Risk Factors for Severe Opioid-Related Adverse Events in a National Cohort of Medical Hospitalizations

Author Department

Medicine; Healthcare Quality; Emergency Medicine; Anesthesiology

Document Type

Article, Peer-reviewed

Publication Date




Opioids are a leading cause of adverse drug events in the hospital. Guidelines recommend that physicians assess the risks of opioids and discuss them with patients when considering opioid use. There are no studies examining patient- and prescribing-related risk factors for opioid-related adverse drug events (ORADEs) in hospitalized medical patients.


To identify independent risk factors for severe ORADEs in hospitalized medical patients.


Retrospective cohort study.


Medical patients hospitalized at US, non-federal, and acute care facilities, with at least one pharmacy charge for an opioid during hospitalization. We excluded patients with metastatic malignancy, hospice, or palliative care billing codes.


We used Cox proportional hazards modeling to identify risk factors for severe ORADEs, defined by a pharmacy charge for naloxone. Candidate risk factors were chosen a priori, based on clinical grounds and prior literature.


Among 731,208 hospitalizations (median age 60, 56.5% female), a severe ORADE occurred in 2727 (0.4%). Independent risk factors included patient characteristics (advanced age, female gender), comorbidities (congestive heart failure, opioid abuse/dependence, non-opioid drug abuse/dependence, psychosis, depression, obstructive sleep apnea), organ failures on admission (respiratory failure, shock/hypotension, renal failure, hepatic failure, acidosis, and neurologic failure), medication co-administrations (antipsychotics and short-acting benzodiazepines), and characteristics of the opioid prescriptions themselves (total dose for the day, parenteral route of administration, and receipt of multiple types of opioids in a day). Although a risk prediction model derived from these factors performed well on stratified k-fold cross-validation (average c-statistics 0.68-0.71), the low incidence of the outcome limited the positive predictive value of the risk score.


In this national cohort of medical patients, we identified several risk factors for ORADEs that can be used to inform physician decision-making, conversations with patients about risk, and development and targeting of harm reduction strategies for at-risk populations.