Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment FREE

IN RESPONSE:

We appreciate the many thoughtful and provocative comments on our consensus guideline for QTc interval screening in methadone treatment. The common theme was a strong endorsement of methadone's role as a cornerstone therapy in opioid addiction. Dr. Byrne and Drs. Cohen and Mao rightly assert that methadone may be a treatment of last resort with limited therapeutic alternatives. We agree and clearly acknowledge in our guideline that methadone is a niche medication (1) that must remain widely available despite the many alternative drugs for treatment of chronic pain and a second approved therapy, buprenorphine, in the addiction field. Indeed, our guideline does not mandate switching to an alternative therapy, even in the setting of marked (>500 ms) methadone-induced QTc prolongation. Instead, we suggest a measured approach of risk stratification that informs both a risk–benefit discussion as well as many individualized clinical actions to mitigate risk.

Dr. Girgis highlights the disproportionate increase in methadone-associated deaths in recent forensic studies (2). Specifically, he notes that coroners' reports have not indicated a link between unexplained methadone-associated sudden death and the QTc interval. This is not surprising, because ECG data obtained before sudden cardiac death are rarely available to coroners. However, a recent autopsy cohort study by Chugh and colleagues (3) suggests that methadone-associated sudden deaths may have been the result of a fatal arrhythmia, because of the relative lack of structural heart disease in persons with modest serum methadone concentrations. Finally, Dr. Girgis cites the work of Lipski and colleagues (4) to suggest that methadone has minimal effect on the QTc interval. We respectfully disagree with this characterization, because 34% of methadone-treated patients in this study had significant QTc prolongation compared with only 18% of methadone-naive drug abusers.

We thank Dr. Bart for pointing out the inherent methodological limitations of our guideline. We acknowledge that the number and types of studies available regarding methadone cardiotoxicity are limited and do not lend themselves to critical appraisal criteria, meta-analytic techniques, or other quantitative quality assessments. Despite these inherent limitations, we adopted a validated clinical tool (5) to determine with certainty the link between methadone and torsade de pointes as a prerequisite to asserting the need for a risk mitigation strategy. Safeguarding patients from potentially fatal drug-induced arrhythmia creates a very different contextual framework than grading evidence for screening and treatment decision algorithms, such as the USPSTF guidelines that Dr. Bart alludes to. It is therefore no surprise that we found no evidence-based guideline recommendations from the USPSTF regarding mitigation of drug-induced torsade de pointes on review of the scientific literature (PubMed, accessed 10 May 2009). We are also unaware of any “effectiveness” evaluations of risk mitigation strategies that require ECG screening for drugs independently associated with torsade de pointes (6), including the methadone derivative levacetylmethadol (7). Finally, no scientific objections were raised to our recommendations during any of the cardiac expert panel meetings convened by the Center for Substance Abuse Treatment. Nonetheless, we respect the autonomy of clinicians to either change their views or decline acknowledgment. This in no way calls into question the integrity of the research process, the clinical science behind our guideline, or the editorial judgment in publishing it.

In conclusion, methadone is associated with a dramatic increase in deaths and cardiac arrhythmias. Arrhythmic events have often been associated with high doses of methadone or concurrent illicit drug use. Many patients in the addiction field fit into these categories, which underscores the importance of defining risk with ECG. We believe it is the increase in methadone deaths that imperils the future of methadone treatment rather than ECG monitoring, which is relatively simple, noninvasive, and inexpensive. The opioid treatment and pain management communities therefore must consider appropriate measures to address this challenge. Understanding the complex pharmacokinetic and pharmacodynamic properties of methadone (especially QTc prolongation) is an essential first step. Disclosure of arrhythmia risk to patients, ECG screening, and risk stratification that informs individualized treatment decisions are responsible next steps to ensure safety in this vulnerable population.

Mori J. Krantz, MD

Colorado Prevention Center

Denver, CO 80203

Judith Martin, MD

BAART Turk Street Clinic

San Francisco, CA 94102

Barry Stimmel, MD

Mount Sinai School of Medicine

New York, NY 10029-6500

Mark C.P. Haigney, MD

Uniformed Services University of the Health Sciences

Bethesda, MD 20814