Published: November 2005

Publications

Cardiac Vigilance Recommended for Methadone

Information on this subject has been updated. Read the most recent information.

Prescriber Update 26(2): 23-25
November 2005

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
References

Methadone is used for analgesia and opioid dependence

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 QT_c^* interval is considered to be prolonged if it is >450ms in men or >460ms in women.  A QT_c of >500ms,⁴ or an increase of >40ms,⁵ is generally accepted to confer a high risk of TdP.

Local and international reports of methadone-associated QT prolongation

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 QT_c.  The methadone dose was reduced to 60mg/day and the QT_c 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.

Biologically plausible mechanism and risk factors identified

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 QT_c 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

The presence of other risk factors for QT prolongation increases the risk of developing QT prolongation or TdP with a medicine.³ Risk factors include^3,4:

• advanced age
• female gender
• electrolyte abnormalities e.g. hypokalaemia or severe hypomagnesaemia
• bradycardia
• heart disease (e.g. heart failure or ischaemia)
• congenital long QT syndrome or pre-existing QT prolongation
• concomitant use of other QT prolonging medicines (e.g. tricyclic antidepressants, some antipsychotics and antibiotics⁹ - see www.torsades.org/medical-pros/drug-lists/drug-lists.htm for a more comprehensive listing)
• concomitant use of medicines that may inhibit the metabolism of methadone (e.g. fluconazole and some SSRI antidepressants¹⁰ ).

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.

The risk of methadone-induced QT prolongation can be managed

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.

• All patients should be evaluated for the presence of risk factors for QT prolongation prior to initiating methadone treatment.  Modifiable risk factors should be corrected.
• Maintain patients on the lowest effective dose of methadone.  Careful dose titration is required due to methadone's long half-life and pharmacokinetic variability.¹⁰
• For patients with chronic pain, the potential for QT prolongation should be considered before prescribing methadone.  Morphine and codeine appear to have little effect on cardiac potassium channels in vitro,⁷ so may be more appropriate choices particularly in patients with other risk factors for QT prolongation.
• For patients being treated for opioid dependence, methadone remains the most effective funded treatment available, although it is noted that buprenorphine may have less effect on cardiac potassium channels in vitro.⁷  Specialist advice should be sought for patients who, despite elimination of all modifiable risk factors, have a persistently prolonged QT_c interval.
• Patients should be informed of the symptoms of arrhythmia and be advised to promptly seek medical advice if symptoms such as palpitations and syncope develop.
• ECG monitoring should be considered for methadone doses >150mg/day and in patients with risk factors for QT prolongation, or symptoms that may be attributable to arrhythmia.⁶
• Serum electrolytes should be measured regularly, particularly in patients with vomiting or diarrhoea, or those taking diuretics.
• If QT prolongation occurs (i.e. QT_c >500ms or an increase in the QT_c of >40ms), specialist advice should be obtained regarding discontinuing or reducing the dose of methadone.

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.

References:

1. Personal correspondence, 7 April 2005.  Drug dependency specialist, Wellington Hospital.
2. Personal communication, June 2005.  Chronic pain specialist, Wellington Hospital.
3. Roden DM. Drug-induced prolongation of the QT interval. New England Journal of Medicine 2004;350(10):1013-1022.
4. Al-Khatib SM, LaPointe NM, Kramer JM et al. What clinicians should know about the QT interval. Journal of the American Medical Association 2003; 289(16): 2120-2127.
5. Martell BA, Arnsten JH, Ray B et al. The impact of methadone induction on cardiac conduction in opiate users [Letter]. Annals of Internal Medicine 2003;139(2):154-155.
6. Swedish update on methadone: QT prolongation, testosterone. Reactions Weekly 2004;No.1006 (19 June):2.
7. Katchman AN, McGroary KA, Kilborn MJ et al. Influence of opioid agonists on cardiac human ether-a-go-go-related gene K+ currents. Journal of Pharmacology and Experimental Therapeutics 2002; 303(2): 688-694.
8. Krantz MJ, Lewkowiez L, Hays H et al. Torsades de pointes associated with very-high-dose methadone. Annals of Internal Medicine 2002:137(6): 501-504.
9. Woosley RL. Drugs that prolong the QT interval and/or induce torsades de pointes. University of Arizona Health Sciences Centre. www.torsades.org/medical-pros/drug-lists/drug-lists.htm
10. Brown R, Kraus C, Fleming M et al. Methadone: Applied pharmacology and use as adjunctive treatment in chronic pain.  Postgraduate Medical Journal 2004;80:654-659.