Background: Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk for the development of pancreatic cancer. In addition to the symptoms that come from loss of endocrine and exocrine function in CP, management of chronic pain associated with CP is challenging. We previously showed that the cholecystokinin (CCK) receptor antagonist, proglumide, could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain of CP through its effects on the central and peripheral nervous systems.
Methods: A Phase 1 open-labeled safety study was conducted in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After enrollment, subjects entered a 4-week observation period where a daily pain diary and pain medications were recorded. Subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg/day) by mouth for 12-weeks, then followed 4 weeks after discontinuation for safety. Blood chemistries were drawn and three Pain surveys completed (Numeric pain scale, COMPAQ-SF, and NIH-PROMIS) before starting proglumide at the screening and baseline visits, and every 4 weeks while on proglumide. A blood microRNA (miR) biomarker panel that measures pancreatic inflammation and fibrosis was analyzed at baseline and again at week-12.
Results: Recruitment to the study was successful and 8 subjects were enrolled. The average age was 48 years (range: 21- 68y). The etiology of the CP included genetic alterations (N=5), autoimmune pancreatitis (N=1), alcohol (N=1) and hyperlipidemia (N=1). No abnormal changes were recorded in blood chemistries with proglumide, and the mean C-reactive protein levels decreased by 25% at week-12 compared to baseline. Two subjects noted nausea and diarrhea with proglumide which improved in one subject with a dose reduction to 800 mg/day, but the 2^nd subject dropped out in the 3^rd month. Pain scores from the surveys showed improvement with proglumide therapy compared to pretreatment scores: Numeric score: decreased by 53% (7.6±0.5 to 3.6±1.0; p=0.007); COMPAQ-SF: decreased by 30% (32.2±2.2 to 22.5±4.1; P=0.02) and NIH-PROMIS: decreased by 15% (66.3±1.6 to 56.5±4.1; P=0.01). Mean microRNA blood biomarkers changed significantly from baseline implying less pancreatic inflammation (miR-122-5p; miR-125-5p; miR-195-5p;miR-210-3p; and miR-224-5p) and less pancreatic fibrosis (miR-185-5p; miR-346-5p; and miR-378-3p).
Conclusion: The CCK-receptor antagonist, proglumide, appears to be safe and well tolerated by most subjects with CP at a dose of 800-1200 mg/day. Proglumide therapy may have a beneficial effect by decreasing the pain associated with CP. The change in the microRNA blood biomarkers suggests that proglumide therapy may also decrease pancreatic inflammation and reverse fibrosis.

Tarek Bakain

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