American College of Physicians Issues Safety Guidelines for Prescribing Methadone

December 5, 2008 — The American College of Physicians (ACP) has issued safety recommendations regarding arrhythmia risk and QTc interval monitoring for clinicians prescribing methadone and has published the new clinical practice guidelines in the December 1 Early Release issue of the Annals of Internal Medicine.

“Methadone, the most widely used agent for opioid maintenance, may prolong the rate-corrected QT interval (QTc) and result in torsade de pointes,” write Mori J. Krantz, MD, from the University of Colorado and the Colorado Prevention Center in Denver, and colleagues from the Center for Substance Abuse Treatment Cardiac Expert Panel. “This association recently came into focus when the U.S. Food and Drug Administration (FDA) issued a physician safety alert regarding increasing fatalities and cardiac arrhythmias, which was followed by a manufacturer’s black box warning….Drug-induced arrhythmia often results from multiple factors, including hypokalemia; structural heart disease; hepatic cytochrome P450 inhibitors; and genetic predisposition, manifested by a prolonged QTc interval at baseline.”

The Center for Substance Abuse Treatment convened an expert panel and charged them with issuing safety recommendations for clinicians prescribing methadone. Members of the expert panel reviewed pertinent English-language literature identified from searches of MEDLINE and EMBASE (1966 – June 2008), US national substance abuse guidelines and those of other countries, information from regulatory authorities, and information concerning clinician awareness of adverse cardiac effects.

This review of the evidence suggested that methadone, both oral and intravenous, is associated with QTc interval prolongation and with torsade de pointes.

The panel issued the following specific recommendations in 5 key clinical areas:

• Recommendation 1 (Disclosure): When clinicians prescribe methadone, they should inform patients about arrhythmia risk.
• Recommendation 2 (Clinical History): Clinicians should ask patients about any history of structural heart disease, arrhythmia, or syncope.
• Recommendation 3 (Screening): All patients should have a pretreatment electrocardiogram (ECG) to measure QTc interval and a follow-up ECG within 30 days and each year. If the methadone dosage is greater than 100 mg/day, or if patients have unexplained syncope or seizures, additional ECG is recommended.
• Screening with ECG may also be done as indicated for patients receiving methadone and who have multiple risk factors for QTc interval prolongation, such as a family history of long QT syndrome or early sudden cardiac death or electrolyte depletion. Screening is also recommended when a cytochrome P450 inhibitor or other QTc interval–prolonging drug, including cocaine, is started.
• Recommendation 4 (Risk Stratification): For patients in whom the QTc interval is between 450 and 500 milliseconds, the potential risks and benefits should be discussed, and they should be monitored more frequently.
• If the QTc interval is greater than 500 milliseconds, discontinuing or decreasing the methadone dose should be considered as well as eliminating other contributing factors such as drugs that cause hypokalemia. Use of an alternative therapy may be indicated.
• Recommendation 5 (Drug Interactions): Clinicians should be knowledgeable concerning interactions between methadone and other drugs that tend to prolong the QT interval or to slow the elimination of methadone.

“Opioid treatment programs in the United States are accordingly challenged with integrating cardiac arrhythmia risk assessment into routine care process without reducing access to vital addiction treatment services,” the authors write. “We believe that increased clinical vigilance will reduce sudden cardiac death among the approximately 250,000 patients receiving methadone in opioid treatment programs as well as the nearly 720,000 patients receiving methadone for chronic pain through U.S. retail pharmacies. These recommendations will strengthen both the product labeling for methadone as well as the CSAT [Center for Substance Abuse Treatment] practice standards for opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration accreditation process.”

For patients in whom marked QTc interval prolongation or torsade de pointes develops while receiving methadone therapy, buprenorphine is the only alternative therapy approved by the FDA. The authors note that pending larger prospective studies, (R) methadone could prove to be a safe therapeutic alternative vs the standard racemic mixture (R,S) methadone. However, (R) methadone is currently unavailable in the United States.

“With regard to cardiac arrhythmia risk, standard methadone can be safely administered as long as the potential for QTc interval prolongation is recognized through ECG screening and appropriate clinical actions are taken in the presence of QTc interval prolongation,” the authors conclude. “We concluded that arrhythmia risk associated with methadone is a direct consequence of its effect on cardiac repolarization. Hence, our guideline is applicable to patients either receiving current treatment or being considered for methadone initiation for addiction or pain management.”

The authors of the guideline note that clinical practice guidelines are intended to improve patient care but not to replace clinical judgment, in that the guideline may not apply to all patients or clinical scenarios. The authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online December 1, 2008.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

1. Describe recommendations for prescribing methadone.
2. Describe the risk for cardiac arrhythmia associated with methadone use.

Clinical Context

A large body of evidence suggests that oral and intravenous methadone is associated with QTc interval prolongation and torsade de pointes. Opioid treatment programs in the United States are currently challenged with integrating cardiac risk assessment into routine care without reducing access to vital addiction treatment. Currently, in patients at risk for arrhythmias from methadone, a second-line treatment, buprenorphine, is available as an alternative therapy approved by the US Food and Drug Administration. There is now an FDA black-box warning regarding increasing fatalities from cardiac arrhythmias associated with methadone use. In the United States, there are currently 250,000 patients in opioid treatment programs and 720,000 patients receiving methadone for chronic pain.

This is a review of the evidence for arrhythmia with the use of methadone constructed by the Center for Substance Abuse and Treatment expert panel of the Substance Abuse and Mental Health Services Administration to guide clinicians on screening for and diagnosing QTc interval prolongation when prescribing methadone.

Study Highlights

• 2 reviewers independently searched MEDLINE and EMBASE databases for articles in English from 1966 to 2008 and used mortality data of the Center for Substance Abuse and Treatment, national opioid guidelines, and background articles on QTc interval prolongation.
• Animal studies were not excluded.
• The articles identified included experimental studies, clinical case series (≥ 1973), forensic series from medical examiner investigations of unexplained methadone-associated deaths, cross-sectional data, and prospective randomized trial data.
• Scores were given for the probability of the association between methadone with QTc interval prolongation and torsade de pointes based on study findings.
• The effects of methadone on cardiac repolarization were found to be dose dependent based on evidence from case reports, cross-sectional studies, and prospective studies.
• There was a positive correlation between dose and delayed cardiac repolarization.
• The evidence suggested that patients with structural heart disease, family history, or drug interactions that affected the cytochrome P450 system or elimination of methadone were at increased risk for QTc interval prolongation.
• Although the threshold for QTc interval prolongation was considered different in men and women, the panel decided to use a common threshold of 450 milliseconds as a pretreatment risk threshold for both sexes.
• Methadone dosage was just 1 consideration to limit arrhythmia risk.
• Arrhythmias were reported at doses as low as 29 mg/day, creating a safety-efficacy paradox.
• 5 guidelines were created based on the findings.
• The guidelines are applicable to patients receiving current methadone treatment or being considered for methadone treatment of addiction or pain management.
• The 5 recommendations include the following:
  1. Clinicians should inform patients of arrhythmia risk when they prescribe methadone (disclosure).
  2. Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope before prescribing methadone.
  3. A pretreatment ECG should be performed for all patients to measure QTc interval, and a follow-up ECG should be performed within 30 days and annually. Additional ECGs are recommended if the methadone dose exceeds 100 mg/day or if patients have unexplained syncope or seizures (screening).
  4. If the QTc interval is greater than 450 milliseconds but less than 500 milliseconds, potential risks and benefits should be discussed with the patient. If the interval exceeds 500 milliseconds, methadone should be tapered or discontinued and contributing factors should be addressed, such as hypokalemia (risk stratification).
  5. Clinicians should be aware of drugs that interact with methadone to increase risk for QTc interval prolongation or slow the elimination of methadone (drug interactions).
• The authors projected that in the United States, approximately 5000 of 250,000 patients in opioid treatment programs would exceed the 500-millisecond prolongation threshold and constitute a principal target for risk reduction interventions.
• They recommended that automated (vs manual) interpretation of QTc interval prolongation during ECG screening was feasible as a screening tool for risk stratification; this was an option in opioid treatment programs and for chronic pain management.
• They concluded that standard methadone can be safely administered as long as the potential for QTc interval prolongation was recognized through ECG screening and appropriate action taken for QTc interval prolongation.

Pearls for Practice

• Clinicians who prescribe methadone should screen for QTc interval prolongation, drug interactions, and a family history of cardiac risk factors; they should also perform an ECG examination and a risk assessment.
• Use of methadone is associated with a dose-dependent increase in the risk for QTc interval prolongation from an effect on cardiac repolarization and torsade de pointes.

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