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After innumerable negative or inconclusive studies to find a pharmacological prophylactic for post-ERCP pancreatitis (PEP), two randomised trials in the USA 1 and China2 ushered a new era of pharmacoprevention by confirming smaller observations that rectal non-steroidal anti-inflammatory drugs (NSAIDs) help. Each trial saw 50% relative risk reductions and low (<10%) absolute rates in high-risk patients who received rectal indomethacin. These and other studies showed a significant risk reduction only for the rectal route of administration, whereas other studies using oral and intravenous routes failed. Why is the rectal route needed? Convincing proof is elusive, but the general consensus is that rectal administration reduces the first-pass metabolism of the oral route and provides sustained bioavailability compared with intravenous dosing. 3 Although the precise prophylactic mechanism of action is unclear, NSAIDs may block the cyclooxygenase 2 pathway that leads to the systemic inflammatory response. The physiological PEP timeline varies. Small biomarker studies did not show consistent cytokine surges in the early (2–4 hours) period after ERCP, but the inflammatory profile of individuals with PEP becomes distinct 8–24 hours after the procedure. 4 5 Since most patients present within the first 48 hours, the general consensus is that prolonged inhibition of the inflammatory cascade is needed to prevent PEP, and this is achieved through the sustained bioavailability provided by rectal administration.