Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality

Pain Med. 2016 Jan;17(1):85-98. doi: 10.1111/pme.12907.


Objective: Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality.

Design: Prospective observational cohort with one year follow-up.

Setting: One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data.

Subjects: Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients.

Methods: Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations.

Results: Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9).

Conclusions: Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk.

Publication types

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

MeSH terms

  • Aged
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / toxicity*
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / toxicity*
  • Cohort Studies
  • Drug Overdose / mortality*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Morphine / administration & dosage
  • Morphine / therapeutic use*
  • Opioid-Related Disorders / drug therapy
  • Opioid-Related Disorders / mortality*
  • Pain / drug therapy
  • Pain / mortality
  • Prescription Drugs / toxicity
  • Prospective Studies


  • Analgesics, Opioid
  • Prescription Drugs
  • Benzodiazepines
  • Morphine