Saturday, August 8, 2009

Methadone Arrhythmia – Debate Rages On

In the August 2009 edition of the Annals of Internal Medicine there is a series of letters highly critical of consensus guidelines on “QTc Interval Screening in Methadone Treatment” published in the journal last spring [See: letters and response; original guidelines article]. The major themes of the letters are:
  1. ECG monitoring in all patients prescribed methadone as recommended in the Annals guidelines is impractical and overly inclusive;

  2. overall incidence rates of potentially hazardous QTc prolongation associated with methadone are low;

  3. fatal arrhythmia (torsade de pointes) due to methadone alone has not been adequately verified;

  4. evidence regarding ECG monitoring to predict methadone-induced arrhythmia is equivocal at best; and

  5. the guidelines might end up restricting access to methadone and, for patients benefitting from methadone therapy, there often is no effective alternative to help them.
Therefore, as a risk mitigation strategy, serial ECG monitoring in all patients prescribed methadone would be an ineffective and costly approach to problems that, at most, probably rarely occur. There appears to be such widely-divergent opinion about this issue because relatively scant research data or documented experience from daily practice is available to guide evidence-based conclusions. In one of the letters, however, the medical director for a group of clinics recounts that in their 10 years of experience with 5,000 patients taking methadone daily (50,000 patient-years, 18.25 million doses) they have not encountered any evidence of fatal arrhythmia (torsade de pointes) attributable to methadone therapy. In response, the general position of the guidelines authors appears to be, the fact that there is no verifiable evidence of significant numbers of patients dying from methadone-induced arrhythmia does not disprove its occurrence. They provide a number of reasons why it is difficult if not impossible to unambiguously determine methadone as a cause of fatal cardiac events; however, this still fails to bolster their argument for routine, serial ECG monitoring as a risk mitigation measure.

Previously, we have expressed doubts about the Annals guidelines in the “Misguided Guidelines” edition of our Pain-Topics e-Briefing Newsletter [click for PDF]. Furthermore, in 2003 we coauthored a report with Mori Krantz, MD — lead author of the recent Annals guidelines paper — titled “Methadone Cardiac Concerns” [see report]. In that, a commonsense approach based on available evidence was proposed:
Some patients prescribed methadone may have conditions associated with increased risks of arrhythmia, including: cardiovascular disease, electrolyte imbalances, and prescribed medications or abuse of cardiotoxic substances that may foster cardiac repolarization disturbances. Furthermore, in some individuals, methadone — alone or, more commonly, in combination with other drugs and/or cardiac risk factors — can prolong the QT interval, which might contribute to the development of the serious arrhythmia torsade de pointes in susceptible patients. A sound understanding of methadone’s potential for QT-prolongation in the context of other arrhythmia risk factors will allow clinicians to provide individualized patient assessments and treatment plans, including ECG monitoring in appropriately selected patients, that preserve heart health and optimize safety. Current evidence, however, does not support altering approved methadone dosing practices or routine, serial ECG monitoring in all patients. The relatively small potential risk of adverse cardiac events with methadone should be weighed against the significant benefits of this medication for pain relief or addiction therapy.
More recent evidence does not seem compelling enough to override the essential recommendations in our 2003 report. In fact, many of the recommendations were recently incorporated into guidance from the American Association for the Treatment of Opioid Dependence (“QTc Interval Screening – AATOD Policy and Guidance Statement,” March 2009 [see document]). Still unknown, however, is what if any guidance may be forthcoming from the U.S. Center for Substance Abuse Treatment (CSAT); this was the agency that convened a meeting more than a year ago to discuss methadone arrhythmia concerns and possibly develop guidelines in the first place. The guidelines article published in the Annals by Krantz and colleagues (who also were on the CSAT panel) does not represent any official position or endorsement of the government.

Thanks to Drew Rosielle MD, at, and Andrew Byrne, MD (Australia), for bringing these latest letters in the Annals to our attention.
ADDENDUM: For an excellent 35-minute audiovisual lecture by Gavin Bart, MD, interpreting the Annals Methadone QTc Guidelines article [click here].