Suzetrigine for acute postoperative pain — FDA Approves novel non-opioid medication

Authors: Bertoch T; D’Aunno D; McCoun J; Solanki D; Taber L; Urban J; Oswald J; Swisher MW; Tian S; Miao X; Correll DJ; Negulescu P; Bozic C; Weiner SG

Affiliation: Multicenter US Trial (sponsored by Vertex Pharmaceuticals)

Journal: Anesthesiology, March 2025

PMID: 40117446

Key takeaways

• JOURNAVX (suzetrigine) was FDA approved on January 30, 2025, with the official indication: treatment of moderate to severe acute pain in adults.

• First‑in‑class oral, selective NaV1.8 inhibitor (non-opioid) studied for moderate‑to‑severe acute pain after abdominoplasty and bunionectomy.

• Primary endpoint (vs placebo) was met in both trials (SPID48 superiority).

  • SPID48 = summed pain intensity difference over 48 h: time‑weighted area under the curve of pain‑score reduction from baseline; higher values = more total relief.

• Overall 48‑h analgesia comparable to hydrocodone/acetaminophen (HB/APAP).

• Lower nausea/vomiting than HB/APAP; adverse events mostly mild–moderate.

Background

Opioids remain common for moderate–severe postoperative pain despite tolerability and dependency concerns. Targeting peripheral sodium channel NaV1.8 offers analgesia without central opioid liabilities.

Objective

Evaluate whether suzetrigine provides superior 0–48 h pain relief (SPID48) versus placebo and compare outcomes to HB/APAP; assess onset of meaningful relief.

Methods

• Design: Two randomized, double‑blind, placebo‑ and active‑controlled phase 3 trials (NAVIGATE‑1 bunionectomy; NAVIGATE‑2 abdominoplasty). Treatment window 48 h.

• Population: Adults (18–80) with moderate–severe pain (NPRS ≥4) post‑procedure. Randomization 2:2:1 to suzetrigine : HB/APAP : placebo.

• Intervention & comparators:

  • Suzetrigine: 100 mg loading, then 50 mg q12h (oral).

  • Active control: hydrocodone/acetaminophen 5/325 mg q6h.

  • Rescue: ibuprofen 400 mg q6h PRN.

  • Double‑dummy blinding.

• Endpoints:

  • Primary: SPID48 vs placebo.

  • Key secondary: SPID48 vs HB/APAP; time to ≥2‑point NPRS reduction vs placebo.

  • Safety and adverse events.

Results

• Primary endpoint (SPID48): Suzetrigine was superior to placebo in both trials on the SPID48 measure (greater time‑weighted pain relief over 0–48 h).

• Versus HB/APAP: No superiority on SPID48; overall analgesia at 48 h was similar.

• Onset: Faster time to clinically meaningful pain relief vs placebo.

• Safety: AEs mostly mild–moderate; lower nausea/vomiting than HB/APAP. Common AEs ≥4% included nausea, constipation, headache, dizziness, hypotension, and vomiting. Serious AEs were uncommon and balanced.

Mechanism of action

• Suzetrigine selectively inhibits NaV1.8, a voltage‑gated sodium channel expressed on peripheral sensory nociceptors.

• NaV1.8 drives nociceptor excitability and action‑potential firing in inflammatory tissue; selective peripheral blockade reduces pain transmission while sparing central nervous system sodium channels (e.g., NaV1.1/1.6), aiming to avoid respiratory depression, euphoria, and addiction liability associated with opioids.

• Unlike nonselective sodium‑channel blockers, NaV1.8 selectivity is designed to preserve motor function and minimize CNS effects.

Contraindications

• CYP3A / grapefruit: Contraindicated with strong CYP3A inhibitors. Avoid grapefruit (CYP3A inhibition ↑ exposure).

• Oral contraceptives: May reduce efficacy; use nonhormonal backup during therapy and for 28 days after.

• Hepatically cleared; avoid in severe hepatic impairment, reduce dose in moderate impairment

Dosing

• Loading: 100 mg PO once (two 50‑mg tablets).

• Maintenance: 50 mg PO q12h for up to 48 h (3–4 maintenance doses).

• Typical course: 5–6 total tablets depending on whether a final 48‑h dose is given.

Pricing

• $15.50 per 50‑mg tablet.

• 6‑tablet course (includes 48‑h dose): $93.00.

Safety profile

• Common AEs: nausea, headache, dizziness, constipation, vomiting; generally mild–moderate.

• Serious AEs: rare and balanced across arms in trials.

• GI tolerability: less nausea/vomiting than HB/APAP.

• CNS/respiratory: No signal of opioid‑type respiratory depression in the controlled 48‑h setting.

Clinical relevance

• Consider suzetrigine (JOURNAVX) as a nonopioid anchor in multimodal protocols in patients prone to opioid‑related nausea/constipation or opioid addiction. 

• Use the simple 100 mg load → 50 mg q12h regimen for a 48‑h course.

• Current evidence addresses acute postoperative pain up to 48 h; data for chronic pain or longer courses are limited.