Suzetrigine’s 2025 approval validated NaV1.8 as a pain target, but the drug missed its endpoint against hydrocodone/acetaminophen, and human neuron studies showed it dampens nociceptor firing without eliminating it—raising doubts about how effective NaV1.8 inhibitors can be. New Phase 2b data on LTG-001, a NaV1.8 inhibitor from a separate program, suggests those limits reflect molecule design and drug exposure rather than the target itself: In the same surgical pain model, it outperformed the opioid comparator by roughly 50%. This review examines the biophysics, human tissue data and clinical results behind both drugs, weighs what a cross-trial comparison can support, and highlights two findings visible only in native human neurons—with direct implications for how peripheral analgesics get screened and developed.