Objective:

Evaluate analgesic efficacy, onset and safety of LTG-001, a selective NaV1.8 inhibitor, in patients with moderate to severe pain after abdominoplasty.

Background:

The opioid crisis remains a public health emergency. Acute pain treatment is a common point of first opioid exposure, but existing nonopioid analgesics lack adequate efficacy and tolerability. Selective NaV1.8 inhibition has recently emerged as a novel non-opioid analgesic mechanism. This study tested LTG-001, a NaV1.8 inhibitor, in acute pain after abdominoplasty, a well-validated postoperative pain model. 

Design/Methods:

Pivotal, randomized, double-blind, double-dummy, placebo- and active-controlled, dose-ranging trial in adults with moderate-to-severe post-abdominoplasty pain. Participants were randomized 1:1:1:1 to oral LTG-001 high dose (450mg loading +300mg q12h; n=86), low dose (300mg loading +150mg q12h; n=85), hydrocodone/acetaminophen 5/325mg q6h (opioid reference; n=86), or placebo (n=86) for 48 h; oxycodone 5mg q6h was permitted as rescue. Primary endpoint was time-weighted SPID0-48 (assessed by Numeric Pain Rating Scale).

Results:

343 participants received >=1 dose; 328 (95.6%) completed the study. High-dose LTG-001 improved SPID0-48 vs placebo (LS mean difference 62.1; p<0.001); as did low-dose (37.8; p=0.003). Placebo-adjusted SPID0-48 was 40.9 for the opioid reference (p=0.001); effect was ~50% larger for LTG-001 vs opioid reference. Median time to meaningful relief (>=2-point NPRS reduction) was 51.7 min with high-dose LTG-001 vs 87.5 min for placebo and 82.8 min for opioid reference. 52.4 % of patients receiving high dose and 49.4% receiving low dose remained opioid-free, vs. 22.1% for placebo. LTG-001 was safe and well-tolerated, with fewer TEAEs for LTG-001 vs. placebo. TEAEs were mostly mild/moderate. No LTG-001-treated participants discontinued due to AEs (vs 4.7% opioid reference).

Conclusions: