Opioid Use Increases the Risk of Delirium in Critically Ill Adults Independently of Pain

Am J Respir Crit Care Med. 2021 Sep 1;204(5):566-572. doi: 10.1164/rccm.202010-3794OC.


Rationale: It is unclear whether opioid use increases the risk of ICU delirium. Prior studies have not accounted for confounding, including daily severity of illness, pain, and competing events that may preclude delirium detection.Objectives: To evaluate the association between ICU opioid exposure, opioid dose, and delirium occurrence.Methods: In consecutive adults admitted for more than 24 hours to the ICU, daily mental status was classified as awake without delirium, delirium, or unarousable. A first-order Markov model with multinomial logistic regression analysis considered four possible next-day outcomes (i.e., awake without delirium, delirium, unarousable, and ICU discharge or death) and 11 delirium-related covariables (baseline: admission type, age, sex, Acute Physiology and Chronic Health Evaluation IV score, and Charlson comorbidity score; daily: ICU day, modified Sequential Organ Failure Assessment, ventilation use, benzodiazepine use, and severe pain). This model was used to quantify the association between opioid use, opioid dose, and delirium occurrence the next day.Measurements and Main Results: The 4,075 adults had 26,250 ICU days; an opioid was administered on 57.0% (n = 14,975), severe pain occurred on 7.0% (n = 1,829), and delirium occurred on 23.5% (n = 6,176). Severe pain was inversely associated with a transition to delirium (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.53-0.97). Any opioid administration in awake patients without delirium was associated with an increased risk for delirium the next day [OR, 1.45; 95% CI, 1.24-1.69]. Each daily 10-mg intravenous morphine-equivalent dose was associated with a 2.4% increased risk for delirium the next day.Conclusions: The receipt of an opioid in the ICU increases the odds of transitioning to delirium in a dose-dependent fashion.

Keywords: delirium; intensive care; medication; opioid; risk factor.

Publication types

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

MeSH terms

  • Aged
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use*
  • Critical Illness / therapy*
  • Delirium / chemically induced*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Netherlands
  • Odds Ratio
  • Pain / drug therapy*
  • Prospective Studies
  • Risk Factors


  • Analgesics, Opioid