Published: November 2005
Prescriber Update 26(2): 23-25
Medsafe Pharmacovigilance Team
Methadone may cause QT prolongation and torsades de pointes. Higher doses, concomitant QT interval-prolonging agents and the presence of other risk factors for QT prolongation may predispose patients to the development of potentially fatal arrhythmias with methadone. Prescribers are advised to evaluate their patients for modifiable risk factors prior to initiating methadone. ECG monitoring is recommended with methadone doses >150mg/day and in patients with either risk factors for QT prolongation or symptoms that may be attributable to arrhythmia.
Methadone is used for analgesia and opioid dependence
Local and international reports of methadone-associated QT prolongation
Biologically plausible mechanism and risk factors identified
The risk of methadone-induced QT prolongation can be managed
Methadone is a synthetic opioid analgesic indicated for the treatment of opioid dependence and moderate to severe pain. It is estimated that 60% of patients treated for opioid dependence in New Zealand receive doses of <100mg per day and approximately 10% of patients receive >200mg per day.1 Most patients with chronic pain require methadone to be administered twice daily, although total daily doses are usually <100mg per day.2
Prolongation of the QT interval is used as a surrogate marker for the risk of developing potentially fatal arrhythmias such as torsades de pointes (TdP).3,4 The QTc* interval is considered to be prolonged if it is >450ms in men or >460ms in women. A QTc of >500ms,4 or an increase of >40ms,5 is generally accepted to confer a high risk of TdP.
There have been two New Zealand reports of arrhythmia in patients taking methadone for opioid dependence. One patient was taking methadone 150mg/day and experienced recurrent syncopal episodes before he collapsed and died suddenly at home. The other patient was taking methadone 120mg/day and was admitted to hospital after experiencing two syncopal episodes. ECG monitoring revealed episodes of self-limiting TdP with prolonged QTc. The methadone dose was reduced to 60mg/day and the QTc interval returned to normal.
In June 2004, the Swedish Medical Products Agency reported on 32 cases of QT prolongation, arrhythmia or sudden death in patients taking methadone.6 As of April 2005, the World Health Organisation's adverse reactions data base included 255 reports of heart rate and rhythm disorders associated with methadone. These included 24 reports of TdP, 26 reports of QT prolongation and 117 reports of cardiac arrest.
In vitro studies have demonstrated that, as with the majority of non-cardiac medicines that cause QT prolongation, methadone prolongs the cardiac action potential by inhibiting cardiac potassium channels.7 In addition, a prospective study in opioid-dependent patients demonstrated a statistically significant increase in the QTc interval after two months of methadone treatment.5 In a review of 17 cases of TdP with methadone, the majority of patients were taking very high doses (mean 400mg/day) or had at least one other risk factor for QT prolongation.8
At present it is not known how often QT prolongation occurs with methadone use, although it appears to be reported infrequently. This may be due to under-recognition, particularly in patients being treated for opioid dependence where sudden death may be attributed to either narcotic overdose or complications arising from long-term narcotic abuse.8 Although in-vitro studies, spontaneous reports and case studies provide clinical evidence for an association between methadone use and QT prolongation, further studies are required to more clearly define this risk.
Based on current evidence Medsafe offers the following advice to prescribers when using methadone for any indication. However, the use of methadone should not be precluded in opioid-dependent patients who would otherwise benefit from treatment.
Please report all cases of suspected QT prolongation, arrhythmia or death associated with methadone to the Centre for Adverse Reactions Monitoring.
* QTc = corrected QT interval; often derived using Bazett's formula (QTc =QT interval/√R-R interval), which corrects for the heart rate.4
Competing interests (authors): none declared.