Vascular Pain as a Model of Mixed Pain: A Systematic Review and Meta-Analysis Protocol

Background: Pain associated with vascular disorders has traditionally been regarded as predominantly nociceptive, resulting from ischemia, inflammation, and tissue injury. However, emerging evidence indicates that neuropathic and nociplastic processes frequently coexist, giving rise to a complex, mixed-pain phenotype. This multidimensional nature of vascular pain reflects overlapping mechanisms of peripheral nerve injury, neuroinflammation, and central sensitization, which may explain the limited efficacy of purely nociceptive-oriented therapies. Objective: This protocol describes the methods for a systematic review and meta-analysis aimed to determine the pooled prevalence of nociceptive and neuropathic pain features in patients with vascular pain, to synthesize current evidence supporting nociplastic mechanisms, and to evaluate treatment outcomes according to mechanistic categories of intervention. Methods: This protocol outlines a comprehensive search strategy to identify observational and interventional studies involving adult patients with arterial, venous, or mixed vascular pain. Meta-analyses will estimate pooled prevalence rates of neuropathic pain features and aggregate effect sizes for pain reduction and responder rates, stratified by causal vascular, pharmacological, and neuromodulatory treatments. Risk of bias will be assessed using validated tools, and the certainty of evidence will be graded according to GRADE recommendations. Detailed eligibility criteria, data extraction procedures, and statistical analysis plans are specified. Discussion: The findings from this planned systematic review and meta-analysis will enhance understanding the mechanistic composition of vascular pain, promoting mechanism-based analgesic approaches, guiding personalized treatment strategies, and informing future health-economic evaluations. The protocol is registered in PROSPERO (CRD420251132877).