Exercise improves neuropathic pain: precision exercise prescription and multimodal synergy advance clinical applications

Abstract

BACKGROUND: Neuropathic pain is a chronic pain condition caused by direct damage or functional abnormalities in the somatic sensory nervous system. Its clinical manifestations include spontaneous pain and tactile hypersensitivity, which are difficult to control effectively with traditional drug therapies. The pathogenesis of neuropathic pain involves multiple physiological processes, including neuronal hyperexcitability, glial cell activation, neurotransmitter imbalance, immune responses, and oxidative stress. Existing medications and invasive treatments often carry side effects and exhibit significant limitations in efficacy. Therefore, exploring safe and effective non-pharmacological interventions, particularly exercise-based interventions for improving neuropathic pain, has become a critical research focus in the field of neuropathic pain. OBJECTIVE: To review advances in understanding the mechanisms of neuropathic pain, analyze the potential and mechanisms of exercise intervention in alleviating neuropathic pain, demonstrate the clinical application prospects of exercise as a non-pharmacological intervention strategy, and emphasize future research directions. METHODS: PubMed and CNKI databases were searched using Chinese and English keywords including neuropathic pain, nerve injury pain, exercise, physical activity, aerobic exercise, resistance training, yoga, pathogenesis, inflammation, neurotransmitter, neurotrophin, oxidative stress, and rehabilitation. A total of 139 articles were included. The core mechanisms of neuropathic pain were analyzed, focusing on the multi-target and multi-pathway synergistic effects of exercise in alleviating neuropathic pain. RESULTS AND CONCLUSION: The pathogenesis of neuropathic pain involves neuronal hyperexcitability, glial cell activation, neurotransmitter imbalance, immune-inflammatory responses, and oxidative stress-induced nerve damage. Exercise intervention alleviates neuropathic pain by regulating neurotransmitter release, promoting neurotrophic factor expression, inhibiting inflammatory responses, and reducing oxidative stress. Specifically, exercise upregulates the expression of neurotrophic factors such as brain-derived neurotrophic factor and nerve growth factor, inhibits the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha, and further regulates core pathways in neuropathic pain development. Exercise also produces analgesic effects by modulating the endogenous opioid system. The specific mechanisms of different exercise types on neuropathic pain need further investigation, and personalized exercise prescription design and exercise parameter optimization face many challenges. Future research should focus on constructing and validating exercise prescriptions, clarifying the synergistic effects of exercise combined with drug therapy, to support the advancement of clinical treatment for neuropathic pain.

1. Introduction

Neuropathic pain arises from direct damage or pathological changes in the somatic sensory nervous system, manifesting as spontaneous pain, tactile hypersensitivity, and hyperalgesia, often persisting long after initial injury healing [1-2]. At its core, neuropathic pain represents a pathological adaptive disorder of the nervous system, involving multiple interrelated mechanisms such as abnormal excitability of peripheral and central neurons, glial cell activation, disruption of neurotransmitter and neuromodulator balance, and persistent neuroinflammation [3-4]. These pathological processes not only amplify pain perception but also affect sensory, motor, and autonomic functions, frequently accompanied by significant anxiety and depression, severely reducing patients' quality of life [2,5]. Although key mechanisms from peripheral ectopic discharge to central sensitization in the spinal cord and brain regions have been progressively elucidated [4,6], clinical management of neuropathic pain remains challenging. First-line drugs such as anticonvulsants and antidepressants are effective only in a subset of patients and often cause intolerable central nervous system side effects, while opioids carry risks of addiction and tolerance [2,7]. Although neuromodulation and surgical interventions hold potential, their invasiveness, cost, and accessibility limit widespread application. Therefore, developing safe, effective, and easily implementable non-pharmacological interventions is an urgent clinical need.

In this context, exercise therapy has emerged as a significant non-pharmacological management strategy with accumulating evidence. Studies have demonstrated that regular exercise can modulate multiple pathways related to neuropathic pain, offering a promising adjunct or alternative to conventional treatments.