Neurology · Medical Literature
Phase 2b Trial of a NaV1.8 Inhibitor for Acute Pain.
Abstract
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. 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. 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%). 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.).
Clinical relevance
Voltage-gated sodium channel NaV1.8 is a peripherally restricted, pain-selective target whose inhibition offers a mechanistically novel, non-opioid analgesic strategy. This Phase 2b trial addresses the critical unmet need for effective opioid-sparing analgesia in the acute postoperative setting, a domain where opioid dependence risk and inadequate pain control remain pervasive clinical challenges. Given the ongoing opioid crisis and the absence of new first-in-class analgesic approvals in recent decades, these findings are of immediate relevance to surgeons, anesthesiologists, and pain specialists managing moderate-to-severe acute pain.
Key findings
1. Primary endpoint (SPID48): High-dose LTG-001 (450 mg load → 300 mg q12h) achieved a least-squares mean SPID48 of 185.30 (95% CI, 167.26–203.34), representing a statistically significant difference from placebo (SPID48 123.22; 95% CI, 105.23–141.21) of +62.08 points (P<0.001). 2. Low-dose LTG-001 (300 mg load → 150 mg q12h) also demonstrated a significant improvement over placebo, with a least-squares mean SPID48 of 161.05 (95% CI, 142.93–179.16) and a difference from placebo of +37.82 (P=0.003). 3. Active comparator benchmark: Hydrocodone bitartrate–acetaminophen (5 mg/325 mg q6h) yielded a least-squares mean SPID48 of 164.08 (95% CI, 146.02–182.14), a difference from placebo of +40.86, placing it numerically between the low- and high-dose LTG-001 arms. 4. Opioid rescue medication consumption: High-dose LTG-001 significantly reduced mean opioid rescue use versus placebo (11.00 MME vs. 18.35 MME; P=0.01), whereas low-dose LTG-001 did not achieve significance on this endpoint. 5. Opioid-free analgesia rate: A significantly higher proportion of patients in the high-dose LTG-001 group required no opioid rescue medication compared to placebo (52% vs. 22%; P<0.001), demonstrating a clinically meaningful opioid-sparing effect. 6. Safety signals: High-dose LTG-001 was associated with higher rates of pyrexia (7% vs. 2%) and presyncope (6% vs. 1%) compared to placebo; the presyncope signal warrants cardiovascular monitoring given the sodium channel pharmacology.
Practice implications
If Phase 3 data confirm these findings, high-dose LTG-001 (450 mg loading dose followed by 300 mg orally every 12 hours for 48 hours) could be positioned as a first-line, non-opioid analgesic for moderate-to-severe acute postoperative pain, with efficacy numerically superior to standard-dose hydrocodone–acetaminophen and a dramatic opioid-sparing effect (52% of patients requiring no rescue opioids). Clinicians should prospectively monitor for presyncope and pyrexia with high-dose therapy, and patients with autonomic instability, orthostatic hypotension, or fever-sensitive comorbidities may warrant individualized risk-benefit assessment before initiation. The peripherally restricted mechanism of NaV1.8 inhibition suggests a favorable CNS safety profile compared to opioids or centrally acting analgesics, making this class particularly attractive for outpatient surgical settings where sedation and respiratory depression pose unacceptable risks.