Response to Katz and Krantz Letter to the Editor

Thank you for the comments regarding the methadone safety guideline from the American Pain Society and College on Problems of Drug Dependence. Regarding the strength of evidence, in situations involving patient safety, clinical practice guideline recommendations and other policy decisions frequently must be made on the basis of limited evidence. For example, black box warnings issued by the Food and Drug Administration and drug withdrawals are often based primarily on case reports of serious adverse events, and recommendations regarding laboratory monitoring for many medications (eg, monitoring patients started on angiotensin-converting enzyme inhibitors for hyperkalemia) are primarily based on the potential for detecting adverse events, rather than on direct evidence that such efforts reduce harms. In the case of methadone safety, the strength of evidence supporting the recommendations is generally low because there are no studies showing that the recommended actions result in a reduction in overdose or other serious adverse events, so that there is low certainty in estimates of benefit. Methods from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for developing clinical practice guidelines allow for strong recommendations to be made despite weak evidence in certain situations, on the basis of the potential benefits relative to harms, cost and burdens, and other factors, despite the uncertainty. In the opinion of the panel of experts convened by the American Pain Society and College on Problems of Drug Dependence to develop the methadone safety guideline, the large increase in the number of methadone deaths, the unique properties of methadone (including its long and variable half-life and association with electrocardiographic QTc interval prolongation), and the availability of alternative therapies warrants a cautious approach that prioritizes patient safety. At the same time, the low strength of evidence grades for many of the recommendations underscore the need for additional research to better understand the benefits, harms, costs, and burdens of strategies intended to improve methadone prescribing safety.