Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain

JAMA. 2016 Jun 14;315(22):2415-23. doi: 10.1001/jama.2016.7789.


Importance: Long-acting opioids increase the risk of unintentional overdose deaths but also may increase mortality from cardiorespiratory and other causes.

Objective: To compare all-cause mortality for patients with chronic noncancer pain who were prescribed either long-acting opioids or alternative medications for moderate to severe chronic pain.

Design, setting, and participants: Retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care.

Exposures: Propensity score-matched new episodes of prescribed therapy for long-acting opioids or either analgesic anticonvulsants or low-dose cyclic antidepressants (control medications).

Main outcomes and measures: Total and cause-specific mortality as determined from death certificates. Adjusted hazard ratios (HRs) and risk differences (difference in incidence of death) were calculated for long-acting opioid therapy vs control medication.

Results: There were 22,912 new episodes of prescribed therapy for both long-acting opioids and control medications (mean [SD] age, 48 [11] years; 60% women). The long-acting opioid group was followed up for a mean 176 days and had 185 deaths and the control treatment group was followed up for a mean 128 days and had 87 deaths. The HR for total mortality was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths (95% CI, 28.2-120.7) per 10,000 person-years. Increased risk was due to out-of-hospital deaths (154 long-acting opioid, 60 control deaths; HR, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years. For out-of-hospital deaths other than unintentional overdose (120 long-acting opioid, 53 control deaths), the HR was 1.72 (95% CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95% CI, 15.7-91.4) per 10,000 person-years. The HR for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95% CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95% CI, 4.6-65.3) per 10,000 person-years. The HR during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95% CI, 2.27-7.63) with a risk difference of 200 excess deaths (95% CI, 80-420) per 10,000 person-years.

Conclusions and relevance: Prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose, with a modest absolute risk difference. These findings should be considered when evaluating harms and benefits of treatment.

Publication types

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

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use
  • Anticonvulsants / therapeutic use
  • Antidepressive Agents / therapeutic use
  • Cardiovascular Diseases / mortality
  • Cause of Death
  • Chronic Pain / drug therapy*
  • Chronic Pain / mortality*
  • Drug Overdose / mortality
  • Drug Prescriptions / statistics & numerical data
  • Female
  • Fentanyl / adverse effects
  • Fentanyl / therapeutic use
  • Humans
  • Male
  • Methadone / adverse effects
  • Methadone / therapeutic use
  • Middle Aged
  • Morphine / adverse effects
  • Morphine / therapeutic use
  • Oxycodone / adverse effects
  • Oxycodone / therapeutic use
  • Propensity Score
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk


  • Analgesics, Opioid
  • Anticonvulsants
  • Antidepressive Agents
  • Morphine
  • Oxycodone
  • Methadone
  • Fentanyl