Novel Nonopioid May Offer Acute Pain Relief

A novel nonopioid analgesic that targets a key pain-signaling pathway was associated with reduced acute postoperative pain and lower use of opioid rescue medication, a new study showed.In a randomized phase 2b trial in patients who underwent abdominoplasty, those who received the oral selective Nav1.8 inhibitor LTG-001 reported meaningful pain relief less than 1 hour after treatment and greater pain reduction over 48 hours than those who received a placebo.More than half of those receiving a higher dose of the experimental drug avoided rescue medication, compared with 22% of patients who received placebo.“The onset of pain relief is important to patients with acute pain and to prescribing clinicians because it reduces both the physiological consequences of pain and the risk of patients using extra doses of analgesics before the onset of meaningful pain relief,” lead investigator Neil Singla, MD, chief medical officer at Latigo Biotherapeutics in Thousand Oaks, California, and colleagues wrote.“Further investigation is warranted to confirm these results, characterize the efficacy and safety profile of LTG-001 in additional models of acute pain, and compare the relative efficacy of LTG-001 with that of other Nav1.8 inhibitors,” they added.The study was published online on July 29 in The New England Journal of Medicine.Investigating Nav1.8 InhibitorsNonopioid pain medications are available for acute pain management, but opioids remain widely used for moderate-to-severe pain because alternatives may not provide adequate relief or be limited by adverse effects (AEs).Nav1.8 is a voltage-gated sodium channel expressed in peripheral pain-sensing neurons, including nociceptors and neurons of the dorsal root ganglia, where it helps transmit pain signals. Since the channel is not expressed in the central nervous system (CNS), selective inhibition may provide analgesia without CNS-related side effects.While the FDA approved the first Nav1.8 inhibitor in 2025, questions about the efficacy of the drug class persisted.The new double-blind, randomized, placebo-controlled phase 2b trial included 343 adults undergoing elective lower abdominoplasty at four US sites. Patients were eligible if they developed moderate-to-severe postoperative pain within 4 hours of surgery, with a pain score of at least 5 on the 11-point Numeric Pain Rating Scale.Participants were randomly assigned in a 1:1:1:1 ratio to receive 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 bitartrate-acetaminophen (5 mg/325 mg every 6 hours), or placebo for 48 hours.The primary outcome was the time-weighted sum of pain-intensity difference over 48 hours. Secondary outcomes included opioid rescue medication use, the proportion of patients who did not require rescue opioids, time to meaningful pain relief, and safety outcomes.Pain Relief and SafetyCompared with placebo, both doses of LTG-001 were associated with a significant pain relief.Patients who received low-dose LTG-001 had a least squares mean difference in pain intensity of 161.05 compared with 185.30 in the high-dose group and 123.22 with placebo. The difference in pain intensity compared to placebo was 37.82 points for low-dose LTG-001 (P = .003) and 62.08 in the high-dose group (P < .001).The mean difference was numerically higher with high-dose LTG-001 than with hydrocodone bitartrate-acetaminophen (185.30 vs 164.08), although the trial was not designed to directly compare the two treatments.The high-dose LTG-001 group also reported lower opioid rescue medication use than placebo (11.00 morphine milligram equivalents vs 18.35; P = .01). Additionally, 52% of patients in the high-dose group did not need opioid rescue medication compared with 22% with placebo (P < .001).Meaningful pain relief, defined as a reduction of at least 2 points on the pain scale, occurred within a median of 51.7 minutes with high-dose LTG-001 vs 87.5 minutes with placebo.The safety profile was generally favorable, with most AEs rated as mild or moderate. The most common were nausea, headache, and dizziness. However, compared with placebo, high-dose LTG-001 was associated with higher rates of pyrexia (7% vs 2%) and presyncope (6% vs 1%).Whereas acute pain is commonly treated with multiple analgesic therapies, LTG-001 was evaluated as monotherapy. Other limitations included the predominantly female population undergoing abdominoplasty and the exclusion of patients with chronic pain or prior opioid use, which may limit the generalizability of the findings.From Trial to PracticeThe findings provide additional evidence supporting Nav1.8 as a viable target for pain treatment, said Stephen Waxman, MD, PhD, Bridget M. Flaherty Professor of Neurology and of Neuroscience at Yale School of Medicine in New Haven, Connecticut, who was not involved in the study.Stephen Waxman, MD, PhD“It adds to proof-of-concept that a peripheral sodium channel blocker can reduce pain in humans,” Waxman told Medscape Medical News.Nav1.8 is an intriguing therapeutic target because it plays a role in peripheral pain signaling but is not present in the brain, Waxman explained, potentially allowing analgesia without CNS side effects or addictive potential.Additional work is needed before these agents can become part of routine pain management, he cautioned.“The degree of pain relief provided by these agents, while statistically significant, is less-than-optimal,” Waxman said. “More effective pain relief may require combinatorial therapy.”It also remains unclear whether Nav1.8 inhibition will extend to chronic pain treatment, he added. “In a mechanistic sense, chronic pain may be different from acute pain.”The study was funded by Latigo Biotherapeutics. Disclosure information for study authors is available in the original study publication. Waxman reported no relevant financial relationships.