PROJECT SUMMARY/ABSTRACT Chronic pancreatitis (CP) is a disabling, chronic fibro-inflammatory disease that impairs quality of life due to chronic pain and complications of pancreatic insufficiency. There is currently no effective, disease-modifying medical therapy for CP. The cyclooxygenase-2 enzyme (COX-2) is overexpressed in the pancreas of humans with CP, and is a promising therapeutic target. COX-2 produces prostaglandin E2 (PGE2), a potent mediator of pancreatic chronic inflammation and stellate cell activity. Pancreas juice (PJ) PGE2 concentrations are elevated in patients with CP compared to normal volunteers. Animal studies suggest that chronic COX-2 inhibition lessens the histologic severity of experimentally induced CP. A single dose of rectal indomethacin (a COX-2 inhibitor) prevents acute post-ERCP pancreatitis (PEP), implying that COX-2 inhibition can prevent pancreatic inflammation in humans. Indomethacin (IN) is potentially suitable for use in CP, however the pharmacodynamics of this drug in human pancreas is poorly studied. There are no data regarding the IN dose required for steady-state inhibition of human pancreatic COX-2 activity. Pancreas juice (PJ) can be collected during GI endoscopy and assayed for PGE2, providing a safe and minimally invasive method of assessing pancreatic COX-2 activity. The objectives of this study are: 1) to assess the physiologic effect of orally administered IN on pancreatic juice PGE2 concentrations, 2) to correlate drug-induced changes in pancreatic juice PGE2 levels with changes in salivary and blood PGE2 levels, blood IN levels, and changes in patient- reported pain outcome (PRO) and quality of life (QOL), and 3) to establish a basis for subsequent multicenter clinical trials of chronic COX-2 inhibition in CP. To accomplish these objectives a pilot blinded, randomized clinical trial will be performed enrolling 32 patients with CP, who will be randomized to receive 28 days of a standard dose of oral IN (50 mg BID) (16 subjects) vs. placebo (16 subjects). PJ PGE2 concentrations will be measured at baseline and after 28 days of study drug administration. Pain and QOL will also be assessed at baseline and day 28 using the Brief Pain Inventory (BPI) and PROMIS-10 questionnaires as well as daily pain and medication diaries. Blood and salivary PGE2 levels and blood IN levels will also be measured and correlated to PJ PGE2 concentrations. Results of this trial will inform the design of subsequent studies of longer-term, daily NSAID administration to patients with CP, and determine whether changes in salivary and/or blood PGE2 levels are adequate for monitoring the effect of IN on pancreatic COX-2 activity. Identification of a disease-modifying medical treatment for CP will be a major clinical advance impacting the health of p...