Comparative Short-term Risk of Severe Gastrointestinal Events Associated With Opioid Type Among Patients Receiving Glucagon-Like Peptide-1 Receptor Agonists

OBJECTIVE To compare the risk of motility-related gastrointestinal (GI) events associated with commonly prescribed opioids among adults with type 2 diabetes (T2D) prescribed glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, a population in whom the GI safety of concomitant opioid use has not been well characterized. RESEARCH DESIGN AND METHODS A population-based, new-user cohort study was conducted using U.S. insurance claims (2016–2025) among adults with T2D prescribed GLP-1RA therapy who initiated use of oxycodone, hydrocodone, or tramadol. We evaluated a composite of motility-related GI events, including severe constipation, bowel obstruction, and gastroparesis, and estimated 30-day weighted absolute risks, risk ratios (RRs), and risk differences (RDs) using propensity score–matching weights. RESULTS Among 411,188 patients (mean age 62.8 years; 53.8% female) with T2D and using a GLP-1RA, 24.4% initiated use of oxycodone, 48.5% hydrocodone, and 27.1% tramadol. The weighted 30-day absolute risk of motility-related GI events was 0.51% for oxycodone, 0.35% for hydrocodone, and 0.33% for tramadol. Oxycodone was associated with a higher risk than hydrocodone (RR 1.48 [95% CI 1.30–1.69]; RD 0.17 [95% CI 0.11–0.22]) and tramadol (RR 1.55 [95% CI 1.33–1.79]; RD 0.18 [95% CI 0.12–0.24]). Hydrocodone and tramadol showed similar risks (RR 1.05 [95% CI 0.91–1.21]; RD 0.02 [95% CI −0.03 to 0.06]). CONCLUSIONS Among adults with T2D who were using a GLP-1RA, initiation of oxycodone was associated with higher short-term risks of severe constipation and bowel obstruction compared with hydrocodone or tramadol. We did not observe differences in the risk of gastroparesis. Risks were similar between patients initiating hydrocodone and tramadol, although variation across secondary analyses warrants cautious interpretation.