Background Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). outcome was post-ERCP pancreatitis which was defined as new upper abdominal DAMPA pain an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure and hospitalization for at least 2 nights. Results A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03). Conclusions Among patients at high risk for post-ERCP pancreatitis rectal indomethacin DAMPA significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number NCT00820612.) ACUTE PANCREATITIS IS THE MOST COMmon major complication of endoscopic retrograde cholangiopancreatography (ERCP) 1 accounting for substantial morbidity occasional death and estimated health care expenditures of approximately $150 million annually in the United States.2 3 Given the magnitude of this problem more than 35 pharmacologic agents have been studied for the prophylaxis of post-ERCP pancreatitis and many prospective clinical DAMPA trials addressing chemoprevention have been conducted. To date however no medication has proved to be consistently effective in preventing post-ERCP pancreatitis on the basis of data from high-quality clinical trials and no pharmacologic DAMPA prophylaxis for post-ERCP pancreatitis is in widespread clinical use. Nonsteroidal antiinflammatory drugs (NSAIDs) are potent inhibitors of phospholipase A2 cyclooxygenase and neutrophil-endothelial interactions all believed to play an important role in the pathogenesis of acute pancreatitis.4 5 NSAIDs are inexpensive and easily administered and have a favorable risk profile when given as a single dose making them an attractive option in the prevention of post-ERCP pancreatitis. Preliminary studies evaluating the protective effects of single-dose rectal indomethacin or diclofenac in post-ERCP pancreatitis have been conducted 6 and a meta-analysis suggests benefit.10 Despite these data rectal NSAIDs are seldom used in clinical practice because there is no conclusive evidence from randomized controlled trials11 and because previous positive meta-analyses of other agents for the prevention of post-ERCP pancreatitis have been disproved by further investigation.12 DAMPA 13 Moreover it remains unclear whether NSAIDs provide incremental benefit over temporary pancreatic stents the only proven prophylactic intervention for post-ERCP pancreatitis.14-16 Therefore we conducted a multicenter randomized controlled clinical trial to evaluate the efficacy of prophylactic rectal indomethacin for the prevention of post-ERCP pancreatitis in high-risk patients. Methods Study Design We enrolled patients at four university-affiliated medical centers in the United States after approval from the human studies review committee DAMPA at each institution. An independent data and safety monitoring board provided regulatory oversight by reviewing blinded subject data quarterly and conducting the a priori scheduled interim analysis. The complete study protocol is available with the full text of this article at NEJM.org. Patients The inclusion criteria selected patients with an elevated baseline risk of post-ERCP pancreatitis on the basis of IkB alpha antibody prospectively validated patient- and procedure-related independent risk factors.17 Patients were eligible if they met one or more of the following major criteria: clinical suspicion of sphincter of Oddi dysfunction (as defined in the Supplementary Appendix available at NEJM.org) a history of post-ERCP pancreatitis pancreatic sphinc ter ot o my precut sphincterotomy (a procedure performed to facilitate biliary access when standard cannulation techniques are unsuccessful) more than eight cannulation attempts (as determined by the endoscopist) pneumatic dilatation of an intact biliary sphincter or ampullectomy. Patients were also eligible for inclusion if they.