What was the outcome of the phase 3 NAVIGATE trials comparing suzetrigine with hydrocodone bitartrate (Hydrocodone)/acetaminophen for the treatment of acute pain after abdominoplasty or bunionectomy in adults?

NAVIGATE Phase 3 Trial Outcomes: Suzetrigine vs. Hydrocodone/Acetaminophen

Suzetrigine successfully achieved its primary endpoint of superior pain reduction versus placebo in both NAVIGATE trials, demonstrating statistically significant and clinically meaningful pain relief after abdominoplasty and bunionectomy, but failed to demonstrate superiority over hydrocodone bitartrate/acetaminophen—the key secondary endpoint—meaning pain reduction with suzetrigine was similar to, not better than, the opioid comparator. 1

Primary Endpoint Results: Suzetrigine vs. Placebo

Both trials met their primary endpoint with robust statistical significance:

• Abdominoplasty trial (n=1,118): Suzetrigine showed a least squares mean difference in SPID48 (time-weighted sum of pain intensity difference over 48 hours) of 48.4 points versus placebo (95% CI: 33.6 to 63.1; P < 0.0001) 1

• Bunionectomy trial (n=1,073): Suzetrigine demonstrated a least squares mean difference in SPID48 of 29.3 points versus placebo (95% CI: 14.0 to 44.6; P = 0.0002) 1

These results represent clinically meaningful pain reduction, as differences exceeding 30 points on SPID48 are generally considered clinically significant in acute pain models 1

Key Secondary Endpoint: Suzetrigine vs. Hydrocodone/Acetaminophen

Neither trial achieved the first key secondary endpoint of superiority versus hydrocodone bitartrate/acetaminophen (5/325 mg every 6 hours) on SPID48. 1 This means that while suzetrigine was effective, it did not provide statistically superior pain relief compared to the opioid combination over the 48-hour treatment period 1

Time to Clinically Meaningful Pain Relief

For the second key secondary endpoint, suzetrigine demonstrated more rapid onset of clinically meaningful pain relief (≥2-point reduction in numeric pain rating scale) versus placebo:

• Abdominoplasty: 119 minutes with suzetrigine vs. 480 minutes with placebo (nominal P < 0.0001) 1
• Bunionectomy: 240 minutes with suzetrigine vs. 480 minutes with placebo (nominal P = 0.0016) 1

This faster onset represents a clinically relevant advantage, as patients experienced meaningful pain relief 6-8 hours sooner than placebo 1

Safety and Tolerability Profile

Adverse events with suzetrigine were similar to those seen in typical postsurgical settings and were predominantly mild to moderate in severity. 1 This contrasts with the known safety concerns of opioids, including respiratory depression, sedation, and addiction potential 1, 2

Suzetrigine's mechanism—selective inhibition of voltage-gated sodium channel NaV1.8 expressed exclusively in peripheral nociceptors—means it does not cross the blood-brain barrier and lacks CNS side effects or addictive potential associated with opioids 2, 3

Clinical Interpretation and Context

The NAVIGATE trials demonstrate that suzetrigine provides non-inferior analgesia to hydrocodone/acetaminophen for moderate-to-severe acute postoperative pain, offering a non-opioid alternative without addiction risk. 1 While suzetrigine did not prove superior to the opioid comparator, achieving equivalent efficacy without opioid-related risks represents a significant clinical advance 1, 2

This positions suzetrigine as a viable first-line option in multimodal analgesia regimens for acute postoperative pain, consistent with guideline recommendations to minimize opioid use. 4, 5 Current guidelines emphasize that opioids should be reserved strictly as rescue medication when non-opioid therapy fails 4, making suzetrigine's non-opioid profile particularly valuable 2

Common Pitfalls to Avoid

Do not interpret the failure to achieve superiority over hydrocodone/acetaminophen as indicating suzetrigine is ineffective—the trials clearly demonstrated robust efficacy versus placebo with clinically meaningful pain reduction 1. The comparison to hydrocodone/acetaminophen was a high bar, as this opioid combination is highly effective for acute pain 6

Recognize that suzetrigine's value lies in providing comparable analgesia without opioid-related morbidity—including respiratory depression, sedation, constipation, and addiction potential—which are critical considerations for patient safety and quality of life 2, 3