Suzetrigine Clinical Data Overview

Citation

Methods

Results

Conclusions

Bertoch T, et al., 2025 

Two phase 3, randomized, double-blind, placebo- and active-controlled trials

Trial VX-548-105, NAVIGATE 2; NCT05558410

Trial VX-548-104, NAVIGATE 1; NCT05553366

suzetrigine vs placebo

Objective: To evaluate suzetrigine for treatment of acute pain

Inclusion:

Adults 18-80 years old with moderate-to-severe acute pain on the verbal categorical rating scale, 4 or greater on the numeric pain rating scale after abdominoplasty or bunionectomy

Exclusion:

History of sensory abnormality, painful physical conditions interfering with pain assessment, long-term use of opioids or nonsteroidal anti-inflammatory drugs

N = 1,118

Suzetrigine (n = 447)

Hydrocodone bitartrate/acetaminophen (HB/APAP; n = 448)

Placebo (n = 223)

Duration of study:

treatment period, 48 hours

Intervention:

In both trials, patients were randomized 2:2:1 to receive either suzetrigine,  HB/APAP, or placebo during a 48-hour treatment period. Suzetrigine was administered as oral tablets, with loading dose of 100 mg followed by 50 mg every 12 hours. HB/APAP (active control) was given orally as 5 mg/325 mg capsules every 6 hours. Ibuprofen was allowed as rescue medication.

Primary outcome:

Sum of the pain intensity difference between treatments per NPRS from 0 to 48 hours (SPID48) after the first dose of study drug

Abdominoplasty 48.4 (95% CI 33.6, 63.1; p < 0.0001) and bunionectomy 29.3 (95% CI 14.0, 44.6; p = 0.0002).

Similar results were found for suzetrigine compared to HB/APAP for SPID48; no significant difference in either trial

Secondary outcomes:

Time to ≥2-point reduction in NPRS from baseline between treatments (suzetrigine vs placebo)

Abdominoplasty 119 min vs 480 min (p < 0.0001) and bunionectomy 240 min vs 480 min (p = 0.0016)

Safety outcomes:

Most adverse events (AEs) were mild to moderate in both trials.

Common AEs: nausea, constipation, headache, dizziness, hypotension, and vomiting in any treatment group (suzetrigine, HB/APAP or placebo)

Any AEs: 50.0%, 60.7%, 56.3%, with suzetrigine, APAP or placebo, respectively, following abdominoplasty

31.0%, 41.8%, 35.2%, respectively, following bunionectomy

In both studies, incidence of nausea/vomiting (N/V) was reduced in the suzetrigine group, compared to the HB/APAP group (both p < 0.001).

Serious AEs: Low incidence, and none were considered related to treatment with suzetrigine.

Authors’ Conclusions:

As compared with placebo, suzetrigine reduced moderate-to-severe acute pain over 48 hours after abdominoplasty or bunionectomy. Pain reduction with suzetrigine was similar to that with HB/APAP. Suzetrigine was associated with adverse events (AEs) that were mild to moderate in severity.

Comment/Critique:

The study population was predominantly female, potentially limiting generalizability to male patients. Furthermore, the use of perioperative regional anesthesia in the bunionectomy trial may have influenced pain scores.

McCoun J, et al., 2025 

Phase 3, multi-center, single-arm study

NCT05661734

suzetrigine

Objective: To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe acute surgical and non-surgical pain conditions

N = 256

Suzetrigine (n = 256)

Inclusion:

Adults, 18-80 years old with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with non-surgical pain of new origin

Exclusion:

History of previous surgery due to the same condition, except for procedures for which a previous surgery on the contralateral limb or organ is allowed; prior surgical procedure in the same region of the body that resulted in any perioperative complications; cardiac dysrhythmias, significant hepatic disease

Duration of study:

Treatment period, 14 days or until pain resolution

Intervention:

Patients at hospitals in the United States received suzetrigine (100 mg first dose, then 50 mg every 12 hours) for 14 days or until their pain resolved. Participants were permitted to use concomitant acetaminophen (650 mg) and ibuprofen (400 mg) every 6 hours as needed for additional pain relief; no other analgesic medications were permitted during study drug treatment.

Efficacy outcomes:

Participant perception of suzetrigine effectiveness in treating acute pain

83.2% of all participants rated suzetrigine as good, very good, or excellent on the Patient Global Assessment.

Surgical participants: 82.0%

Non-surgical participants: 91.2%

Safety outcomes:

Majority adverse events were mild (27.7%) or moderate (8.2%).

Common adverse events: headache (7.0%), constipation (3.5%), nausea (3.1%), fall (2.3%), and rash (2.0%)

Serious AEs: suicidal ideation (0.8%) and cellulitis (0.8%)

Four patients discontinued therapy due to AEs, and 5 discontinued due to perceived lack of efficacy.

Authors’ Conclusions:

Suzetrigine provides safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain.

Comment/Critique:

The study employed a single-arm design, which may preclude a direct comparison of suzetrigine efficacy and safety to placebo or active comparators. Additionally, the reliance on patient-reported outcomes may introduce subjectivity and limit generalizability.

Amaral S, et al., 2025 

Systematic review and meta-analysis

suzetrigine vs placebo vs. hydrocodone/acetaminophen

Objective: To explore the efficacy and safety of suzetrigine compared with placebo or usual pain regimens for perioperative pain management in adult patients

N = 4 randomized controlled trials (RCTs), 2,768 patients

Suzetrigine (n = 1,179)

Hydrocodone with acetaminophen (n = 1015) Placebo (n = 575)

Inclusion:

RCTs comparing suzetrigine with placebo or standard analgesic regimens in adult patients (>18 yr old) undergoing any kind of surgical procedure

Exclusion:

Involved overlapping populations; clinical trials with unpublished results

Studies were identified through a comprehensive search of PubMed/MEDLINE, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Central up to May 2025, using terms including “suzetrigine,” “NAV 1.8,” and “VX-548.” Patients received suzetrigine or a comparator (placebo or standard analgesic regimen, including hydrocodone with paracetamol [acetaminophen]) for perioperative pain management following various surgical procedures. Dosing and administration schedules varied slightly across studies but were consistent with protocols for evaluating acute postoperative pain.

Primary outcome:

SPID-48

Mean difference (MD) vs. control: 13.12 (95% CI 2.96 to 23.9; p < 0.01)

Suzetrigine vs. placebo: MD 38.64 (95% CI 26.96 to 47.32; p < 0.01)

Suzetrigine vs. hydrocodone/acetaminophen: MD 5.27 (95% CI -15.03 to 25.57; p = 0.61)

Subgroup analyses

Bunionectomy: MD 4.27 (95% CI -4.45 to 13.0)

Abdominoplasty: MD 21.76 (95% CI 12.99 to 30.52)

Safety outcomes:

Adverse events (AEs) in suzetrigine group: RR 0.83 (95% CI 0.76 to 0.90; p < 0.01)

Severe AEs: RR 0.80 (95% CI 0.38 to 1.70; p = 0.56)

AEs leading to discontinuation: RR 1.37 (95% CI 0.48 to 3.96; p = 0.56)

Authors’ Conclusions: 

Suzetrigine appears to offer effective peri-operative analgesia with a favorable safety profile. Although further research is needed to confirm its clinical utility across diverse surgical populations, our results support its inclusion as a promising nonopioid alternative in acute pain management strategies.

Comment/Critique: 

The study is limited by the small number of trials, variability in study designs, and limited long-term safety data. All included trials were sponsored by the pharmaceutical industry, raising concerns about potential sponsor-driven bias. The use of SPID-48 as the primary outcome measure is not aligned with core outcome measures, and key patient-centered outcomes were not reported. Further research is needed to confirm clinical utility across diverse surgical populations.

Burhan et al., 2025 

Systematic review and meta-analysis

suzetrigine vs placebo

Objective: To assess the efficacy and safety of suzetrigine compared to placebo in adults with acute postoperative pain

N = 4 trials (2,768 patients)

Inclusion:

Randomized controlled trials of adults (aged 18 years and older) with acute pain, with suzetrigine (VX-548) at any dose or regimen compared to placebo or an active comparator; reported efficacy measured by pain intensity reduction and safety measured by the incidence of adverse events.

Exclusion:

Non-randomized studies; case reports, reviews, conference abstracts; non-English publications

The following databases were searched: PubMed, Google Scholar, ScienceDirect, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception to July 25, 2025, without language restrictions.

Primary outcome:

Standardized pain intensity difference over 48 hours (SPID48):

(suzetrigine vs placebo)

MD: 38.76 (95% CI 28.97 to 48.54; p < 0.00001); I² = 5%

Secondary outcomes:

Incidence of nausea:(suzetrigine vs placebo) RR: 0.72 (95% CI 0.57 to 0.90; p = 0.004)

Incidence of dizziness: (suzetrigine vs placebo) RR: 0.57 (95% CI 0.38 to 0.88; p = 0.01)

Safety Outcomes:

Overall adverse events (suzetrigine vs placebo): 55% vs 70%; RR 0.86 (95% CI 0.77 to 0.96; I² = 0%; p = 0.008)

Serious adverse events (suzetrigine vs placebo): 2.5% vs 2.3%; RR 0.98 (95% CI 0.36 to 2.64; I² = 0%; p = 0.97)

Authors’ Conclusions:

Suzetrigine offers effective and well-tolerated analgesia for acute postoperative pain, supporting its role in opioid-sparing postoperative pain regimens. It provides significant pain relief and reduces common opioid-related adverse events such as nausea and dizziness.

Comment/Critique:

The generalizability is limited due to the focus on specific surgical models and a predominantly female participant population. The short duration of trials (48 hours) does not provide insight into long-term safety or efficacy.

Bansal et al., 2026 

Systematic review and meta-analysis

suzetrigine vs placebo vs. hydrocodone/acetaminophen (HB/APAP)

Objective: To evaluate the efficacy and safety of suzetrigine by cumulating data from available evidence

N = 4 trials (2,599 patients)

Suzetrigine (n = 1009)

Placebo (n = 575)

Hydrocodone bitartrate/acetaminophen (HB/APAP) (n = 1015)

Inclusion:

Randomized clinical trials assessing the efficacy and safety of suzetrigine in postoperative pain management

Exclusion:

Cross-sectional studies, case studies, review articles, preclinical investigations; published in languages other than English

The following databases were searched: ClinicalTrials.gov, PubMed, and Cochrane Central Register of Controlled Trials until June 15, 2025, with the search terms 'suzetrigine,' 'VX-548,' and 'pain.'

Efficacy outcomes:

50% reduction in NPRS score at 48 hours (suzetrigine vs placebo)

OR: 1.74 (95% CI 1.41 to 2.15; p < 0.00001); I² = 0%

Proportion of participants with ≥70% reduction in NPRS score at 48 hours (suzetrigine vs placebo)

OR: 1.81 (95% CI 1.43 to 2.29; p < 0.00001); I² = 0%

Safety outcomes:

Overall incidence of any adverse events (suzetrigine vs placebo):

41.2% vs 48.4%; RR 0.86 (95% CI 0.77 to 0.96; I² = 0%; p = 0.007)

Overall incidence of nausea (suzetrigine vs placebo):

13.8% vs 19.5%; RR 0.71 (95% CI 0.57 to 0.90; I² = 0%; p = 0.004)

Overall incidence of vomiting (suzetrigine vs placebo):

1.9% (19/1,010) vs 2.6% (15/574); RR 0.73 (95% CI 0.36 to 1.50; I² = 0%; p = 0.40)

Overall incidence of vomiting

(suzetrigine vs HB/APAP)

significantly less in suzetrigine group as compared to HB/ APAP: RR = 0.42 (95% CI 0.25‐0.70; I² = 0%; p = 0.001)

Authors’ Conclusions:

Suzetrigine appears to be an effective, well‐tolerated option for acute pain management, showing superiority to placebo and comparable efficacy to HB/APAP, with a better safety profile. However, future long‐term studies are needed to assess its efficacy and safety in various acute pain settings.

Comment/Critique:

Limitations include the short duration of trials, which fails to demonstrate the long-term efficacy and safety of suzetrigine. The study is also limited by its focus on surgical settings, which may not generalize other settings. Additionally, publication bias could not be assessed due to the small number of studies included in the analysis. The high heterogeneity observed in some outcomes suggests variability in study designs or populations.

Alvarez-Aguilar et al., 2026

Systematic review and meta-analysis

suzetrigine vs placebo

Objective: To evaluate the efficacy and safety of suzetrigine (a NaV1.8 inhibitor) compared with placebo for the treatment of acute postoperative pain by synthesizing evidence from randomized controlled trials.

N= 4 studies (1,584 patients)

Suzetrigine (n= 1,009)

Placebo (n= 575) 

Inclusion:

Eligible studies were randomized controlled trials enrolling adult patients (≥18 years) undergoing elective or emergency surgical procedures under any type of anesthesia who experienced acute postoperative pain. Studies were required to compare suzetrigine (a NaV1.8 inhibitor) at an optimal clinical dose versus placebo and report at least one relevant outcome, including postoperative pain intensity measured by the Numeric Pain Rating Scale at 24 or 48 hours, change in pain intensity from baseline, or adverse events. Additionally, studies had to provide sufficient numerical data to allow calculation of effect estimates such as mean differences or risk ratios.

Exclusion:

Studies were excluded if they included pediatric populations, evaluated chronic or non-surgical pain conditions, or were conducted exclusively in emergency-only settings. Trials involving combination therapies without isolatable effects of suzetrigine, single-arm designs, subtherapeutic dosing regimens, or non-randomized and non–placebo-controlled designs were also excluded. Studies lacking sufficient or extractable outcome data, as well as abstracts, conference proceedings, or reports without complete numerical data, were not considered.

A systematic literature search was conducted on May 21, 2025 across PubMed, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), and the Cochrane Central Register of Controlled Trials in accordance with Cochrane Handbook and PRISMA guidelines, with the protocol prospectively registered in PROSPERO (CRD420251057157). Search terms included combinations of “postoperative pain” and NaV1.8-related keywords such as “NaV1.8 inhibitor,” “suzetrigine,” “VX-548,” “A-803467,” and “Journavx.”

Efficacy outcomes:

Suzetrigine significantly reduced postoperative pain compared with placebo at both time points.
At 24 hours, pain scores were lower with a pooled mean difference (MD) of −0.93 (95% CI −1.38 to −0.48; I² = 66.0%), with a prediction interval of −1.77 to −0.09.

At 48 hours, the reduction remained consistent (MD −1.02, 95% CI −1.32 to −0.72; I² = 11.8%).

Change-from-baseline analyses supported these findings, showing reductions at 24 hours (MD −0.66, 95% CI −1.11 to −0.21; I² = 85.2%) and 48 hours (MD −0.66, 95% CI −1.11 to −0.21; I² = 85.2%), although prediction intervals crossed the null.

Subgroup analyses by surgical type showed consistent benefit in both abdominoplasty (MD −0.97, 95% CI −1.57 to −0.37; I² = 0%) and bunionectomy (MD −0.93, 95% CI −5.37 to 3.51; I² = 86.9%), with no significant subgroup differences.

Safety outcomes:

Suzetrigine was associated with a lower risk of several adverse events compared with placebo.
Nausea was reduced (RR 0.63, 95% CI 0.42–0.95; I² = 13.8%).

Dizziness was also reduced (RR 0.57, 95% CI 0.34–0.96; I² = 0%).
No significant differences were observed in:

Vomiting (RR 0.74, 95% CI 0.26–2.12)

Headache (RR 0.85, 95% CI 0.33–2.20)

Constipation (RR 0.99, 95% CI 0.64–1.54)

Authors’ Conclusions: 

Suzetrigine demonstrates modest short-term analgesic benefits versus placebo in postoperative settings. Evidence on opioid-sparing effects, overall opioid consumption, and long-term safety remains limited, underscoring the need for independent, adequately powered randomized trials with standardized co-analgesic reporting and longer follow-up. Given its peripheral NaV1.8 blockade, minimal CNS penetration, and emerging short-term safety profile, suzetrigine and NaV1.8 inhibitors more broadly may serve as promising nonopioid components of multimodal, enhanced recovery after surgery-aligned analgesia. Further trials should assess durability of benefit, opioid-sparing potential, and prevention of chronic postsurgical pain across diverse surgical populations.

Comment/Critique: 

Only two studies were at low risk of bias across all domains, while the remaining two had “some concerns” due to unclear randomization methods, limiting confidence in the internal validity of the evidence. Additionally, the small number of trials and inability to formally assess publication bias further weakens certainty in the pooled estimates.

Irfan et al, 2026

suzetrigine vs. placebo; suzetrigine vs. hydrocodone/acetaminophen

Objective: To evaluate the safety and efficacy of Suzetrigine for acute moderate to severe pain.

N= 5 studies (2,855 patients)

Inclusion: 

Studies were included if they enrolled adults with acute moderate-to-severe pain of postoperative, musculoskeletal, or other acute etiologies. Eligible studies evaluated suzetrigine (VX-548) at any therapeutic dose or regimen and compared it against placebo or active analgesic controls such as NSAIDs or opioids in controlled trials, with an additional single-arm study included for descriptive safety data. Included studies were required to report at least one relevant outcome, including safety outcomes (treatment-emergent or serious adverse events) and/or efficacy outcomes such as SPID48 or change in NPRS from baseline. Only studies with sufficient data for extraction and analysis were included.

Exclusion:

Studies were excluded if they were review articles or did not provide sufficient data on outcomes of interest. Studies lacking extractable information for safety or efficacy endpoints were also excluded from the analysis.

A predefined systematic search strategy was conducted following PRISMA guidelines using PubMed, Embase, Cochrane Library, and Scopus from inception to August 2025. The search included terms related to “non-opioid,” “pain relief,” “pain,” and “suzetrigine.” Additional studies were identified through manual screening of reference lists from included articles and relevant review papers. All stages of study identification, screening, and data extraction were performed using prespecified criteria to ensure consistency and reproducibility.

Efficacy outcomes:
Suzetrigine demonstrated clinically relevant analgesic efficacy in acute postoperative pain, with consistent reductions in pain intensity across included trials compared with control groups.

Pooled analysis showed improved SPID48 outcomes versus placebo (SMD = 0.42; 95% CI 0.31–0.53; I² = 9%), indicating greater cumulative pain relief over 48 hours.

NPRS scores were reduced from baseline across studies, supporting short-term analgesic benefit in acute and postoperative pain settings.

Safety outcomes:

Suzetrigine was associated with a lower incidence of overall adverse events compared with placebo (RR = 0.86; 95% CI 0.77–0.96; I² = 0%) and compared with HB/APAP (RR = 0.81; 95% CI 0.74–0.89; I² = 0%).

No significant difference was observed in serious adverse events (RR = 0.97; 95% CI 0.11–8.68; I² = 0%).

Nausea (RR = 0.72; 95% CI 0.57–0.90) and dizziness (RR = 0.57; 95% CI 0.38–0.88) were significantly reduced with suzetrigine versus placebo.

No significant differences were seen for vomiting, headache, or constipation between groups.

Authors’ Conclusions: 

Suzetrigine was better tolerated and more efficacious than placebo making it a promising medication for moderate to severe acute pain treatment in adults.

Comment/Critique: 

Overall, the evidence is limited by small and heterogeneous datasets, with restricted outcome reporting and short follow-up, preventing assessment of long-term efficacy and safety. In addition, demographic imbalance (predominantly female surgical populations) and exclusion of non-English studies may reduce the generalizability of the findings. 

Abbreviation: HB/APAP= hydrocodone bitartrate/acetaminophen; CI= confidence interval; I²= I squared statistic; MD= mean difference; N= sample size; NCT= clinical trial registry number; NPRS= numeric pain rating scale; RR= risk ratio; SMD= standardized mean difference; SPID48= summed pain intensity difference over 48 hours; VX-548= suzetrigine compound code