What information is available about the use of suzetrigine, an oral sodium channel blocker, for moderate to severe acute pain in adults?

Introduction

Background
Pain, as defined by the International Association for the Study of Pain (IASP), is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.”¹ Acute pain is sudden in onset and limited in duration to less than 1 month.² Unresolved acute pain can lead to chronic pain, which can occur for more than 3 months. Moderate to severe acute pain is usually related to traumatic injuries and surgeries.

The complex pathophysiologic process of pain involves various receptors, chemical substances, channels, and inflammatory mediators, which present pharmacologic targets for treatment.^3,4 These targets include voltage-gated sodium channels, which are present in 9 isoforms (Na_V 1.1–1.9). Due to an inability to selectively target a single isoform, analgesics targeting these channels have previously been administered locally to prevent off-target effects. One isoform, Na_V 1.8, is concentrated in the peripheral nervous system, where its function is to transmit pain signals. Investigators have previously hypothesized that a drug that targets Na_V 1.8 is unlikely to cause the same adverse effects as nonspecific sodium channel blockers.

Standard of care
To treat acute pain, clinicians aim to provide the greatest analgesic effect while minimizing adverse effects.^2,5,6 Pain treatment should be patient-centered and individualized, and clinicians should assess analgesic effect with a validated scale such as the numerical pain rating scale (NPRS) or visual pain rating scale (VPRS). Treatment should involve a multimodal approach, which refers to using nonpharmacologic modalities and multiple pharmacologic agents with different physiologic mechanisms of producing analgesia to effectively relieve pain. A goal of multimodal analgesia is to reduce opioid exposure and, therefore, reduce adverse effects associated with opioid use, particularly opioid use disorder and overdose. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are baseline therapies used to treat mild to moderate acute pain. In moderate to severe acute pain, opioids are often necessary in addition to these. However, there is an association between opioid use for acute pain and long-term opioid use. Therefore, providers should prescribe the lowest dose for no longer than the expected duration of pain that warrants their use. Some NSAIDs are indicated as monotherapy for moderate to severe pain, including celecoxib, ketorolac, or meloxicam.^7-9 However, the adverse effects of NSAIDs can limit their use in some patient populations. For postoperative pain, local anesthetics and gabapentinoids (eg, gabapentin, pregabalin) are additional adjunctive treatment options.^5,6

Drug Overview
On January 30^th, 2025, the Food and Drug Administration (FDA) approved suzetrigine, a first-in-class selective sodium channel inhibitor, for the treatment of moderate to severe acute pain.¹⁰ This new drug may present a useful tool in addressing certain limitations of the current standard of care. An overview of suzetrigine, including its FDA-approved indication and dosing, is provided in Table 1.

Mechanism of Action
Suzetrigine selectively inhibits the voltage-gated sodium channel isoform Na_V 1.8 by binding allosterically to the voltage-sensing domain 2 and stabilizing the closed state of the channel.^12,13 In contrast, local anesthetics block the inactivated and open states of multiple channel isoforms. The allosteric binding results in persistent inhibition of Na_V 1.8, which reduces pain signals in the peripheral nervous system. Due to this distinct mechanism, suzetrigine, in combination with non-specific sodium channel blockers (eg, bupivacaine, ropivacaine), demonstrates additive pharmacology. Suzetrigine inhibits Na_V 1.8 with a greater than 31,000-fold selectivity ratio and less than 0.1% inhibition of any other isoform. It is selective against 180 other human targets, including 44 targets associated with abuse potential. In animal studies, suzetrigine demonstrated no stimulant or sedative effects, and it is not similar to opioids or any known drug of abuse. Suzetrigine has a major active metabolite, M6-SUZ, which is a less potent inhibitor of Na_V 1.8 than suzetrigine.¹¹ Additional information on the pharmacokinetics of suzetrigine is provided in Table 2.

Safety Considerations
Cytochrome P450 3A (CYP3A) inhibition or the presence of hepatic impairment increases exposure to suzetrigine and its active metabolite, potentially causing adverse reactions.¹¹ Therefore, concomitant use of strong CYP3A inhibitors (eg, clarithromycin, azole antifungals, protease inhibitors) with suzetrigine is contraindicated, and it is recommended to avoid its use in patients with severe hepatic impairment. Suzetrigine is an inducer of CYP3A and may decrease the exposure, and therefore efficacy, of CYP3A substrates. Suzetrigine may reduce the efficacy of hormonal contraceptives containing progestins other than levonorgestrel and norethindrone. In clinical trials, adverse reactions that occurred more frequently with suzetrigine than placebo were pruritus, muscle spasms, increased blood creatine phosphokinase (CPK), and rash. Decreased estimated glomerular filtration rate (eGFR) was also observed more frequently with suzetrigine than placebo but appeared to be transient. Suzetrigine was not studied in patients with an eGFR less than 15 mL/min, in pediatrics, in pregnancy, or in lactation, so it should be avoided in these patient populations. Clinical studies included an insufficient number of geriatric patients to evaluate pharmacodynamic differences from younger patients, but pharmacokinetic analyses suggest age does not have a clinically relevant impact on suzetrigine exposure.

Literature summary
The efficacy and safety of suzetrigine are supported by data from 2 randomized, double-blind, multi-arm, placebo and active-controlled trials (NAVIGATE 1 and NAVIGATE 2).^11,14 Safety of suzetrigine is further supported by an open-label safety study.¹⁵ Results of these trials are summarized in Table 3.

In NAVIGATE 1 and NAVIGATE 2, adult patients with moderate to severe pain on the verbal categorical rating system and a pain score greater than 4 on the numeric pain rating scale (NPRS) who underwent bunionectomy (NAVIGATE 1) or abdominoplasty (NAVIGATE 2) were randomized to receive suzetrigine 100 mg orally for the first dose, followed by 50 mg orally every 12 hours, or hydrocodone/acetaminophen 5 mg/325 mg orally every 6 hours, or placebo, for a study duration of 48 hours.¹⁴ A double dummy design was used so participants received the same number of tablets every 6 hours. Analgesic medications were not permitted within 5 half-lives of admission. Perioperatively, fentanyl, midazolam, propofol, ropivacaine, and lidocaine could be used, dependent on the procedure. No pain treatments were administered after the first dose of the study drug, which was given within 4 hours of abdominoplasty completion (NAVIGATE 2) or within 9 hours of discontinuation of regional anesthesia following bunionectomy (NAVIGATE 1). The only rescue treatment that was permitted during the study period was ibuprofen 400 mg orally every 6 hours as needed. Pain intensity was recorded at 19 time points, ranging from half an hour to 4 hours apart, using an 11-point NPRS ranging from 0 to 10, with higher scores indicating greater pain intensity. In the pre-specified statistical analysis with imputation, scores in the subsequent 6 hours after rescue medication use were replaced by the pre-rescue score, to assess the effect of suzetrigine if the patient had not used rescue medication.

The primary endpoint for both trials was the difference between suzetrigine and placebo in the time-weighted sum of the pain intensity difference, as measured on the NPRS, from 0 to 48 hours (SPID-48), a validated, time-weighted composite that measures pain intensity differences from baseline.¹⁴ This endpoint gives greater weight to sustained pain relief with a higher SPID-48 value, indicating greater pain relief. In both trials, suzetrigine was more effective than placebo at increasing SPID-48. The difference in SPID-48 between suzetrigine and hydrocodone/acetaminophen was assessed as a key secondary endpoint. There was no significant difference between suzetrigine and hydrocodone/acetaminophen in increasing SPID-48 in either trial. Suzetrigine demonstrated a small, nonsignificant increase in SPID-48 compared to hydrocodone/acetaminophen after abdominoplasty, but after bunionectomy, hydrocodone/acetaminophen resulted in a higher SPID-48 than suzetrigine. Another key secondary endpoint was the time to onset of clinically meaningful pain relief, defined as a greater than 2-point reduction in NPRS. In the prespecified analysis, suzetrigine demonstrated clinically meaningful pain relief around 2 hours after abdominoplasty and within 4 hours after bunionectomy, compared to 8 hours for placebo in both trials.

A post-hoc analysis without imputation for rescue ibuprofen was conducted to assess the impact of suzetrigine as multimodal therapy with ibuprofen.¹⁴ The results showed that suzetrigine plus ibuprofen rescue, compared to placebo plus ibuprofen rescue, resulted in a 1-hour faster onset of clinically meaningful relief in the bunionectomy trial and a 1.5-hour faster onset in the abdominoplasty trial. In both trials, the proportion of participants with any adverse events was lower in the suzetrigine group than in the placebo and hydrocodone/acetaminophen groups. The most common adverse events observed in the suzetrigine groups in both trials were nausea, headache, constipation, and dizziness. A majority of these occurred less frequently in the suzetrigine groups than in the hydrocodone/acetaminophen and placebo groups. In the pooled data from the 2 trials, adverse events that occurred more frequently with suzetrigine than with placebo were pruritus (2.1% vs. 1.6%), muscle spasms (1.3% vs 0.5%), increased blood CPK (1.1% vs 0.5%), and rash (1.1% vs 0.5%).¹¹ In the abdominoplasty trial, the incidence of serious adverse events was 2.5% with suzetrigine (compared to 1.6% with hydrocodone bitartrate/acetaminophen and 2.3% with placebo).¹⁴ None of the serious adverse events were considered related to suzetrigine. In the bunionectomy trial, there were no serious adverse events.

Safety of suzetrigine was evaluated in a single-arm open-label safety study of 256 adult patients with moderate to severe acute surgical or non-surgical pain of new origin.¹⁵ Patients were given suzetrigine 100 mg orally followed by 50 mg every 12 hours for 14 days, or until their pain resolved, and were permitted to use concomitant acetaminophen 650 mg and ibuprofen 400 mg orally every 6 hours as needed. All participants who received at least 1 dose of suzetrigine were analyzed. Participants had a mean of 9.8 days of exposure to suzetrigine. The mean age (SD) was 44 (14.1) years, and most patients (73%) used multimodal therapy. Adverse events occurred in 36.7% of the study population. The most common adverse events reported were headache (7%), constipation (3.5%), nausea (3.1%), and rash (2%). Six participants (2.3%) who had distal lower extremity surgeries had falls, but these events were all considered unlikely related to suzetrigine. Five (2.0%) participants discontinued suzetrigine because of adverse events (accidental overdose, exacerbation of pre-existing arrhythmia, nausea, rash, and somnolence). All adverse events that led to treatment discontinuation were non-serious. Two (0.8%) participants experienced serious adverse events (suicidal ideation and cellulitis), which were considered not related to suzetrigine.

Upcoming Trials

A phase 3 randomized controlled trial evaluating the safety and efficacy of suzetrigine compared to placebo or pregabalin for painful diabetic peripheral neuropathy (NCT06628908) is currently recruiting and is estimated to be completed in 2027.¹⁶ This trial will follow patients for 12 weeks, which will offer insight into the effects of longer treatment durations. An additional open-label safety study that is also in the recruiting phase (NCT06696443) will study suzetrigine in patients with painful diabetic peripheral neuropathy for 54 weeks.¹⁷

Conclusion
Suzetrigine offers a unique mechanism of action and is a promising new option to overcome the limitations of current treatment options for acute moderate to severe pain. Although clinical trials have yielded encouraging results, randomized controlled trials were only 48 hours in length, and only studied adult patients after abdominoplasty or bunionectomy. Additional studies are underway that may verify the efficacy and safety of suzetrigine for longer durations of treatment and other pain indications. In randomized controlled trials, suzetrigine was administered as monotherapy with ibuprofen rescue. Studies are also needed to further evaluate suzetrigine when administered concomitantly with other analgesics as a component of multimodal analgesia.

References

1. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-1982. doi: 10.1097/j.pain.0000000000001939
2. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain. MMWR Recomm Rep. 2022;71(3):1-95. doi: 10.15585/mmwr.rr7103a1
3. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth. 2001;48(10):1000-10. doi: 10.1007/BF03016591
4. McEntire DM, Kirkpatrick DR, Dueck NP, et al. Pain transduction: a pharmacologic perspective. Expert Rev Clin Pharmacol. 2016;9(8):1069-80. doi: 10.1080/17512433.2016.1183481
5. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008
6. Apfelbaum JL, Ashburn MA, Connis RT et al; American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273. doi:10.1097/ALN.0b013e31823c1030
7. Celebrex. Package insert. Viatris Specialty LLC; 2021.
8. Ketorolac tromethamine. Package insert. Mylan Pharmaceuticals Incorporated; 2024.
9. Xifyrm. Package insert. Azurity Pharmaceuticals; 2025.
10. FDA approves novel non-opioid treatment for moderate to severe acute pain. US Food and Drug Administration. Updated January 30, 2025. Accessed July 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain
11. Journavx. Package insert. Vertex Pharmaceuticals Incorporated; 2025.
12. Osteen JD, Immani S, Tapley TL, et al. Pharmacology and mechanism of action of suzetrigine, a potent and selective Na_V1.8 pain signal inhibitor for the treatment of moderate to severe pain. Pain Ther. 2025;14(2):655-674. doi:10.1007/s40122-024-00697-0
13. Vaelli P, Fujita A, Jo S, et al. State-dependent inhibition of Nav1.8 sodium channels by VX-150 and VX-548. Mol Pharmacol. 2024;106(6):298-308. doi:10.1124/molpharm.124.000944
14. Bertoch T, D’Aunno D, McCoun J, et al. Suzetrigine, a nonopioid Na V 1.8 inhibitor for treatment of moderate-to-severe acute pain: two phase 3 randomized clinical trials. Anesthesiology. 2025;142(6):1085-1099. doi:10.1097/ALN.0000000000005460
15. McCoun J, Winkle P, Solanki D, et al. Suzetrigine, a non-opioid Na_V1.8 inhibitor with broad applicability for moderate-to-severe acute pain: a phase 3 single-arm study for surgical or non-surgical acute pain. J Pain Res. 2025;18:1569-1576. doi:10.2147/JPR.S509144
16. Evaluation of efficacy and safety of suzetrigine for pain associated with diabetic peripheral neuropathy. ClinicalTrials.gov identifier: NCT06628908. Updated June 26, 2025. Accessed August 13, 2025. https://clinicaltrials.gov/study/NCT06628908
17. Evaluation of the long-term safety and effectiveness of suzetrigine (SUZ) in participants with painful diabetic peripheral neuropathy (DPN). ClinicalTrials.gov identifier: NCT06696443. Updated June 26, 2025. Accessed August 13, 2025. https://clinicaltrials.gov/study/NCT06696443

Prepared by:
Amber M Beck, PharmD Candidate 2025
University of Illinois at Chicago Retzky College of Pharmacy

Reviewed by:
Jacqueline Wasynczuk, PharmD
Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

September 2025

The information presented is current as of August 15, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.