Mechanism-Based Management of Pain in Chronic Pancreatitis: An Integrated Narrative Review

Pain is the most frequent and debilitating manifestation of chronic pancreatitis (CP), substantially impairing quality of life and driving healthcare utilization. Despite advances in imaging and interventional therapies, effective pain control remains challenging because pain mechanisms are heterogeneous and often poorly correlated with the extent of structural pancreatic disease. Contemporary evidence indicates that CP-related pain arises from interacting nociceptive, neuropathic, and nociplastic pathways, shaped by pancreatic ductal obstruction, ongoing inflammation, neural remodeling, and central sensitization. This narrative review summarizes and contextualizes current evidence on the epidemiology, pathophysiology, and management of pain in CP, with a focus on a mechanism-based, multidisciplinary treatment approach. Conservative management, including lifestyle modification, nutritional optimization, pancreatic enzyme replacement for exocrine insufficiency, and stepwise analgesic and neuromodulatory pharmacotherapy, forms the cornerstone of care. Endoscopic and endoscopic ultrasound-guided interventions are beneficial in carefully selected patients with large-duct obstruction or identifiable nociceptive drivers but have limited efficacy in small-duct or centrally mediated pain. Surgical intervention offers the most durable pain relief in appropriately selected patients, particularly when undertaken early, before the establishment of central sensitization or opioid dependence; randomized trials support early surgery over prolonged endotherapy in painful obstructive CP. Recurrent pain following surgery is multifactorial and necessitates systematic reassessment to distinguish remediable structural disease from neuropathic or nociplastic pain. Overall, aligning therapeutic strategies with pancreatic ductal morphology and dominant pain mechanisms is critical to achieving sustained pain relief, minimizing opioid use, and improving long-term outcomes.