Chasing the Wrong Door for 30 Years: Is Suzetrigine the Key to Selective Pain Relief?

For a long time, pain management has relied on relatively old opioids and broad-spectrum non-opioids, which display efficacy gaps and non-negligible safety risks. This review explores why voltage-gated sodium channels, particularly NaV1.7 and NaV1.8, emerged as prime targets for pain relief, and why early development efforts failed. NaV1.7 was initially considered a promising target due to its role in nociception and genetic evidence linking it to pain disorders. However, clinical trials of selective NaV1.7 inhibitors have repeatedly failed. We explore the reasons for these failures and discuss the clinical shortcomings of non-selective blockers and early NaV1.7 inhibitors. In contrast, NaV1.8 has emerged as a much stronger drug target, because it is mostly limited to peripheral nerves, directly drives continuous pain signaling, and shows less apparent functional redundancy in specific nociceptive axonal compartments. Nevertheless, compensatory mechanisms involving NaV1.7, NaV1.9, and other conductances remain context-, tissue-, and disease-dependent. Suzetrigine, a highly selective inhibitor of this channel, recently gained regulatory approval for acute pain, marking a major breakthrough in non-opioid options, even though its Phase 3 efficacy was comparable to hydrocodone/acetaminophen rather than superior to it. Its clinical success is built on high selectivity, excellent pharmacokinetics, and a smart trial design that focused specifically on standardized postoperative pain models. While suzetrigine shows that NaV1.8 can be successfully targeted, it represents a regulatory and mechanistic victory rather than a complete replacement for opioids in daily practice. Progress in this field will ultimately require precise targeting, better pharmacology, and trials that better match patient phenotypes.