Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.