Methadone Toxicity

Methadone toxicity causes prolonged respiratory depression, coma, QT prolongation and torsades de pointes. Its long and variable half life means that opioid effects outlast the effect of naloxone, so relapse of respiratory depression is common.

Methadone is used for opioid dependence and chronic pain, and it is a leading cause of opioid related deaths in some countries, particularly in people not tolerant to opioids and in children with accidental ingestion. A dose over 1 mg/kg is dangerous in the opioid naive, and 0.2 mg/kg may cause serious toxicity in children.

Risk factors for harm. Opioid naive status, dose escalation or recent restarting after a break, co-use of benzodiazepines or alcohol, CYP3A4 or CYP2B6 inhibitors (azole antifungals, macrolides, ciprofloxacin), hepatic impairment and cardiac disease.

Course. Onset is delayed (30 to 90 minutes orally), peak at 2 to 4 hours, and respiratory depression can last 24 to 48 hours or longer, with a half life of 15 to 60 hours.

Pathophysiology.

Agonist action at mu opioid receptors suppresses the medullary respiratory drive and consciousness. Methadone also blocks cardiac potassium (hERG) channels, delaying repolarisation.

Its large volume of distribution and slow metabolism produce the prolonged course.

• Drowsiness, miosis, slow shallow breathing (under 10 breaths/minute), cyanosis and coma.
• Hypotension, bradycardia, hypothermia, pulmonary oedema and aspiration.
• QT prolongation, torsades de pointes and syncope.
• Hypoglycaemia in children; seizures are uncommon.

Red flags.

• Respiratory rate under 8 breaths/minute, hypoxia or apnoea.
• QTc over 500 ms or syncope.
• Child with any ingestion.

• History of dose, time, tolerance and co-ingestants; paracetamol and salicylate levels.
• Clinical triad of coma, pinpoint pupils and respiratory depression; response to naloxone supports the diagnosis.
• ECG on arrival and repeated; potassium, magnesium and calcium; glucose, renal and liver function, creatine kinase and venous gas.
• Urine drug screens often miss methadone on routine opiate immunoassays.

Differential diagnosis. Other opioid overdose, benzodiazepine or barbiturate overdose, alcohol intoxication, hypoglycaemia, stroke and head injury.

• Airway protection, oxygen and ventilation as needed.
• Naloxone 0.4 mg intravenously, repeated every 2 to 3 minutes and increased up to 2 mg for each dose until the respiratory rate is over 10 breaths/minute and breathing is adequate (intramuscular 0.4 to 2 mg, or intranasal 4 mg, if no intravenous access). Maximum 10 mg before reviewing the diagnosis. Monitor respiratory rate, oxygen saturation, withdrawal (agitation, vomiting, pulmonary oedema) and re-sedation. In opioid dependent patients, titrate in 0.04 to 0.1 mg steps; no renal or hepatic adjustment; acceptable in pregnancy (may precipitate foetal withdrawal).
• Naloxone infusion because of the short effect (30 to 90 minutes) against a long acting opioid: two thirds of the total bolus dose that restored breathing, given each hour in 5% glucose, titrated to a respiratory rate over 10 breaths/minute. Maximum 4 mg/hour. Monitor respiratory rate, oxygen saturation and withdrawal signs; stop after 12 hours if no re-sedation.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness without a protected airway, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Torsades de pointes: correct potassium to over 4.0 mmol/L and give magnesium sulphate 2 g (8 mmol) intravenously over 10 minutes, repeated once if needed. Maximum 4 g in the first hour. Monitor reflexes, respiratory rate and magnesium; reduce dose in renal impairment. Use overdrive pacing or isoprenaline for recurrent torsades (specialist), and defibrillate for pulseless arrhythmia.
• Hypotension: fluids, then noradrenaline 0.05 micrograms/kg/minute intravenously, titrated to a mean arterial pressure of 65 mmHg or higher. Maximum 1 microgram/kg/minute. Give by central line; monitor blood pressure, extravasation and arrhythmia.
• Admit for at least 24 hours of monitoring after any significant ingestion, including children; observe for 6 hours after the last naloxone dose.
• Avoid flumazenil and antiarrhythmics that prolong QT.
• Psychiatric assessment in intentional ingestion; review the prescribing and supply of methadone.

Monitoring. Respiratory rate, oxygen saturation and conscious level hourly; continuous ECG with QTc review every 4 to 6 hours.

Referral and escalation. Poisons information centre; intensive care for infusion, hypoventilation or arrhythmia; addiction services after recovery.

Special groups. Children: admit for 24 hours with any ingestion. Opioid dependent patients: avoid abrupt full reversal.