Comparative out-of-hospital mortality of long-acting opioids prescribed for non-cancer pain: A retrospective cohort study

Pharmacoepidemiol Drug Saf. 2019 Jan;28(1):48-53. doi: 10.1002/pds.4619. Epub 2018 Jul 12.


Purpose: Despite significant growth of opioid prescriptions, only limited data are available regarding the comparative safety of long-acting opioids for chronic non-cancer pain. Recent data suggest that transdermal fentanyl and oxycodone CR may have greater toxicity than morphine SR in patients with non-cancer pain. Thus, we compared the risk of out-of-hospital deaths in patients with non-cancer pain filling prescriptions for transdermal fentanyl or oxycodone CR with that for morphine SR.

Methods: We conducted a retrospective cohort study in 50 658 patients enrolled in Tennessee Medicaid who filled prescriptions for transdermal fentanyl (n = 8717), oxycodone CR (n = 14 118), or morphine SR (n = 27 823) between 1999 and 2011. We excluded individuals with cancer or other life-threatening diagnoses and used propensity scores to adjust for multiple potential confounders. The primary outcome was out-of-hospital mortality.

Results: During 44 385 person-years of follow-up, 689 patients died. The out-of-hospital mortality rate among all study subjects was 155/10 000 patient-years. Contrary to earlier data suggesting greater risk, mortality was not significantly different in patients filling prescriptions for transdermal fentanyl compared with morphine SR (adjusted HR = 0.96, 95% C.I.: 0.77-1.21); moreover, patients filling prescriptions for oxycodone CR had lower mortality risk compared with those filling prescriptions for morphine SR (adjusted HR = 0.79, 95% C.I. 0.66-0.95).

Conclusion: In the study population, long-acting opioids for non-cancer pain were associated with high out-of-hospital mortality rates. We found comparable out-of-hospital mortality risks associated with transdermal fentanyl and morphine SR. The risk of out-of-hospital death for oxycodone CR was lower than that for morphine SR.

Keywords: fentanyl; morphine; mortality; opioids; oxycodone; pharmacoepidemiology.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / poisoning*
  • Chronic Pain / drug therapy*
  • Delayed-Action Preparations / administration & dosage
  • Delayed-Action Preparations / poisoning*
  • Drug Overdose / etiology
  • Drug Overdose / mortality*
  • Female
  • Fentanyl / administration & dosage
  • Fentanyl / poisoning
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Morphine / administration & dosage
  • Morphine / poisoning
  • Oxycodone / administration & dosage
  • Oxycodone / poisoning
  • Retrospective Studies
  • Transdermal Patch / adverse effects


  • Analgesics, Opioid
  • Delayed-Action Preparations
  • Morphine
  • Oxycodone
  • Fentanyl