Neurophysiological Mechanisms of Neuropathic Pain and Their Clinical Implications

Abstract Chronic neuropathic pain is a serious and significant clinical challenge affecting more than 10% of the global population. Despite its prevalence, the precise mechanisms and reasons for the significant burden of neuropathic pain remain incompletely understood, in part due to the complexity of pain signaling circuits and their integration across the nervous system. Preclinical studies have identified 3 key intraneuronal processes that contribute to the persistent nociceptive barrage underlying neuropathic pain: ectopic discharges, primary afferent depolarization with dorsal root reflexes (PAD/DRRs), and autoreceptor-mediated excitation. Interventions that remove or silence the ectopic focus, restore normal inhibitory balance, or block specific ion channels involved in these mechanisms may dramatically improve outcomes. With a rising incidence of nerve injuries and amputations, the role for surgical and multidisciplinary interventions in managing chronic pain is expanding, making it critical for peripheral nerve surgeons treating these patients to understand these foundational mechanisms. The goal of this review is to synthesize our current understanding of these mechanisms, translating these insights into clinically relevant knowledge that may assist surgeons in patient counseling, treatment planning, and multidisciplinary care.