Inflammatory Biomarkers and Clinical Response to Spinal Cord Stimulation: A Scoping Review

Introduction: Despite widespread clinical use of spinal cord stimulation (SCS) for chronic pain, the absence of objective physiological markers of treatment response remains a barrier to advancing personalized neuromodulation. SCS is an FDA-approved neuromodulatory therapy for managing intractable pain in conditions such as failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS). While up to 70% of patients report substantial pain relief, the lack of widely adopted objective biomarkers limits the standardization of outcome assessment and demonstration of physiological effects across patient populations. SCS may exert its analgesic effects by dampening sympathetic overactivity and modulating descending neurogenic inflammatory pathways—processes linked to changes in pro- and anti-inflammatory cytokines, chemokines, adipokines, and growth factors, many measurable in peripheral blood. These biomarkers offer a promising path toward objective, physiologically-grounded indicators of efficacy. However, their associations with clinical outcomes differ across pain phenotypes and study designs. This scoping review synthesizes clinical evidence on SCS-related biomarker changes, explores their correlation with outcomes, and highlights knowledge gaps to inform future research.

Methods: We conducted a scoping review of PubMed, Scopus, Embase from inception to July 29, 2025, utilizing PRISMA-ScR guidelines. Full-length, peer-reviewed articles presenting original research in humans evaluating changes in inflammatory biomarkers after SCS to treat FBSS or CRPS were included. Studies were excluded if invasive SCS was not the primary intervention, inflammatory biomarkers were not reported, or original data were not presented (reviews, editorials, clinical trial protocols).

Results: Of 70 unique articles identified, 7 met the inclusion criteria. Six were prospective cohort studies in FBSS patients, and one was a double-blinded randomized controlled trial in CRPS. Publication dates ranged from 2013 to 2020. Biomarkers examined varied considerably across studies. Several reported increased anti-inflammatory markers (e.g., TGF-β, IL-10) relative to controls, with higher levels correlating with lower pain and disability scores. Reductions in pro-inflammatory cytokines, including IL-1β, IL-15, and IP-10, were also observed. Two studies reported a significant decrease in VEGF following SCS, while separate investigations of adipokines (leptin, adiponectin, ghrelin) and metalloproteinases found no consistent changes, except for an increase in metalloproteinase-2 in one study.

Conclusion: While heterogeneous and limited in scope, the available evidence supports a potential correlation between SCS, modulation of inflammatory biomarkers, and clinical improvement in chronic pain syndromes. Larger, well-controlled trials are needed to confirm these associations, define their magnitude, and assess the utility of biomarker monitoring in guiding patient selection and optimizing therapy.