The rise and fall of TRPV1-targeted analgesia in osteoarthritis: a critical appraisal

INTRODUCTION: Transient receptor potential vanilloid 1 (TRPV1) has been pursued as a therapeutic target in osteoarthritis (OA) pain for over two decades. Both systemic antagonism and localized agonism advanced into clinical development, supported by mechanistic rationale and preclinical data. AREAS COVERED: We critically appraise TRPV1-targeted drug development in OA, examining the biological basis of the target, translational trajectories of antagonist and agonist programs, and clinical trial outcomes that define the current landscape. Literature was identified through a PubMed search for peer‑reviewed articles on TRPV1 and OA over the past 5 years, followed by manual selection of key references. We review why systemic TRPV1 antagonists were abandoned, and why intra-articular TRPV1 agonists, despite expedited regulatory designations, failed to meet primary endpoints in Phase III trials. EXPERT OPINION: TRPV1-targeted therapy in OA has completed a full translational cycle without yielding regulatory approval. The mechanistic rationale remains valid; what failed was clinical translation. Key contributors include over-reliance on preclinical models poorly capturing central sensitization, lack of stratification by peripheral versus central pain phenotypes, and use of composite pain endpoints in phenotypically mixed populations. The TRPV1 experience offers lessons for peripheral analgesic development in OA: patient phenotyping and enrichment must precede pivotal trials.