Double Jeopardy: Risks of Opioid–Benzodiazepine Co-prescription in Older Adults with Gastrointestinal Cancer

BACKGROUND: Opioid analgesics and benzodiazepines are frequently prescribed to manage pain, anxiety, and insomnia in older adults with gastrointestinal (GI) cancers, yet outcomes of concurrent use are incompletely defined. PATIENTS AND METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare (2014-2018), daily exposure was classified as no opioid/benzodiazepine, opioid only, or opioid-benzodiazepine co-prescription and overdose; falls/fractures, all-cause hospitalization, and all-cause mortality within 12 months were assessed. Time-varying Cox models compared opioid-only and co-prescription versus no exposure, and for incremental risk, co-prescription versus opioid-only. RESULTS: Among 26,896 patients (median age 74 years; 53.1% female), 5086 (18.9%) received concurrent opioid-benzodiazepine prescriptions and 2288 (8.5%) received opioids alone. Within 12 months, among patients unexposed, opioid-only, and co-prescribed, unadjusted first-event rates per 100,000 person-days (95% CI) were: falls/fractures 27.8 (26.7-28.9), 55.0 (47.1-63.9), and 61.0 (50.8-72.5); all-cause hospitalizations 393.0 (388.0-398.0), 439.0 (410.0-470.0), and 441.0 (406.0-480.0); overdose 1.40 (1.20-1.70), 6.20 (3.80-9.50), and 8.80 (5.32-13.83); and mortality 11.5 (10.8-12.2), 20.6 (15.9-26.1), and 29.6 (22.8-37.9), respectively (global p < 0.001). In adjusted models versus no exposure, both opioid-only and co-prescribed patients had higher hazards of adverse outcomes. Using opioid-only as reference, co-prescription was associated with incremental hazards of all-cause hospitalization (HR 1.12, 95% CI 1.03-1.23) and all-cause mortality (HR 1.35, 95% CI 1.06-1.73). CONCLUSIONS: Opioid exposure was associated with elevated risk, while the addition of benzodiazepines conferred incremental increases in hospitalization and mortality versus opioid-only use.