Endoscopic retrograde cholangiopancreatography (ERCP) is a commonly performed invasive procedure, with post-ERCP pancreatitis (PEP) being the most frequent and clinically significant complication. Rectal non-steroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac and indomethacin, have been shown to reduce the incidence of PEP. However, real-world data comparing their efficacy remains limited. This study aimed to compare the efficacy of rectal diclofenac and indomethacin in preventing PEP among patients undergoing ERCP and to identify patient subgroups that may benefit more from one drug over the other.

A single-center, retrospective observational study was conducted, analyzing ERCP procedures. A total of 2344 procedures were evaluated, whereas 767 patients were included after exclusion of whom 322 received rectal indomethacin and 445 received rectal diclofenac. The primary outcome was the incidence of PEP, while secondary outcomes included post-ERCP bleeding, cardiorespiratory complications, and other adverse events. Subgroup analyses were performed to evaluate the effectiveness of each drug based on clinical risk factors.

The overall incidence of PEP was 6.6%, with approaching but not reaching significant difference between the indomethacin (8.7%) and diclofenac (5.2%) groups (p = 0.057). Subgroup analyses revealed that diclofenac was more effective in preventing PEP in patients with a naive papilla undergoing sphincterotomy (p = 0.048).

This study suggests that rectal diclofenac may offer a slight advantage over indomethacin in preventing PEP, particularly in high-risk groups, such as patients undergoing sphincterotomy; which was not previously published in the existing literature.