Suzetrigine (VX-548) exhibits activity-dependent effects on human dorsal root ganglion neurons with differential pain etiology
Source: Pain
Authors: Megan L Uhelski, Mandee K Schaub, Felipe Espinosa, Mario Heles, Nicolas Cortes, Yan Li, Claudio E Tatsui, Lawrence D Rhines, Robert Y North, Christopher Alvarez-Breckenridge, Geoffrey Funk, Peter Horton, Anna Cervantes, Joseph B Lesnak, Michele Curatolo, Gregory Dussor, Theodore J Price, Patrick M Dougherty, Publication Date: Mon, 09 Mar 2026 06:00:00 -0400
Pain. 2026 Jun 1;167(6):1430-1439. doi: 10.1097/j.pain.0000000000003931. Epub 2026 Mar 2.
ABSTRACT
Nonselective antagonists of voltage-gated sodium channels (VGSCs) provide effective local analgesia, but systemic administration is fraught with unwanted cardiovascular and central nervous system toxicity. The development of antagonists targeting VGSCs preferentially expressed in peripheral neurons, such as Na V 1.7, 1.8, and 1.9, could mitigate these risks. One such new small molecule that selectively inhibits Na V 1.8, is orally bioavailable, and has recent FDA approval for the treatment of acute pain is suzetrigine (VX-548, brand name JOURNAVX). Here we tested the effects of this agent on human dorsal root ganglion neurons obtained from either patients undergoing surgical thoracic vertebrectomy or from organ donors in parallel electrophysiology studies across 2 laboratories. Bath application of 10 nM suzetrigine abolished spontaneous discharges previously shown to be associated with on-going neuropathic pain within minutes. In contrast, suppression of discharges evoked by intracellular current injection was moderate. These results suggest that suzetrigine will likely show efficacy vs spontaneous pain but may have less robust effects on evoked or breakthrough pain.
PMID:41800743 | DOI:10.1097/j.pain.0000000000003931
Pubmed ID: pubmed:41800743
Identifiers: pmid:41800743, doi:10.1097/j.pain.0000000000003931,
Paper chosen by Rajesh Khanna
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Selective NaV1.8 inhibitors promise effective analgesia without the cardiovascular and CNS toxicity of nonselective sodium-channel blockers, and suzetrigine (VX-548, Journavx) is the first such drug to win FDA approval for acute pain. Using human dorsal root ganglion neurons from vertebrectomy patients and organ donors, tested in parallel across two laboratories, Uhelski and colleagues found that 10 nM suzetrigine abolished spontaneous neuronal discharges (the activity linked to ongoing neuropathic pain) within minutes, while only moderately suppressing discharges evoked by current injection. This predicts that suzetrigine should work well against spontaneous pain but less reliably against evoked or breakthrough pain.
This finding speaks directly to the growing controversy over suzetrigine’s apparent efficacy ceiling. Trials have shown it did not outperform hydrocodone/acetaminophen, performed inconsistently across surgical models, and failed to beat placebo in a Phase 2 lumbosacral radiculopathy study, raising doubts about how much pain relief NaV1.8 blockade alone can deliver.
What makes this exciting: it offers a concrete cellular explanation for that ceiling, recorded in real human nociceptors rather than animal models, reframing suzetrigine’s limits as a spontaneous-versus-evoked signaling distinction and pointing toward combination or broader-spectrum strategies for breakthrough pain.