The Pharmacological and Clinical Features of Methadone Poisoning

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine. I'm Rahul Damania from Cleveland Clinic Children’s Hospital and we are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Here's the case presented by Rahul:

A 21-month-old girl was brought to an OSH ED for somnolence and difficulty breathing, which developed after she accidentally ingested an unknown amount of liquid medicine that was used by her grandfather. Per the mother, the patient’s grandfather was given the liquid medication for the treatment of his opioid addiction. The patient took some unknown amount from the open bottle that was left on the counter by the grandfather. Immediately after ingestion of the medicine, the patient initially became irritable and had some generalized pruritus. The patient subsequently became sleepy followed by difficulty breathing and her lips turned grey. The patient was rushed to an outside hospital ED for evaluation.

OSH ED: The patient arrived unresponsive and blue, she was noted to be sleepy and difficult to arouse on arrival, with pinpoint pupils and hypoxic to 88%. , but After receiving Naloxone, however, she became awake and interactive. Her glucose on presentation was 58 mg/dL and Her initial VBG resulted 7.3/49.6/+2. She continued to have intermittent episodes of somnolence without apnea. Poison control called and recommend starting a naloxone infusion; she was also given dextrose bolus. The patient was admitted to the PICU.

To summarize key elements from this case, this patient has:

Accidental ingestion of an unknown medication

Altered mental status

Difficulty breathing—with grey lips suggestive of hypoventilation/hypoxia

All of which brings up a concern for a toxidrome which is our topic of discussion for today

The typical symptoms seen in our patient of pinpoint pupils, respiratory depression, and a decreased level of consciousness is known as the “opioid overdose triad” Given the history of opioid addiction in the grandfather, the liquid medicine given to him is most likely methadone.In fact, in this case, the mother brought the bottle of medicine, which was subsequently confirmed to be prescription methadone given to prevent opioid withdrawal in the grandfather.

To dive deeper into this episode, let’s start with a multiple choice question:

Which of the following opioids carries the greatest risk of QTc prolongation?

A. Methadone

B. Morphine

C. Fentanyl

D. Dilaudid

The correct answer is methadone. Methadone prolongs QT interval due to its interactions with the cardiac potassium channel (KCNH2) and increases the risk for Torsades in a dose-dependent manner. Besides the effect on cardiac repolarization, methadone is also associated with the development of bradycardia mediated via its anticholinesterase properties and through its action as a calcium channel antagonist. Hypokalemia, hypocalcemia, hypomagnesemia, and concomitant use of other drugs belonging to the family of CYP3A4 system inhibitors such as erythromycin can prolong Qtc. Even in absence of these risk factors, methadone alone can prolong QTc.

Thanks for that, I think it is very important to involve your Pediatric Pharmacy team to also help with management as children may be concurrent qt prolonging meds.

Rahul, what are some of the pharmacological and clinical features of methadone poisoning?

Methadone is a synthetic opioid analgesic made of a racemic mixture of two enantiomers d-methadone and l-methadone. besides its action on mu and kappa receptors, it is also an NMDA receptor antagonist. Due to its long action, methadone is useful as an analgesic and to suppress opioid withdrawal symptoms (hence used for opioid detoxification). Methadone causes constipation, nausea, and vomiting (due to its effect on the chemoreceptor trigger zone).

Methadone is well absorbed in the GI tract and can be detected in the plasma within 30 minutes. Although its half-life is 10-18 hours, it can be as high as 25 hours or longer in acute overdoses. In infants and children, a single dose of methadone clinical manifestations can last X 72 hours. The action of methadone is similar to morphine and is primarily on mu, delta, and kappa receptors. It causes drowsiness, respiratory depression, hypotension, and miosis. Cerebral edema has been associated with severe toxicity.

Pradip, If you had to work up this patient with methadone ingestion, what would be your diagnostic approach?

The classic triad of miosis + respiratory depression and altered mental status with a quick response to Naloxone is diagnostic of opioid poisoning. History of methadone exposure such as in our case above will help clinch the diagnosis.

Blood gas, CMP, CBC, Routine and comprehensive drug screens (may help with co-existing toxins).

Methadone is usually not tested on a standard drug screen unless specifically requested. Standard urine immunoassays are not able to detect synthetic opioids such as methadone.

Methadone ingestion is confirmed when both methadone and methadone metabolite (EDDP) are detected in the urine using high-performance liquid chromatography. However such testing is costly and may take time. The window of methadone detection can range from 3-4 days (rarely up to 14 days).

EKG

beta-HCG in a female teenager.

Always follow your state's poison control recommendations.

If our history, physical, and diagnostic investigation led us to methadone ingestion as our diagnosis, what would be your general management of framework?

Symptomatic and good supportive PICU care with continuous monitoring of airway patency is the mainstay of treatment in patients who present with mild to moderate methadone toxicity. Charcoal lavage may be tried in mild intoxication in a patient who is not altered.

Administer oxygen and assist ventilation for respiratory depression.

Naloxone is an opioid antagonist and the antidote of choice, especially in severe toxicity. For children under 5years of age (or < 20Kg): Use 0.1mg/kg. For children > 5 years or over 20Kg 2mg IV every 2-3hours. Naloxone can be administered SC, IM, IV, via the endotracheal tube or even intranasally. Continuous infusion is likely to be necessary for patients who have ingested methadone, as the duration of action of Naloxone is 1 to 2 hours, compared with a duration of action of 24 hours for methadone. The infusion should be started at a rate such that two-thirds of the dose effective for initial reversal is administered each hour, and titrated as needed. Naloxone can potentiate withdrawal in opioid-dependent patients. A side effect of naloxone use can be transient hypertension or pulmonary edema (both rare) and such risks should not preclude its use.

Early intubation and ventilation assistance should be performed if respiratory depression does not respond to naloxone. Adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if a patient presents with a circulatory collapse that does not reverse with naloxone. Treat seizures with benzodiazepines, propofol, and/or barbiturates.

Monitor for QT prolongation and dysrhythmias. Torsades de pointes

Correct electrolyte abnormalities. Intravenous magnesium and overdrive pacing as indicated

Very rarely ECMO may be required if life-threatening pulmonary edema refractory to standard measures.

Pradip, it was found in our case that the patient had significant hypoglycemia. Can you shed some light on this in relation to the methadone overdose?

Blood glucose needs to be carefully monitored. Most studies report hypoketotic, hyperinsulinemic, and hypoglycemia after an acute, unintentional methadone exposure, especially with high doses. Possible etiologies of hypoglycemia may include promotion of pancreatic insulin release, suppression of counter-regulatory mechanisms such as glucagon, epinephrine, and sympathoadrenal responses to hypoglycemia as well as impairment of glycogenolysis and gluconeogenesis.

As we wrap up today, let’s also go through the criteria for observation, admission, and ICU-level care. All patients who develop CNS or respiratory depression should be admitted for observation (for at least 24 hours) even after adequate response to naloxone therapy. Patients who require intubation or a naloxone infusion will obviously require an intensive care unit admission. Patients should not be discharged until they have remained awake and alert for 4 to 6 hours after the Naloxone infusion has been discontinued.

Patients with mild toxicity who do not require Naloxone should be observed for at least 8 hours.

Please also work closely with toxicologists and local poison control as well!

Pradip, what are some clinical pearls or pitfalls to avoid?

Remember the triad of pinpoint pupils+respiratory depression+altered mental status is highly suggestive of opioid poisoning

Naloxone is the drug of choice in opioid overdose, an infusion may be needed for longer-acting agents such as methadone.

In addition to Naloxone, close attention to airway patency and maintenance of respiration is required in the PICU

So today we learned about the management of methadone ingestion in a toddler. Liquid methadone is highly toxic and even as one little teaspoon can lead to fatality in a toddler. Besides appropriate storage of methadone to prevent accidental ingestion by toddlers, early recognition of the classic opioid triad (AMS+Pinpoint pupils+respiratory depression) and prompt medical intervention can be life-saving.

This concludes our episode on Methadone ingestion. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References:

Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 126 Toxidromes and Their treatment by Prashant Joshi. Page 1497.

Reference 1: Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers. J Emerg Med. 2005 Jul;29(1):77-84. doi: 10.1016/j.jemermed.2004.12.015. PMID: 15961014.

Reference 2: Boyer EW, McCance-Katz EF, Marcus S. Methadone and buprenorphine toxicity in children. Am J Addict. 2010 Jan-Feb;19(1):89-95. doi: 10.1111/j.1521-0391.2009.00002.x. PMID: 20132125.

Reference 3: Glatstein M, Finkelstein Y, Scolnik D. Accidental methadone ingestion in an infant: case report and review of the literature. Pediatr Emerg Care. 2009 Feb;25(2):109-11. doi: 10.1097/PEC.0b013e318196faff. PMID: 19225381.