Investigational Nav1.8 Inhibitor Demonstrates Efficacy in Alleviating Post-Operative Pain

LTG-001, an investigational selective Nav1.8 inhibitor, demonstrated superior pain reduction compared to placebo for two days following abdominoplasty in a phase IIb clinical trial.

The study’s primary endpoint measured the time-weighted sum of the pain intensity difference over the 48-hour treatment period (SPID48), calculated using numeric pain rating scores ranging from 0 to 10, with higher SPID48 values reflecting more substantial pain relief.

As reported by Neil Singla, MD, of Latigo Biotherapeutics in Thousand Oaks, California, and colleagues in the New England Journal of Medicine, mean SPID48 scores were 161.05 for the low-dose LTG-001 group, 185.30 for the high-dose LTG-001 group, 164.08 for the hydrocodone bitartrate-acetaminophen (Vicodin) group, and 123.22 for the placebo group.

Significant differences in mean SPID48 between LTG-001 and placebo were observed for both the low dose (37.82, P=0.003) and the high dose (62.08, P<0.001); the mean SPID48 difference between hydrocodone bitartrate-acetaminophen and placebo was 40.86.

Singla and colleagues noted that only the high-dose LTG-001 regimen was linked to significantly reduced opioid consumption compared to placebo (11.00 vs 18.35 morphine milligram equivalents, P=0.01). Additionally, a greater proportion of patients in the high-dose LTG-001 group required no opioid rescue medication (52% vs 22%, P<0.001).

High-dose LTG-001 delivered meaningful pain relief in under one hour. However, it was associated with a higher incidence of pyrexia (7% vs 2%) and presyncope (6% vs 1%) compared to placebo.

Although opioids effectively manage acute pain, they carry numerous side effects alongside a risk of abuse and addiction. Singla and co-authors noted that “the marginal efficacy of non-opioid analgesics to manage moderate-to-severe pain, combined with side effects and coexisting conditions that limit their use, results in opioids continuing to be commonly prescribed.”

Targeting the peripheral voltage-gated sodium channel Nav1.8 represents a promising strategy for managing pain with minimal to no risk of addiction. In 2025, the FDA approved the first Nav1.8 blocker, suzetrigine (Journavx), for the treatment of moderate to severe acute pain, based on two phase III trials.

“We first reported a ‘slow’ sodium channel responsible for hyperactivity in human pain-signaling neurons back in 1987,” said Stephen Waxman, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, who was not involved in the trial.

“This channel was subsequently cloned and designated Nav1.8. Its critical role in peripheral nerve pain signaling—and its lack of involvement in the central nervous system—made it a primary target for developing non-addictive pain medications,” Waxman told MedPage Today.

The LTG-001 study “further validates proof-of-principle that peripheral Nav1.8 blockers can deliver analgesia in humans without the side effects or addictive potential associated with opioids,” he observed.

The modest degree of pain relief offered by the new drug—approximately 2 points on the 10-point numerical rating scale—is consistent with the relief reported earlier for suzetrigine, Waxman noted. “Research conducted in my laboratory indicates that this limited efficacy is not a result of inadequate drug design, but rather reflects a ceiling on the therapeutic effect of Nav1.8 suppression,” he explained.

The phase IIb trial of LTG-001 enrolled 343 patients experiencing moderate-to-severe pain following abdominoplasty, randomly assigning them to one of four oral regimens administered over 48 hours:

• Low-dose LTG-001: 300-mg loading dose, followed by 150 mg every 12 hours
• High-dose LTG-001: 450-mg loading dose, followed by 300 mg every 12 hours
• Hydrocodone-acetaminophen: 5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours
• Placebo: every 6 hours

Participants were excluded if they had current or long-term opioid use, or a history of chronic pain or unstable psychiatric disorders for at least 90 days. The mean age of participants was 40, and nearly all were women.

The high-dose LTG-001 group had the lowest percentage of participants experiencing at least one adverse event. The most common adverse events reported in the study were nausea, headache, and dizziness.

Singla and colleagues acknowledged that while acute pain is typically managed with multimodal treatments in clinical practice, this study evaluated LTG-001 as monotherapy.

“Furthermore, since the vast majority of abdominoplasties are performed in women—a demographic well-represented in our trial population—and because patients with chronic pain conditions or prior opioid use were excluded, these factors limit the external validity,” they wrote.

Latigo announced plans to launch a placebo-controlled phase III trial evaluating patients undergoing bunionectomy.

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