Neurophysiological, Radiological, and Molecular Biomarkers of Pain-Related Conditions: An Umbrella Review

<b>Background/Objectives</b>: Pain and pain-related conditions are considered a global health and financial burden. In order to improve pain management, pain intensity assessment, and pain diagnosis, various biomarkers have been proposed. Since their clinical utility is not proven yet, the aim of this umbrella review is to synthesize existing evidence of all types of pain biomarkers available. <b>Methods</b>: Systematic searches were conducted in PubMed, Scopus, and the Cochrane Library from inception to 2 June 2025. Eligible studies were systematic reviews and meta-analyses examining any clinical, biochemical, genetic, neurophysiological, or imaging biomarker related to pain. The screening of studies, data extraction, and assessment of methodological quality using the AMSTAR-2 tool were conducted by two independent reviewers. Findings were summarized narratively. <b>Results</b>: A total of 49 systematic reviews and meta-analyses were included. Most reviews were rated as low or critically low quality. Inflammatory biomarkers (CRP, IL-6, TNF-α) reported the most consistent associations with chronic musculoskeletal pain, while neuroimaging and EEG measures reflected central nervous system alterations. Proteomic multi-protein panels demonstrated exploratory diagnostic potential, particularly for fibromyalgia, but lacked clinical validation. Evidence for genetic, hormonal, metabolic, neurochemical, and tissue-specific biomarkers was inconsistent and methodologically limited, supporting mechanistic rather than clinical inference. <b>Conclusions</b>: No single biomarker has achieved clinical validation for chronic pain, but several biomarker classes show promise. Future implications include high-quality longitudinal studies, standardized protocols, and multidimensional biomarker panels.