Prurigo Nodularis and the Pain Cascade: Understanding the Pathogenesis and Approach to Management

Prurigo nodularis (PN) is a chronic inflammatory dermatologic condition characterized by symmetrically distributed, intensely pruritic, hyperkeratotic nodules. This review aims to explore the role of the central and peripheral nervous systems in PN, focusing on the pain cascade pathway and its implications for novel therapeutic approaches.

A review of the literature on PN and the pathophysiology of the pain cascade was performed. Original and review articles published before April 1, 2025, were evaluated for relevance.

The pathophysiology of PN involves repetitive scratching that leads to skin thickening and an exaggerated immune response, with key roles played by eosinophils, helper T (Th) cell 2 cytokines (interleukin [IL]-4, IL-13, IL-31), and neuroimmune interactions that perpetuate the itch-scratch cycle and the pain cascade. Management requires a multimodal approach including behavioral strategies, topical corticosteroids, intralesional therapies, and phototherapy. Systemic treatments, ranging from immunosuppressants and neuromodulators to targeted biologics, are often necessary due to the refractory nature of PN. Monoclonal antibodies such as dupilumab and nemolizumab, which target specific cytokine pathways, have significantly advanced treatment options. Ongoing trials with emerging agents emphasize the importance of immunomodulation in transforming PN care and guiding future therapies.

PN is a chronic dermatologic condition that severely impacts quality of life. Emerging research into its pathophysiology indicates immune and neuronal dysregulation. Recent therapeutics have changed the standard of care for patients with PN. Continued future research into pathophysiology and the pain cascade can inform development of additional novel therapeutics.