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J Pain. 2014 Apr;15(4):321-37. doi: 10.1016/j.jpain.2014.01.494.

Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society.

Author information

Departments of Medicine and Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, and Pacific Northwest Evidence-based Practice Center, Portland, Oregon. Electronic address:
Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York.
School of Public Health, Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
UCLA School of Nursing, Los Angeles, California.
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
Cardiology Uniformed Services, University of the Health Sciences, Baltimore, Maryland.
Department of Pharmacology, Weill Cornell Medical College, New York, New York.
Center for Adolescent Substance Abuse Research, Children's Hospital Boston, Boston, Massachusetts.
Division of Nursing Research and Education, Department of Population Sciences, City of Hope National Medical Center, Duarte, California.
School of Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey.
Departments of Medicine and Cardiology, Icahn School of Medicine at Mount Sinai, New York, New York.
Departments of Gynecology and Maternal Fetal Medicine, University of Vermont, Burlington, Vermont.
Department of Anesthesiology, Dartmouth Medical School, Hanover, New Hampshire.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky College of Medicine, Lexington, Kentucky.
Pediatric Pain Program, Mattel Children's Hospital at UCLA, Los Angeles, California.


Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence.


This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.


Clinical practice guideline; chronic pain; methadone; opioid addiction; safety

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