From Nociception to Function: The Principles of MSK Pain and Selection of Appropriate Outcome Measures in Clinical Trials

Abstract Genicular artery embolization (GAE) has emerged as a minimally invasive therapy for knee osteoarthritis (OA) with encouraging early safety and efficacy data. However, interpretation of outcomes in broader transarterial musculoskeletal embolization (TAME) research is limited by an incomplete understanding of OA pain mechanisms, heterogeneity in pain phenotypes, and uncertainty regarding predictors and characterization of treatment response. This review synthesizes the structural, biologic, and neural mechanisms underlying OA pain, emphasizing the whole-joint disease model and the coexistence of nociceptive, neuropathic, nociplastic, and psychosocial pain mechanisms. We examine how these phenotypes influence expected response to TAME and review patient-reported outcome measures, imaging findings, and emerging biomarker data used in existing GAE trials. Particular attention is given to limitations of currently utilized treatment response thresholds and the impact of placebo-related effects in minimally invasive pain intervention trials. Finally, we outline priorities for future clinical trial design, including utilization and validation of robust, TAME-specific outcome thresholds, standardized and phenotype-informed enrollment, and expanded use of imaging and biomarkers. Improved trial design can improve signal detection, refine patient selection, and better define the role of TAME within multidisciplinary OA care.