Association Between Opioid Dose Variability and Opioid Overdose Among Adults Prescribed Long-term Opioid Therapy

JAMA Netw Open. 2019 Apr 5;2(4):e192613. doi: 10.1001/jamanetworkopen.2019.2613.


Importance: Attempts to discontinue opioid therapy to reduce the risk of overdose and adhere to prescribing guidelines may lead patients to be exposed to variability in opioid dosing. Such dose variability may increase the risk of opioid overdose even if therapy discontinuation is associated with a reduction in risk.

Objective: To examine the association between opioid dose variability and opioid overdose.

Design, setting, and participants: A nested case-control study was conducted in a large Colorado integrated health plan and delivery system from January 1, 2006, through June 30, 2018. Cohort members were individuals prescribed long-term opioid therapy.

Exposures: Dose variability was defined as the SD of the milligrams of morphine equivalents across each patient's follow-up and categorized based on the quintile distribution of the SD in the cohort (0-5.3, 5.4-9.1, 9.2-14.6, 14.7-27.2, and >27.2 mg of morphine equivalents).

Main outcomes and measures: Opioid overdose cases were identified using International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Each case patient with overdose was matched to up to 20 control patients using risk set sampling. Conditional logistic regression models were used to generate matched odds ratios and 95% CIs, adjusted for age, sex, race/ethnicity, drug or alcohol use disorder, tobacco use, benzodiazepine dispensings, medical comorbidities, mental health disorder, opioid dose, and opioid formulation.

Results: In a cohort of 14 898 patients (mean [SD] age, 56.3 [16.0] years; 8988 [60.3%] female) prescribed long-term opioid therapy, 228 case patients with incident opioid overdose were matched to 3547 control patients. The mean (SD) duration of opioid therapy was 36.7 (33.7) months in case patients and 33.0 (30.9) months in control patients. High-dose variability (SD >27.2 mg of morphine equivalents) was associated with a significantly increased risk of overdose compared with low-dose variability (matched odds ratio, 3.32; 95% CI, 1.63-6.77) independent of opioid dose.

Conclusions and relevance: Variability in opioid dose may be a risk factor for opioid overdose, suggesting that practitioners should seek to minimize dose variability when managing long-term opioid therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage*
  • Benzodiazepines / administration & dosage*
  • Case-Control Studies
  • Cohort Studies
  • Colorado
  • Dose-Response Relationship, Drug
  • Drug Dosage Calculations
  • Drug Overdose / etiology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Morphine / administration & dosage*
  • Odds Ratio
  • Risk Factors
  • Withholding Treatment


  • Analgesics, Opioid
  • Benzodiazepines
  • Morphine