Risk of gastrointestinal bleeding with gabapentin versus duloxetine in older adults with neuropathic pain: a target trial emulation cohort study.

Gabapentin and duloxetine are common treatments for neuropathic pain in adults over 65, but data on their gastrointestinal (GI) bleeding risk are limited. We compared GI bleeding risk after starting gabapentin or duloxetine in this population. We used the TriNetX US Collaborative Network to conduct an active-comparator cohort study using target trial emulation. Patients aged 65 years and above with neuropathic pain diagnosed between January 2020 and December 2024 were included, excluding those with prior GI bleeding, major depressive disorder, or thrombocytopenia. Propensity score matching balanced key covariates. The main outcome was GI bleeding within 24 months, analyzed with Cox regression; secondary analyses included upper/lower GI bleeding, mortality, and hospitalization. Negative controls assessed confounding. The study analyzed 62,926 patients (55,236 gabapentin; 7,690 duloxetine) and matched 7,599 pairs. GI bleeding was less common with gabapentin initiators (1.22%) than duloxetine initiators (2.49%), showing an absolute risk reduction of 1.27% (HR 0.86, 95% CI 0.84-0.89, p < 0.0001), mainly for upper GI bleeding (HR 0.39, 95% CI 0.29-0.53). Lower GI bleeding results were not significant. Gabapentin also showed slightly lower all-cause mortality (HR 0.87, 95% CI 0.84-0.90). Negative control outcomes revealed no notable associations. In older adults with neuropathic pain, gabapentin initiation was associated with a lower risk of GI bleeding than duloxetine, especially for upper GI bleeding. As both drugs offer comparable analgesic efficacy, GI bleeding risk may be a relevant consideration when choosing between them. These findings are hypothesis-generating and should be confirmed in independent datasets and prospective comparative studies will confirm the data.