Unlocking Pain Therapeutics: How to Find the Right Target and Treatment Approach

The approval of the selective NaV1.8 inhibitor Suzetrigine for acute pain has renewed optimism for developing novel analgesics, yet the clinical failure of its successor VX993 highlights the persistent difficulty of translating promising pain targets into effective therapies. This review examines why progress has been limited and how modern human centered approaches can reshape pain drug discovery. Human genetic studies from large biobanks demonstrate that genetically supported targets have a higher likelihood of clinical success. However, for pain, the relationship between genetic association and therapeutic efficacy is complex. Rare mutations in NaV1.7 and NaV1.8 strongly validate these channels as valid pain targets, yet common variant studies reveal little association with chronic pain risk, underscoring a polygenic and pathway level architecture rather than single gene causation. Human transcriptomic atlases of dorsal root ganglia (DRG) reveal extensive redundancy across NaV channel isoforms, helping explain the modest efficacy of selective NaV1.8 inhibition and pointing toward the need for multi target or pathway wide approaches. Multiomic analyses in osteoarthritis highlight additional pain generating mechanisms, including synovial inflammation, neuroimmune interactions, metabolic dysregulation, and osteoclast activity, along with the involvement of specific nociceptor subtypes. Human DRG electrophysiology and PK/PD modeling show that Suzetrigine achieves high NaV1.8 target engagement yet cannot fully silence nociceptors, and that central not solely peripheral NaV1.8 channel blockade may be required for robust analgesia. This helps explain the failures of peripherally restricted NaV1.7, NaV1.8 and TRPA1 channel blockers. Despite limitations, animal models remain essential for capturing integrated physiological responses and active drug metabolites not evident in vitro. Together, these findings support a more rigorous framework for target validation, integrating human genetics, multiomics, electrophysiology, and translational pharmacology to guide the development of next generation of pain therapeutics.