Published July 29, 2026
N Engl J Med 2026;395:454-464
DOI: 10.1056/NEJMoa2602910
Abstract
Background
Nav1.8, a voltage-gated sodium channel expressed in the peripheral nervous system, has a critical role in pain signaling. Previous trials of NaV1.8 inhibitors have shown effectiveness in reducing postoperative pain.
Methods
We conducted a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate LTG-001, a selective Nav1.8 inhibitor, in patients with moderate-to-severe pain after abdominoplasty. Patients were randomly assigned in a 1:1:1:1 ratio to receive a 300-mg loading dose of LTG-001, followed by 150 mg every 12 hours (low-dose group); a 450-mg loading dose of LTG-001, followed by 300 mg every 12 hours (high-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen) every 6 hours; or placebo every 6 hours. All doses were administered orally over a 48-hour period. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour treatment period (SPID48), based on scores on the Numeric Pain Rating Scale (range, 0 to 10, with higher values indicating more severe pain; higher SPID48 values indicate greater pain reduction). Secondary end points included the amount of opioid rescue medication consumed in morphine milligram equivalents (MME) and no receipt of opioid rescue medication.
Results
A total of 343 patients underwent randomization. The least-squares mean SPID48 was 161.05 (95% confidence interval [CI], 142.93 to 179.16) in the low-dose group, 185.30 (95% CI, 167.26 to 203.34) in the high-dose group, 164.08 (95% CI, 146.02 to 182.14) in the hydrocodone bitartrate–acetaminophen group, and 123.22 (95% CI, 105.23 to 141.21) in the placebo group. The least-squares mean difference in the SPID48 between LTG-001 and placebo was significant for each dose (low dose: 37.82 [P=0.003]; high dose: 62.08 [P<0.001]), and that between hydrocodone bitartrate–acetaminophen and placebo was 40.86. High-dose LTG-001, but not low-dose LTG-001, was associated with significantly lower opioid use than placebo (11.00 MME vs. 18.35 MME, P=0.01), as well as a significantly higher percentage of patients who received no opioid rescue medication (52% vs. 22%, P<0.001). High-dose LTG-001 was associated with a higher incidence of pyrexia than placebo (7% vs. 2%) and a higher incidence of presyncope (6% vs. 1%).
Conclusions
LTG-001 led to significantly greater reductions in pain scores than placebo over the course of 48 hours after abdominoplasty. (Funded by Latigo Biotherapeutics; LTG-001-010 ClinicalTrials.gov number, NCT07102459.)
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Notes
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by Latigo Biotherapeutics.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the trial participants, investigators, site staff, and support staff; Bryan Moyer, Ph.D., and John Gilchrist, Ph.D., of Latigo Biotherapeutics, for nonclinical pharmacology discussions; Holly Carlisle, Ph.D., of Latigo Biotherapeutics, for clinical pharmacology discussions; and Amy W. Rachfal, Ph.D., of Stage Gate Partners, for medical writing assistance.
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History
Published online: July 29, 2026
Published in issue: July 30, 2026
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Facts Only
* The trial was a phase 2b, double-blind, randomized, placebo-controlled study.
* The intervention was LTG-001, a selective Nav1.8 inhibitor, tested in patients with moderate-to-severe pain after abdominoplasty.
* Patients were assigned in a 1:1:1:1 ratio across four treatment arms.
* Dose regimens included low-dose (300 mg loading, 150 mg q12h), high-dose (450 mg loading, 300 mg q12h), hydrocodone bitartrate–acetaminophen every 6 hours, or placebo every 6 hours over 48 hours.
* The primary endpoint was SPID48, the time-weighted sum of pain-intensity difference over 48 hours.
* Mean SPID48 scores were: 161.05 (low-dose LTG-001), 185.30 (high-dose LTG-001), 164.08 (hydrocodone group), and 123.22 (placebo group).
* The difference in SPID48 between LTG-001 and placebo was significant for both doses (low dose: 37.82 [P=0.003]; high dose: 62.08 [P<0.001]).
* High-dose LTG-001 was associated with lower opioid use (11.00 MME vs. 18.35 MME for placebo; P=0.01) and a higher rate of no opioid rescue medication receipt (52% vs. 22%; P<0.001).
* High-dose LTG-001 was associated with increased pyrexia (7% vs. 2%) and presyncope (6% vs. 1%) compared to placebo.
Executive Summary
Full Take
The trial demonstrates that targeted inhibition of Nav1.8 can provide significant pain relief beyond the effects observed in placebo groups following abdominoplasty. The differential response across dose levels suggests a complex pharmacology where higher doses yield greater pain reduction and reduced reliance on rescue opioids, yet this benefit is accompanied by increased incidence of transient side effects like pyrexia and presyncope. This highlights a crucial tension in pain management: achieving substantial analgesia versus managing potential adverse events.
The finding that high-dose LTG-001 correlated with lower opioid consumption and less need for rescue medication suggests a pathway where channel modulation directly impacts endogenous pain signaling pathways, potentially reducing the need for exogenous opioids. However, the concurrent increase in febrile and syncope rates introduces an important layer of trade-off; efficacy appears linked to increased physiological fluctuation, raising questions about the safety margin when modulating fundamental ion channels during acute post-surgical recovery.
This pattern forces consideration of what constitutes "successful" pain management: maximizing pain reduction (SPID48) or minimizing analgesic burden (opioid use). The observed dose-dependent effects on both efficacy and adverse events suggest that the optimal therapeutic window for Nav1.8 modulation is narrow, necessitating further investigation into the interplay between sodium channel activity, peripheral nociception, and autonomic regulation in post-operative pain states. What are the long-term implications of this trade-off for patient outcomes?
Sentinel — Human
The text exhibits the highly structured, precise language characteristic of published medical research reporting, indicating a strong likelihood of human origination.