- LTG-001, an investigational drug, reduced acute pain scores after abdominoplasty in a phase IIb trial.
- The high-dose of the sodium channel blocker was associated with significantly lower opioid use after surgery.
- Peripheral Nav1.8 blockers like LTG-001 may help manage pain with little to no risk of addiction.
The sodium channel blocker LTG-001, an investigational selective Nav1.8 inhibitor, reduced pain scores more than placebo for 2 days after abdominoplasty, a phase IIb trial showed.
The primary endpoint was the time-weighted sum of the pain intensity difference over a 48-hour treatment period (SPID48), based on numeric pain rating scale scores, which range from 0 to 10. Higher SPID48 values indicate greater pain reduction.
The mean SPID48 was 161.05 in the low-dose LTG-001 group, 185.30 in the high-dose LTG-001 group, 164.08 in the group treated with hydrocodone bitartrate-acetaminophen (Vicodin), and 123.22 in the placebo group, reported Neil Singla, MD, of Latigo Biotherapeutics in Thousand Oaks, California, and colleagues, in the New England Journal of Medicine.
Mean SPID48 differences between LTG-001 and placebo were significant 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.
Only high-dose LTG-001 was associated with significantly lower opioid use compared with placebo (11.00 vs 18.35 morphine milligram equivalents, P=0.01), Singla and colleagues said. The high-dose LTG-001 group also had a greater percentage of patients who received no opioid rescue medication (52% vs 22%, P<0.001).
High-dose LTG-001 achieved meaningful pain relief in less than 1 hour. Compared with placebo, high-dose LTG-001 was associated with a greater incidence of pyrexia (7% vs 2%) and presyncope (6% vs 1%).
While opioids can effectively manage acute pain, they come with a range of side effects and risk of abuse and addiction, Singla and co-authors noted. “However, 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,” they pointed out.
Inhibiting the peripheral voltage-gated sodium channel Nav1.8 may be a way to manage pain with little to no risk of addiction. In 2025, the FDA approved suzetrigine (Journavx), the first Nav1.8 blocker to treat 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, in 1987,” said Stephen Waxman, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, who wasn’t involved with the trial.
“That channel was subsequently cloned and then named Nav1.8. Its essential role in pain signaling within peripheral nerve — and lack of a role in the central nervous system — made it a focus in attempts to develop non-addictive pain medications,” Waxman told MedPage Today.
The LTG-001 study “adds to proof-of-principle that peripheral Nav1.8 blockers can provide analgesia in humans without the side effects or addictive potential of opioids,” he observed.
“The limited degree of pain relief with the new drug — about 2 points on the 10-point numerical rating scale — is similar to that reported earlier for suzetrigine,” Waxman noted. “Research in my laboratory suggests that this limited efficacy is not due to less-than-good drug design, but rather represents a ceiling on the effect of Nav1.8 suppression.”
The phase IIb trial of LTG-001 evaluated 343 patients with moderate-to-severe pain after abdominoplasty, randomly assigning them to one of four oral treatment regimens 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
Patients were excluded if they had current or long-term opioid use, or a history of chronic pain or psychiatric disorders that was not stable 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 with at least one adverse event. Nausea, headache, and dizziness were the most common adverse events in the study.
In clinical practice, acute pain is managed with multimodal treatments but this study evaluated LTG-001 as monotherapy, Singla and colleagues acknowledged.
“Furthermore, the vast majority of abdominoplasties are performed in women, a fact that was represented in our trial population, and patients with chronic pain conditions and previous use of opioids were excluded; these factors limit the external validity,” they wrote.
Latigo plans to launch a placebo-controlled phase III trial of patients undergoing bunionectomy, the company said.
