Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain

Pain. 2011 Aug;152(8):1789-1795. doi: 10.1016/j.pain.2011.03.023. Epub 2011 Apr 27.


Data on comparative safety of opioid analgesics are limited, but some reports suggest disproportionate mortality risk associated with methadone. Our objective was to compare mortality rates among patients who received prescribed methadone or long-acting morphine for pain. This is a retrospective observational cohort drawn from Department of Veterans Affairs (VA) health care databases, January 1, 2000, to December 31, 2007. We included 28,554 patients who received methadone and 79,938 who received long-acting morphine from VA pharmacies. Compared with those who received long-acting morphine, patients who received methadone were younger, less likely to have some medical comorbidities, and more likely to have psychiatric and substance use disorders. Patients were stratified into quintiles according to propensity score; the probability of receiving methadone was conditional on demographic, clinical, and VA service area variables. Overall propensity-adjusted mortality was lower for methadone than for morphine. Hazard ratios varied across propensity score quintiles; the magnitude of the between-drug difference in mortality decreased as the propensity to receive methadone increased. Mortality was significantly lower for methadone in all but the last quintile, in which there was no between-drug difference in mortality (hazard ratio=0.92, 95% confidence interval=0.74, 1.16). Multiple sensitivity analyses found either no difference in mortality between methadone and long-acting morphine or lower mortality rates among patients who received methadone. In summary, we found no evidence of excess all-cause mortality among VA patients who received methadone compared with those who received long-acting morphine. Randomized trials and prospective observational research are needed to better understand the relative safety of long-acting opioids.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Analgesics, Opioid / administration & dosage*
  • Benzodiazepines / therapeutic use
  • Cohort Studies
  • Drug Delivery Systems / methods
  • Female
  • Humans
  • Male
  • Methadone / therapeutic use*
  • Middle Aged
  • Morphine / administration & dosage*
  • Pain / drug therapy*
  • Pain / epidemiology
  • Pain / mortality*
  • Prescription Drugs / therapeutic use*
  • Retrospective Studies
  • Sensitivity and Specificity
  • Survival Analysis
  • Treatment Outcome
  • United States
  • United States Department of Veterans Affairs / statistics & numerical data


  • Analgesics, Opioid
  • Prescription Drugs
  • Benzodiazepines
  • Morphine
  • Methadone