Pathophysiology of pain in acute pancreatitis: A narrative review

Pain affects between 80 and 95% of patients with acute pancreatitis (AP). However, despite its importance and severity, the pathophysiological mechanisms are not well understood. This narrative review aims to review current knowledge about the pathophysiological mechanisms of pain in AP.

A search of electronic databases (PubMed/MEDLINE, Embase, and Cochrane) was conducted from January 31 2024 to July 25 2025. Inclusion criteria included any study on acute pancreatitis and pain (management). Exclusion criteria included the absence of relevant content or specific information about pain in AP.

We identified 11 studies. Two potential pain pathways were identified, categorised as nociceptive and neuropathic. Nociceptive signals are enhanced through the release of inflammatory mediators, such as nuclear factor-kappa B, nitric oxide and interleukin-6, in response to tissue damage. Furthermore, the characteristic visceral and referred pain is likely attributed to high levels of overlap of primary sensory afferent fibre activation and neuronal convergence. Damage of the central and peripheral nervous system through the upregulation of voltage-gated ion channels, vanilloid receptors and transmembrane proteins may cause neuropathic-like pain. This triggers neurogenic inflammation and further release of neuropeptides, inducing an auto-amplification loop between neurogenic inflammation and neuropathic pain, with one positively reinforcing the other.

Diagnostic approaches in AP should consider nociceptive and neuropathic mechanisms, which should guide specific pain management. However, the knowledge gap remains significant, for example, for specific biomarkers and mechanisms enabling the development of target-specific personalised treatments for pain in AP in the future.

In 2023, the James Lind Alliance priority-setting partnership in pancreatitis indicated that the number one priority for AP is establishing more effective ways to manage pain.¹ Therefore, a complete comprehensive understanding of the pathophysiology of pain in AP should be obtained, to advise specific pain management guidelines in AP. This review is the first of its kind, attempting to synthesise the collective knowledge on pathophysiology of pain in AP.