Purpose of Review <p>Traditional pain management of painful chronic pancreatitis (CP) follows a trial-and-error approach, often leading to long-term opioids and ineffective interventions. A precision medicine approach, tailoring treatment based on pain mechanisms, may allow a more targeted and rational use of interventions for painful CP. This review provides clinical pearls on how to diagnose each pain mechanism and presents a framework for mechanism-based management of CP.</p> Recent Findings <p>Pain from CP can be caused by nociceptive, neuropathic, and/or nociplastic mechanisms. These pain mechanisms are not mutually exclusive and can co-exist within the same individual. The mechanisms leading to pain on an individual patient can be determined using a combination of medical history, survey instruments, abdominal imaging, response to different therapies, quantitative sensory testing, neuroimaging, and complex genetics. Treatments should be tailored to the underlying pain mechanism: (A) analgesics, lifestyle modification, endoscopic procedures, and surgery for nociceptive pain; (B) gabapentinoids and celiac plexus block for neuropathic pain; and (C) non-pharmacologic interventions (e.g. exercise, cognitive behavioral therapy, yoga), antidepressants (e.g. duloxetine, amitriptyline), acupuncture and neuromodulation approaches for nociplastic pain.</p> Summary <p>A mechanism-based management of painful CP is feasible. However, there is a need to further refine the tools to diagnose pain mechanisms at the bedside and to develop more effective interventions for painful CP.</p>