse by patients seeking euphoria or withdrawal symptom relief. Furthermore, the low cost, legal status, and lack of social stigma also precluded this medication to misuse.

An FDA June 2016 report linked the abuse/misuse of loperamide to serious cardiac events, and urged health care providers to ‘consider loperamide as a possible cause of unexplained cardiac events including QT interval prolongation, torsades de pointes or other ventricular arrhythmias, syncope, and cardiac arrest.

Cardiac Effects of Loperamide: 

In cardiac tissue, loperamide has been shown to inhibit the human Ether-a-go-go Related Gene (hERG) product, a slow K channel. Resultantly, this prolongs phase 3 of the action potential, preventing repolarization, and lengthening the QTc interval.

Cardiotoxicity of Other Opioids: 

Propoxyphene (Darvocet when combined with acetaminophen) is a synthetic weak opioid introduced in 1957, that has subsequently been withdrawn from the US market after multiple black box warnings regarding cardiac effects. Propoxyphene exhibits Vaughn-Williams class Ic antiarrhythmic effects (more potent than lidocaine) and promotes cardiac Na channel blockade, subsequently prolonging phase 0 of the action potential, and prolonging the QRS interval. 

Methadone, commonly used in the treatment of opioid dependence since the 1960s in the US, also exhibits QTc prolongation effects. Similar to loperamide, methadone has been shown to also block the same slow K channel, precluding patients to risk of torsades de pointes.

Figure 1: Borrowed from https://www.pinterest.com/krazeniq/diastolic-dysfunction/?lp=true

Figure 1: Borrowed from https://www.pinterest.com/krazeniq/diastolic-dysfunction/?lp=true

Treatment/conclusions:

When presented with ingestions of loperamide or the other aforementioned opioids with cardiac effects, after appropriate resuscitation, an ECG should be collected to assess the QRS and QTc intervals. The QTc prolongation effects of loperamide and methadone should be treated supportively with magnesium sulfate to prevent torsades de pointes. If TdP develops, the provider should consider isoproterenol (if there is intermittent bradycardia), and further transcutaneous/transvenous pacing.

Faculty Reviewer: Dr. Jason Hack 

References:

Marraffa J, Holland M, Sullivan R, et al. Cardiac conduction disturbance after loperamide abuse. Clin Toxicol. 2014;52,952-957.

Daniulaityte R, Carlson R, Falck R. “I just wanted to tell you that loperamide WILL WORK”: a web-based study of extra-medical use of loperamide. Drug Alcohol Depend. 2013;130,241-244.

Dierksen J, Gonsoulin M, Walterscheid J. Poor man’s methadone: a case report of loperamide toxicity. Am J Forensic Med Pathol. 2015;36,268-270.

Vakkalanka J, Charlton N, Holstege C. Epidemiologic trends in loperamide abuse and misuse. Ann Emerg Med. 2017;69,73-78.

Uphadyay A, Bodar V, Malekzadegan M, et al. Loperamide induced life threatening ventricular arrhythmia. Case Rep Cardiol. 2016;1-3.

Lasoff D, Schneir A. Ventricular dysrhythmias from loperamide misuse. J Emerg Med. 2012;508-509.

Aschenbrenner D. Loperamide abuse or misuse triggers cardiac events. AJN. 2016;116,26-27.

Eggleston W, Clark K, Marraffa J. Loperamide abuse associated with cardiac dysrhythmia and death. Ann Emerg Med. 2017;69,83-86.

Gussow L. Opioid abusers using loperamide to get high or alleviate withdrawal, with fatal consequences. Emergency Medicine News. 2016;38,8.

Adler A, Viskin S, Bhuiyan Z, et al. Propoxyphene-induced torsades de pointes. Heart Rhythm. 2011;8,1952-54.

Jang D, Hoffman R, Nelson L, et al. Fatal outcome of a propoxyphene/acetaminophen (Darvocet) overdose: should it still be used in the United States? Ann Emerg Med. 2011;57,421-22.

Barkin R, Barkin S, Barkin D. Propoxyphene (Dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity. Am J Ther. 2006;13,534-542.

Latta K, Ginsberg B, Barkin R. Meperidine: a critical review. Am J Ther. 2002;9,53-68.

Song M, Bae E, Baek J. QT prolongation and life threatening ventricular tachycardia in a patient injected with intravenous meperidine (Demerol). Korean Circ J. 2011;41,342-45.

Alinejad S, Kazemi T, Zamani N, et al. A systematic review of the cardiotoxicity of methadone. EXCLI Journal. 2015;14,577-600.

Caffrey C, Pinchbeck C. Methadone Induced Torsades. NUEM Blog. Retrieved from http://nuemblog.com/blog/methadone-torsades.

Chen A, Ashburn M. Cardiac effects of opioid therapy. Pain Medicine. 2015;16,S27-S31.

Asynchrony EM: Code Gray (The Agitated Patient)

New to Asynchrony EM? It's an asynchronous learning course in its third year at Brown EM. Digital resources and #FOAMed are curated and packaged by topic, following Brown EM's curricular calendar. In the spirit of #FOAMed, we've started putting it out there for the EM community at large. Check out the theme song, the 'extras', and the discussion questions, and other modules -- and leave us your thoughts in the comments section. Follow us on Twitter at @AsynchronyEM.
Note: Brown EM residents must complete the modules (including discussion/quiz) in Canvas to obtain credit hours.
 
Time to pull out your agitated patient skills!

Time to pull out your agitated patient skills!

Code Gray -- known at our local community hospital as 'behavioral team to the trauma room'!

This module contains information on management of the agitated, combative patient who will likely present to the ED during your next shift.  We deal with this type of patient encounter more often than any other medical specialty, and thus we need to be able to recognize those is psychological distress, act quickly to control the situation, and work to keep the patient, our staff and ourselves safe.  In fact I would argue that this is on of the many things that ER docs are best at; we take control of a chaotic situation.  

Before we jump into the craziness, a song to set the mood...any day may have a Touch of Grey.

 

When patients arrive agitated, they are often acting in this way because they feel a loss of control.  It is important that you try and engage the patient and then start of give the control back to them.  

 

Signs of an agitated patient include:

  • increasing tone of speech (yelling louder)
  • foul language
  • foreboding tone of voice
  • demanding content
  • verbal abuse to staff
  • inability to sit still
  • making fists or other aggressive body positioning
  • flexing of the muscles/tensing of the jaw

Recommended helpful statements include:

  • I can see you're angry.  Let's talk, and you can tell me what is troubling you.
  • I am here to help you, but you have to tell me what is going on.
  • I can see you're upset; tell me what you need to help you feel better. 
  • I'll bet you didn't plan for this ER visit; tell me how you got here.

For more tips and info keep clicking, learn & enjoy!

From Life in the Fast Lane: Behavioral Emergencies

From EM Crit and Reuben Strayer: a podcast

From the March 2017 ER Cast my effort to provide you with the most up to date evidence based medicine because I know you can't get enough of journal club:)

From EM Cases, notes and podcast

From EM Crit: don't need to do the full podcast, just focus on video for proper way to restrain the patient in the ED. 

 

Our work environment is better than most for agitated patients, as we have the resources to help us with these situations: nursing, security, training, and most importantly drugs !!

From EP Monthly: Understanding Haloperidol

From REBEL EM: Chemical Sedation of the Agitated Patient

From The Poison Review: Is Ketamine Safe in Excited Delirium?

 

If you have the time extras for you to enjoy :)

The Upset Patient Protocol, from ER Cast

Medical Clearance of the Psychiatric Patient, from Emergency Medicine Cases

Also from EM Cases: Managing the Difficult Patient

 

That's it! See you next time! Brown residents, make sure to complete the module in Canvas for credit. 

Ultrasound Case of the Month

Case # 1: Submitted by Dr. Ravi Sapatwari 

This is a 25 year old male who presented to the ED with sore throat, fever, and dysphagia for 5 days. He was recently seen at urgent care, diagnosed with pharyngitis, and given amoxicillin. He had relief of symptoms on "the left side" but had increased pain and swelling of the right throat with persistent dysphagia.  

Peritonsillar abscess (PTA)

Discussion:

This image was taken with the endocavitary probe directed in the right posterior oropharnx in the transverse plane. A PTA was identified as a well-circumscribed, heterogeneous mass noted in both transverse and sagittal planes, and the depth of the mass was measured. Vascular structures (notably the internal carotid artery) were also identified posterolaterally to the abscess. A 20 gauge 3.5” spinal needle was used with its sheath cut to the appropriate depth to avoid reaching vascular structures. The needle was then visualized entering the mass in real-time and aspirated.

Ultrasound is a useful tool to distinguish between peritonsillar cellulitis and abscess, which can be difficult to distinguish on physical exam alone. This is particularly important as management differs between the two conditions, namely antibiotics versus definite treatment with aspiration or I&D. In a recent study by Constanino et al. of 28 patients with suspected PTA, ultrasound provided increased sensitivity of 100% compared to the physical exam of 64%, as well as a decreased need to consult ENT (7% vs. 50%) (1). Although the sample size of this study was small, other studies appear to confirm an increased sensitivity and specificity of US in the diagnosis of PTA, with the caveat being the skill level of the sonographer (2).

Although aspiration of a PTA can be performed blind, there is risk to this procedure given adjacent structures, particularly the internal carotid artery and jugular vein. These vascular structures can be identified on US, particularly with the use of color doppler, and real-time visualization of the needle can prevent unwanted complications. So the next time you see throat swelling as a chief complaint, be sure to grab an endocavitary probe if available.

Additional Resources:

http://www.ultrasoundpodcast.com/tag/peritonsillar-abscess/

http://sonoguide.com/smparts_ent.html

Case # 2: Submitted by Dr. Dwyer and Liebmann 

45 year old ill appearing male with an unclear past medical history who presents with a few days of atraumatic low back pain that radiates down his right leg. Patient also complains of fevers and weight loss. Exam is significant for a thin appearing male. He is febrile with a heart rate of 139. He has lateral low back tenderness, but no midline tenderness. There is no evidence of trauma. His neurological examination is within normal limits.

Iliopsoas Abscess

Discussion:

This patient was diagnosed with an iliopsoas abscess, which was seen on bedside ultrasound. The cat scan showed bilateral psoas abscesses, right side larger than left (12.3cm) with evidence of hematogenous spread to the lungs with pulmonary abscess formation.

This ultrasound was performed with a curvilinear probe in the RUQ and LUQ, as if performing a FAST exam.  The marker was pointed to the head of the patient, and obliqued slightly to get between the ribs. In your FAST views it is common to see the iliopsoas muscle posterior-inferior to the kidney on both sides.  In this image, we see a large mass, which is heterogenous and represents the abscess also demonstrated on CT.

Normal:

Image 1: Normal RUQ view

Image 1: Normal RUQ view

Psoas abscesses are associated with high mortality and are often misdiagnosed. Because we see them infrequently, they aren’t always on our differential diagnosis and this results in a delay in identification. Because the musculature is highly vascular, it is predisposed to hematogenous spread as seen in this case.

There is not a significant amount of data available on the identification of psoas abscess with bedside ultrasound, and it can be difficult to differentiate from a hematoma sonographically, however the clinical history should help you differentiate. 

Image 2: RUQ US view demonstrating heterogenous mass within the psoas musculature

Image 2: RUQ US view demonstrating heterogenous mass within the psoas musculature

Faculty Reviewer: Dr. Kristin Dwyer 

References:

1:  Constantino TG, Satz WA, Dehnkamp W, Goett H. Randomized Trial Comparing Intraoral Ultrasound to Landmark-based Needle Aspiratino in Patients with Suspected Peritonsillar Abscess. Acad Emerg Med. 2012;19(6):626-31.

2:  Secko M, Sivitz A. Think ultrasound first for peritonsillar swelling. Am J Emerg Med. 2015;33(4)569-72.