Background: Despite widespread use and emerging safety concerns, data on the comparative safety and effectiveness of long-acting opioid (LAO) analgesics are weak.

Objective: To compare rates of adverse events among patients newly prescribed an LAO.

Methods: A retrospective observational cohort study using Medicaid administrative claims data was conducted examining time until first adverse outcome among patients with new prescriptions for methadone, extended-release (ER) oxycodone, ER morphine, or transdermal fentanyl. Adverse outcomes included emergency department (ED) encounters or hospitalizations for opioid-related adverse events, all-cause ED encounters or hospitalizations, death, and diagnoses for opioid-related adverse effects. Cox proportional hazards models were used to adjust for a variety of measured covariates overall and within subgroups of patients with and without cancer.

Results: This study included 5684 subjects. Patients prescribed ER oxycodone were 55[corrected]% less likely (adjusted hazard ratio [HR] 0.45; 95% CI 0.26 to 0.77) to experience an ED or hospitalization involving an opioid-related adverse event, 23% lower risk of hospitalization (adjusted HR 0.77; 95% CI 0.66 to 0.91), 41% lower risk of constipation (adjusted HR 0.59; 95% CI 0.35 to 1.00), and a 29% lower risk of death (adjusted HR 0.71; 95% CI 0.54 to 0.94) compared with those prescribed ER morphine. Among subjects with noncancer pain, fentanyl was associated with a higher risk of ED encounters (adjusted HR 1.27; 95% CI 1.02 to 1.59) and methadone was associated with a greater risk of overdose symptoms (adjusted HR 1.57; 95% CI 1.03 to 2.40) compared with ER morphine.

Conclusions: Our results support a modest safety advantage with ER oxycodone compared with ER morphine. Among subjects with noncancer pain, fentanyl and methadone were associated with an increased risk of an adverse event compared with ER morphine. Additional studies are needed to confirm our findings and further clarify risks associated with different LAOs.