Potential of Vagus Nerve Stimulation to Modulate Fibromyalgia's Network Physiology: A Systematic Review

Background: Chronic pain conditions such as fibromyalgia syndrome (FMS) reflect maladaptive network physiology across perceptual-autonomic-immune axes, yet most treatments remain symptomatic and incompletely effective. Methods: We conducted a comprehensive systematic review to evaluate vagus nerve stimulation (VNS) and FMS within a network physiology framework. PubMed, Embase, and Cochrane CENTRAL were searched on October 24, 2025. Risk of bias was assessed using the ROB-2 tool. An iterative thematic synthesis was performed to develop an integrative conceptual framework and to identify knowledge gaps and future research directions. Results: We first summarize physiological evidence showing autonomic imbalance (e.g., decreased heart rate variability), neuroinflammatory activation, and aberrant cortical network connectivity in FMS, supporting a network-dysregulation model. We then included 6 studies (4 clinical studies and 2 protocols) on VNS effects, highlighting improvements in pain, fatigue, sleep disturbance and autonomic regulation, along with emerging mechanistic insights. Key methodological heterogeneity-such as stimulation parameters, outcome metrics, type of control arm, sham definition, and small samples-limits current interpretability. Finally, we outline a research agenda centered on network-based biomarkers, immunophenotyping, adaptive trial designs and stratification of responders, with the aim of validating taVNS as a scalable neuromodulatory intervention for FMS. Conclusions: By reframing FMS from a symptom-centric pharmacologic model to a network-centric neuromodulation approach, taVNS is a promising tool for mechanism-based therapeutics in central sensitization syndromes and chronic pain.