Selective Nav1.8 inhibition by suzetrigine, a novel nonopioid analgesic for acute pain management: A systematic review and metanalysis

Abstract

Background:

Suzetrigine, a novel nonopioid analgesic, selectively inhibits voltage-gated sodium channel 1.8 (NaV1.8) and has recently been approved for the management of moderate to severe acute pain. This meta-analysis aimed to evaluate the efficacy and safety of suzetrigine by cumulating data from available evidence.

Methods:

A literature search was conducted using ClinicalTrials.gov, PubMed, and Cochrane Central Register of Controlled Trials. Five randomized controlled trials (RCTs) were included in the systematic review, with four RCTs in the meta-analysis. The primary efficacy outcomes were time-weighted sum of pain intensity difference over 48 h (SPID 48) and 24 h (SPID 24) between suzetrigine and placebo. Secondary outcomes included proportion of participants achieving ≥30%, ≥50%, and ≥70% reduction in numeric pain rating scale (NPRS) scores at 48 h and safety analysis.

Results:

Suzetrigine showed significantly better efficacy versus placebo in reducing pain, with a standard mean difference of 5.55 (95% CI 2.97-8.13, P < 0.00001) for SPID 48 and 5.33 (95% CI 2.50-8.16, P < 0.00001) for SPID 24. Odds of achieving ≥30%, ≥50%, and ≥70% reduction in NPRS scores at 48 h were significantly higher in the suzetrigine group (OR 1.95, 1.74, and 1.81, respectively; all P < 0.00001). Suzetrigine showed comparable efficacy to hydrocodone bitartrate-acetaminophen (HB/APAP) with a better safety profile, showing lower incidence of adverse events and gastrointestinal side effects.

Conclusion:

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.

Introduction

Acute postoperative pain is a common outcome of surgical intervention. Approximately 20% of patients report pain within the first 24 h following surgery, a number that has remained relatively constant over the past 3 decades. Postoperative pain requires adequate analgesia as poorly controlled postoperative pain is associated with increased morbidity, impaired quality of life, delayed recovery time, prolonged duration of opioid use, and higher healthcare costs.[1,2]

Opioids are the most common and effective agents used in the management of moderate to severe postoperative surgical pain. However, opioids have their own constraints that limit optimal dosing of opioid analgesia. These limitations include addiction potential, physical dependence, nausea, vomiting, constipation, and respiratory depression.[3,4] Hence, there is a high unmet need for safe and effective nonopioid medicines that are as effective as opioid analgesics but devoid of their adverse effects.

Voltage-gated sodium channels (NaV) have emerged as a novel approach for the management of peripheral pain. These channels are the membrane proteins that are found in nociceptors, facilitate the conduction of sodium ions across cell membranes, and are responsible for the generation of action potentials. There are nine mammalian NaV subtypes (NaV1.1–NaV1.9) that are widely distributed throughout the body. Certain agents, such as local anesthetics and anticonvulsants, exert their analgesic effects through these channels, and are used as adjuvant analgesics in pain management. However, these agents are often associated with side effects due to their nonselective inhibition of NaV channels. Among these channels, NaV1.8 is most selectively expressed in nociceptors and plays a crucial role in transmitting pain signals in primary human dorsal root ganglion sensory neurons. Notably, NaV1.8 is absent in the central nervous system (CNS). The selective nature of NaV1.8 makes it a promising target for analgesic drugs that do not pose a risk of addiction.[5]

Suzetrigine is a potent and highly selective inhibitor of voltage-gated sodium channel 1.8 (Na_V1.8), which stabilizes the closed state of the channel and reduces pain signals in peripheral neurons. It was approved by the US Food and Drug Administration (FDA) on January 30, 2025, for moderate to severe acute pain in adults.[6] The current meta-analysis was planned to evaluate the efficacy and safety of suzetrigine by synthesizing all available phase 2 and phase 3 data, along with other pertinent evidence.

Material and Methods

Protocol and registration

The present systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [Figure 1]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under protocol number CRD420251070133. The study was approved by the institutional ethics committee (IEC Approval Number: AIIMS/ RAJKOT/6^th IEC/ER/23, Date: 10/06/2025).

Figure 1.

PRISMA flow chart of included studies

Study inclusion criteria

Randomized clinical trials (RCTs) assessing the efficacy and safety of suzetrigine in postoperative pain management were included. All other study designs, including cross-sectional studies, case studies, review articles, and preclinical investigations, were excluded from the analysis.

Search strategy and study selection

An electronic literature search was conducted using databases such as ClinicalTrials.gov, PubMed, and the Cochrane Central Register of Controlled Trials until June 15, 2025. In addition, the bibliographies of the published articles were examined. There were no restrictions on the publication status of the included articles. Articles published in other than the English language were excluded. The search strategy employed medical subject headings: “suzetrigine,” “VX-548,” and “pain.” Two independent researchers (SB and SS) screened the articles, removed duplicates, and assessed their potential eligibility. Following the initial screening, full-text articles were evaluated, and any discrepancies were resolved with the assistance of the other authors (SD, SG, and RBS).

Data extraction

Individual study data on research design, suzetrigine dose, regimens, comparator group, number of participants in each group, safety outcomes, and efficacy parameters were recorded. All data were entered into a preformatted form.

Study outcomes

This study aimed to evaluate the impact of suzetrigine on pain intensity and its safety profile. Efficacy was primarily assessed by analyzing the time-weighted sum of the pain intensity difference over 48 h (SPID 48) and 24 h (SPID 24) between suzetrigine and placebo. To calculate SPID 48, the initial step involved determining the difference in pain intensity by subtracting the Numeric Pain Rating Scale (NPRS) score at each time point from the baseline. Each score was then multiplied by a weight factor corresponding to the time elapsed since the previous observation. Finally, all the values were aggregated. The NPRS score was recorded at 19 time points (0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h after the first dose of VX-548, hydrocodone bitartrate–acetaminophen, or placebo). Similarly, SPID 24 was calculated over the period of 24 h.

Additional secondary efficacy parameters included the proportion of participants who experienced a reduction of ≥30%, ≥50%, and ≥70% in the NPRS at 48 h in the suzetrigine group compared to the placebo and hydrocodone bitartrate/acetaminophen (HB/APAP) groups. Safety analysis was conducted by aggregating data from the reported adverse events in the included trials.

Data synthesis and summary measures

The evaluation of SPID 48 and SPID 24 was conducted using the standard mean difference (SMD) with a 95% confidence interval (CI). The proportion of participants experiencing a reduction of ≥30%, ≥50%, and ≥70% in the NPRS score was analyzed using the odds ratio (OR) with a 95% CI. For safety parameters, the risk ratio with a 95% CI was used. Review Manager Version 5.4.1 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was utilized to estimate the pooled effect using a random effects model. Heterogeneity was assessed using the I² statistic, with an I² value greater than 50%, indicating significant heterogeneity. The meta-analysis was interpreted based on the results of the random-effects model.

Quality assessment of studies

The methodological quality of the RCTs was evaluated independently by two authors (SB and SD) using the Cochrane Collaboration risk of bias (ROB)-2 tool and categorized as low, high, or with some concerns.[7] The figure plots of the ROB were synthesized using Robvis (visualization tool) software.[8] Publication bias was not assessed because the number of studies was less than ten.

Results

Literature search

Initially, 63 records were identified for the evaluation of the efficacy and safety of suzetrigine in postoperative pain management. After removing duplicates (n = 15), review articles (n = 11), preclinical studies (n = 6), editorials/correspondence (n = 5), infographics (n = 1), and abstracts (n = 1), 24 articles were subjected to an eligibility assessment. Subsequently, five articles satisfied the inclusion criteria and were incorporated into the systematic review [Figure 1]. However, only four articles were included in the meta-analysis because one study in the systematic review was a single-arm study.

Study characteristics

This systematic review encompassed five randomized controlled trials (RCTs): NCT04977336, NCT05034952, NCT05558410, NCT05553366, and NCT05661734. The initial two trials were Phase II studies, while the subsequent two were Phase III studies. Notably, NCT05661734 was a single-arm study and was therefore excluded from the meta-analysis due to its design.

The clinical trial NCT04977336 assessed the efficacy and safety of suzetrigine in patients after unilateral bunionectomy. Total 274 patients were allocated to five groups in a 2:2:1: 2:2 ratio. The high-dose group received 100 mg loading dose of suzetrigine, followed by 50 mg every 12 h. The medium-dose group received 60 mg loading dose, followed by 30 mg every 12 h. The low-dose group received 20 mg loading dose, followed by 10 mg every 12 hours. The fourth group received hydrocodone bitartrate and acetaminophen (HB/APAP) capsule (5 mg hydrocodone, 325 mg acetaminophen), and the fifth received placebo. Our meta-analysis compared high-dose suzetrigine with placebo (primary endpoint) and HB/APAP (secondary endpoint) as it showed higher efficacy. The high-dose suzetrigine, HB/APAP, and placebo groups had 60, 60, and 59 patients, respectively, with mean ages of 47.6 ± 13.7, 50 ± 12.5, and 47.8 ± 13.6 years. Study endpoints included SPID 48 and SPID 24, percentage of patients with pain reduction ≥30%, ≥50%, and ≥70% from baseline on NPRS at 48h, and adverse events. The LSM value of SPID 48 in high-dose suzetrigine, HB/APAP, and placebo groups was 137.8 ± 11.5, 115.6 ± 11.5, and 101 ± 11.6, respectively. SPID 24 values were 45.2 ± 5.5, 41 ± 5.5, and 31.5 ± 5.6, respectively. Higher SPID indicates greater pain reduction. In the suzetrigine group, 83%, 67% and 52% participants experienced ≥30%, ≥50%, and ≥70% NPRS pain reduction at 48 hours. No serious adverse events were reported in any group.[9]

The clinical trial NCT05034952 focuses on abdominoplasty as a model for soft tissue pain to assess suzetrigine’s efficacy and safety. Total 303 participants were randomly assigned in a 1:1:1:1 ratio into four groups: high-dose suzetrigine, medium-dose suzetrigine, HB/APAP, and placebo. From this trial also, values of high-dose suzetrigine were incorporated into metanalysis. Seventy-six participants were enrolled in the high-dose suzetrigine and HB/APAP groups, respectively, with 77 in the placebo group. The mean ages were 43.1 ± 9.7, 45.4 ± 10.7, and 42.6 ± 9.5 years for suzetrigine, HB/APAP, and placebo groups. The LSM value of SPID 48 in suzetrigine, HB/APAP, and placebo group was 110.5 ± 10.3, 85.2 ± 10.3, and 72.7 ± 10.2. The LSM value of SPID 24 was 45.5 ± 4.7, 30 ± 4.7, and 26 ± 4.7, respectively. In the suzetrigine group, 61%, 45%, and 25% participants experienced ≥30%, ≥50%, and ≥70% NPRS pain score reduction at 48 hours. Three serious adverse events were reported, but none of them found to be related with study drugs.[9]

NCT05553366 and NCT05558410 are Phase 3 studies that assessed the efficacy and safety of suzetrigine in patients who underwent bunionectomy and abdominoplasty, respectively. In both trials, participants were allocated into three groups in a ratio of 2:2:1. The first group received a suzetrigine tablet of 100 mg as a loading dose, followed by 50 mg every 12 hours. The second group received a combination of HB/APAP at a dose of 5 mg/325 mg, and the third group received a placebo. A total of 1073 patients were enrolled in the bunionectomy trial, while 1118 patients were enrolled in the abdominoplasty trial. The design, objectives, endpoints, duration of treatment, and NPRS analysis were consistent with the Phase 2 trials as previously mentioned. The mean age of bunionectomy trial participants was 48 ± 13 years, while the mean age of abdominoplasty trial participants was 42 ± 9 years. The LSM value of SPID 48 in bunionectomy trial was 99.9 ± 4.5, 120.1 ± 4.5, and 70.6 ± 6.3 in suzetrigine, HB/APAP, and placebo group, respectively. The LSM value of SPID 48 in abdominoplasty trial was 118.4 ± 4.3, 111.8 ± 4.3, and 70.1 ± 6.1 in suzetrigine, HB/APAP, and placebo group, respectively. In both trials, the most frequently reported adverse events, occurring in 4% or more of participants in any treatment group, included nausea, constipation, headache, dizziness, hypotension, and vomiting. The majority of these adverse events were classified as mild or moderate in severity. In the abdominoplasty trial, the incidence of serious adverse events was low and comparable: 2.5% with suzetrigine, 1.6% with HB/APAP, and 2.3% with placebo. None of the serious adverse events were potentially related to the study drugs. No serious adverse events were reported in the bunionectomy trial.[10]

NCT05661734 is a single-arm study that primarily focused the safety of suzetrigine in managing acute pain resulting from surgical or nonsurgical conditions. Participants received an initial dose of 100 mg of suzetrigine, followed by 50 mg every 12 hours for 14 days or until pain resolution, whichever occurred first. A total of 256 patients were enrolled, comprising 173 females and 83 males. The mean age of participants was 43.9 ± 14.1 years. Suzetrigine was found to be safe and well tolerated, with most adverse events classified as mild to moderate. The most common reported adverse events include headache, constipation, nausea, falls, and rash. Two participants experienced serious adverse events, namely, suicidal ideation and cellulitis, neither of which was found to be related to suzetrigine[11] [Table 1].

Table 1.

Characteristics of included studies

Clinical Trial ID	Total Number of participants	Gender (no.)	Age: Yr (Mean±SD)	Intervention	Comparator	#NPRS score at baseline	$ VRS-no (%) at baseline	End Points
NCT05034952	229 patients (Suzetrigine: 76 *HB/APAP: 76 Placebo: 77)	Suzetrigine: ^M1; F 75 HB/APAP: M2; F73 Placebo: M1; F 76	Suzetrigine: 43.1±9.7 HB/APAP: 45.4±10.7 Placebo: 42.6±9.5	Suzetrigine: Loading dose of 100 mg, followed by a maintenance dose of 50 mg every 12 hours for 48 hours	HB/APAP Placebo	Suzetrigine: 7.2±1.7 HB/APAP: 7.3±1.8 Placebo: 6.7±1.6	Suzetrigine: Moderate: 44 (58) Severe: 32 (42) HB/APAP: Moderate: 45 (59) Severe 31 (41) Placebo: Moderate: 42 (55) Severe: 35 (45)	1) @SPID 48 Suzetrigine Vs Placebo 2) %SPID24 Suzetrigine Vs Placebo 3) Percentage of patients with reduction in pain at least 30%, 50% and 70% from baseline on the NPRS at 48 hours after the first dose of active treatment or placebo 4) Adverse events
NCT04977336	179 patients (Suzetrigine: 60 HB/APAP: 60 Placebo: 59)	Suzetrigine: M7; F 53 HB/APAP: M10; F50 Placebo: M 10; F 49	Suzetrigine: 47.6±13.7 HB/APAP: 50.0±12.5 Placebo: 47.8±13.6	Suzetrigine: Loading dose of 100 mg, followed by a maintenance dose of 50 mg every 12 hours for 48 hours	HB/APAP Placebo	Suzetrigine: 6.7±1.7 HB/APAP: 6.9±1.9 Placebo: 6.9±1.7	Suzetrigine: Moderate: 44 (73) Severe: 16 (27) HB/APAP: Moderate: 37 (62) Severe 23 (38) Placebo: Moderate: 39 (66) Severe: 20 (34)	1) SPID 48 Suzetrigine Vs Placebo 2) SPID24 Suzetrigine Vs Placebo 3) Percentage of patients with reduction in pain at least 30%, 50% and 70% from baseline on the NPRS at 48 hours after the first dose of active treatment or placebo 4) Adverse events
NCT05558410	1118 Patients (Suzetrigine: 447 HB/APAP: 448 Placebo 223)	Suzetrigine: M10; F 437 HB/APAP: M7; F441 Placebo: M 03; F 220	Suzetrigine: M: 38 10 F: 42 9 HB/APAP: M: 40 08 F: 42 9 Placebo: M: 33 16 F: 42 8	Suzetrigine: Loading dose of 100 mg, followed by a maintenance dose of 50 mg every 12 hours for 48 hours	HB/APAP Placebo	Suzetrigine: 7.3±1.7 HB/APAP: 7.4±1.7 Placebo: 7.5±1.7	Suzetrigine: Moderate: 266 (60) Severe: 181 (40) HB/APAP: Moderate: 262(58) Severe: 186 (42) Placebo: Moderate: 127 (57) Severe: 96 (43)	1) SPID 48 Suzetrigine Vs Placebo 2)SPID24 Suzetrigine Vs Placebo 3) Percentage of patients with reduction in pain at least 30%, 50% and 70% from baseline on the NPRS at 48 hours after the first dose of active treatment or placebo 4) Adverse events
NCT05553366	1073 Patients (Suzetrigine: 426 HB/APAP: 431 Placebo: 216	Suzetrigine: M60; F 366 HB/APAP: M72; F 359 Placebo: M 29; F 187	Suzetrigine: M: 46±15 F: 48±13 HB/APAP: M: 47±13 F: 48±13 Placebo: M: 46±15 F: 48±13	Suzetrigine: Loading dose of 100 mg, followed by a maintenance dose of 50 mg every 12 hours for 48 hours	HB/APAP Placebo	Suzetrigine: 6.7±1.8 HB/APAP: 6.8±1.9 Placebo: 6.8±1.8	Suzetrigine: Moderate: 291(68) Severe: 135 (32) HB/APAP: Moderate: 279 (65) Severe: 152 (35) Placebo: Moderate: 147 (68) Severe: 69 (32)	1) SPID 48 Suzetrigine Vs Placebo 2)SPID24 Suzetrigine Vs Placebo 3) Percentage of patients with reduction in pain at least 30%, 50% and 70% from baseline on the NPRS at 48 hours after the first dose of active treatment or placebo 4) Adverse events
NCT05661734	Single-arm study Total Patients in Suzetrigine: 256	M: 83 F: 173	M: 44±14.1 F: 43.9±14.1	Suzetrigine: Loading dose of 100 mg, followed by a maintenance dose of 50 mg every 12 hours for 14 days	Single arm study	Suzetrigine: 6.7±1.7	Suzetrigine: Moderate: 191(74.6) Severe: 65 (25.4)	1) Primary end point: Safety/ Adverse vents 2) Participant’s perception of suzetrigine efficacy using a patient global assessment

^M: male; F: female, *HB/APAP: Hydrocodone bitartrate/Acetaminophen, ^#NPRS: Numeric Pain Rating Scale (NPRS) ranges from 0 to 10 with 0 indicates no pain while 10 indicates maximum pain, ^$VRS: Verbal Categorical Rating Scale Pain measuring scale ranges from no pain to mild, moderate and severe pain, @SPID48: Time weighed sum of the pain intensity difference (SPID) over a period of 48 hours in NPRS score. % SPID 24: Time weighed sum of the pain intensity difference (SPID) over a period of 24 hours in NPRS score

Study quality assessment

Four studies underwent Risk of Bias (ROB) assessment, and it was found to be low for all studies, and hence, the total ROB was rated as “Low”. One study (NCT5661734) included in the systematic review did not undergo ROB as it was a single-arm study [Figure 2].

Figure 2.

Risk of bias (ROB) of included studies

Primary outcome

Efficacy of Suzetrigine in comparison to placebo

Efficacy of suzetrigine in comparison to placebo was evaluated by sum of pain intensity difference over a period of 48 and 24 hours.

1. Sum of pain intensity difference over a period of 48 hours (SPID 48)

   Overall efficacy of suzetrigine was evaluated by SPID 48 in 1584 participants, of which 1009 were in suzetrigine group and 575 in placebo group. A significant difference in SPID 48 value was observed in suzetrigine group as compared to placebo group [standard mean difference (SMD) = 5.55 (95% CI 2.97-8.13), I² = 99%, P < 0.00001] [Figure 3].

2. Sum of pain intensity difference over a period of 24 hours (SPID 24)

   SPID 24 evaluated the efficacy of suzetrigine over a period of 24 hours, and it was found to be significantly high in suzetrigine group as compared to placebo [SMD = 5.33 (95% CI 2.50-8.16), I² = 99%, P < 0.00001] [Figure 3].

Figure 3.

Efficacy of suzetrigine

Secondary outcome

1. SPID 48 between suzetrigine and HB/APAP

   SPID 48 value was evaluated in 1584 suzetrigine participants and 1015 HB/APAP recipients. No statistically significant difference was found in SPID 48 value between suzetrigine and HB/APAP recipients [SMD = 0.35 (95% CI -3.05-3.75), I² = 100%, P = 0.84] [Supplementary Figure 1 ^{(479.2KB, tif)} ].

2. Proportion of participants with ≥30%, ≥50%, and ≥70% reduction in NPRS score at 48 hours (Suzetrigine vs Placebo)

   Proportion of participants with ≥30% [Odds Ratio (OR) = 1.95 (95% CI 1.57-2.42), I² = 0%, P < 0.00001], ≥ 50% [OR = 1.74 (95% CI 1.41-2.15), I² = 0%; P < 0.00001], and ≥70% [OR = 1.81 (95% CI 1.43-2.29), I² = 0%; P < 0.00001] reduction in NPRS score at 48 hours was significantly higher in suzetrigine group as compared to placebo [Figure 4].

3. Proportion of participants with ≥30%, ≥50%, and ≥70% reduction in NPRS score at 48 hours (Suzetrigine Vs HB/APAP)

   Proportion of participants with ≥30% [OR = 1.16 (95% CI 0.94 -1.42), I² = 10%; P = 0.16], ≥50% [OR = 1.02 (95% CI 0.85-1.22), I² = 0%; P = 0.84], and ≥70% [OR = 1.08 (95% CI 0.90-1.29), I² = 0%; P = 0.42] reduction in NPRS score at 48 hours was comparable between suzetrigine and HB/APAP group [Supplementary figure 2 ^{(1.5MB, tif)} ].

4. Overall incidence of any adverse events

   Overall incidence of any adverse events was observed in 1010 patients in suzetrigine group, 574 patients in placebo group, and 1015 patients in HB/APAP group. (In the evaluation of efficacy, 447 participants were included in the suzetrigine group. However, in the abdominoplasty trial (NCT05558410), an error occurred in the dispensing of the study drug kit at one site, resulting in one participant being randomized to receive a placebo but inadvertently receiving a dose of suzetrigine. Consequently, there is a discrepancy in the number of participants between the suzetrigine, and placebo groups as compared to the efficacy evaluation). Incidence of adverse events was significantly less in suzetrigine group (416/1010) as compared to placebo (278/574) [RR = 0.86 (95% CI 0.77-0.96), I² = 0%; P = 0.007] and HB/APAP (523/1015) [RR = 0.81 (95% CI 0.74-0.88), I² = 0%; P < 0.00001] [Figure 5].

5. Overall incidence of serious adverse events

   Overall incidence of serious adverse events was comparable in suzetrigine (11/1010), placebo (6/574) [RR = 0.97 (95% CI 0.36-2.63), I² = 0%;, P = 0.96], and HB/APAP (8/1015) [RR = 1.39 (95% CI 0.56-3.42), I² = 0%; P = 0.48] groups [Supplementary figure 3 ^{(842.9KB, tif)} ].

6. Overall incidence of nausea and vomiting

   Overall incidence of nausea was significantly less in suzetrigine group (139/1010) as compared to placebo (112/574) [RR = 0.71 (95% CI 0.57-0.90), I² = 0%; P = 0.004] and HB/APAP (243/1015) [RR = 0.57 (95% CI 0.48-0.69), I² = 0%; P < 0.00001] [Figure 6].

   Incidence of vomiting was comparable between suzetrigine group (19/1010) and placebo group (15/574) [RR = 0.73 (95% CI 0.36-1.50), I² = 0%; P = 0.40] [Supplementary Figure 4 ^{(412.7KB, tif)} ] while significantly less in suzetrigine group (19/1010) as compared to HB/APAP (48/1015) [RR = 0.42 (95% CI 0.25-0.70), I² = 0%; P = 0.001] [Figure 6].

Figure 4.

Proportion of participants with ≥30%, ≥50%, and ≥70% reduction in NPRS score at 48 hours (suzetrigine Vs placebo)

Figure 5.

Participants with any adverse events (AEs)

Figure 6.

Participants experiencing nausea and vomiting

Discussion

A systematic review and meta-analysis were undertaken to evaluate the efficacy and safety of suzetrigine, a novel analgesic, for the acute management of postoperative pain. The analysis focused on two surgical procedures: bunionectomy and abdominoplasty. Bunionectomy serves as a model for bone pain, whereas abdominoplasty represents a model for soft tissue pain. Both procedures are associated with moderate to severe postoperative pain.[12,13]

Postoperative pain is an unpleasant physical and psychological experience associated with actual or potential tissue damage caused by the surgery. Approximately 75% of patients experienced postoperative pain following surgery, out of which less than half of patients achieved adequate pain relief. The control of postoperative pain is crucial as it decides the recovery following surgery, number of stay in hospital, quality of life, and health care cost.[2,14,15] The perception of pain involves the detection of stimuli by nociceptors, which converts the painful stimuli into electrical activity and subsequently transmission to the central nervous system via peripheral sensory nerves.[16] Nociceptors use voltage-gated sodium channels (Nav) for propagation of impulses. There are nine types of Nav channels; among them, Nav 1.7, 1.8, and 1.9 are present on nociceptors and become a prime target for analgesic drug development.[17]

Suzetrigine is a recently approved nonopioid analgesic that produces its action by selective inhibition of Nav1.8. Nav 1.8 is the voltage-gated sodium channel that is selectively found on nociceptors of peripheral sensory nerve ending. Suzetrigine stabilizes the channel in closed state and inhibits the influx of sodium ion across the cell, which further limits the transmission of pain. The selective inhibition of the Nav1.8 channel not only minimizes the side effects of suzetrigine but also reduces the risk of addiction as these channels are not present in the central nervous system.[18]

The results of the metanalysis suggest that suzetrigine has significantly better efficacy as compared to placebo in reducing pain. The standard mean difference for SPID 48 was 5.55 (95% CI 2.97-8.13, P < 0.00001), and that for SPID 24 was 5.33 (95% CI 2.50-8.16, P < 0.00001). Improvement in SPID 24 and SPID 48 supports sustained analgesic effect of suzetrigine and strengthens the evidence for suzetrigine efficacy in managing acute pain. The other efficacy parameters which we considered in our metanalysis were proportions of patients who experienced ≥30%, ≥50%, and ≥70% improvement in NPRS score at 48 hours. The odds of achieving ≥30%, ≥50%, and ≥70% reduction in NPRS scores at 48 hours were all significantly higher in the suzetrigine group (OR 1.95, 1.74, and 1.81, respectively, all P < 0.00001), which suggests that suzetrigine offers meaningful relief to a broad range of patients, albeit with varying degrees of pain reduction efficacy.

The analysis also compared suzetrigine with active comparator hydrocodone bitartrate- acetaminophen and found that both drugs are comparable in efficacy. No significant differences were observed in SPID 48 or in the proportion of patients achieving ≥30%, ≥50%, or ≥70% reduction in NPRS scores at 48 hours between the suzetrigine and HB/APAP groups (P > 0.05). These findings are significant as they suggest that suzetrigine may serve as an alternative analgesic to opioids, which could be beneficial for patients at risk of developing opioid-related side effects or those who are resistant to optimal opioid dosing due to opioid dependence.

The metanalysis also evaluated the safety of suzetrigine in comparison to placebo and HB/APAP. The overall incidence of adverse events was significantly lower in the suzetrigine group compared to both placebo (RR 0.86, 95% CI 0.77-0.96, P = 0.008) and HB/APAP (RR 0.81, 95% CI 0.74-0.89, P < 0.00001). These findings are in line with the other trial where efficacy of suzetrigine was evaluated in painful diabetic neuropathy. However, in diabetic neuropathy trial, the highest dose of suzetrigine is less than the dose of suzetrigine use in surgical trials.[19] This suggests that suzetrigine is not only effective but also well tolerated and provides a safer alternative for acute pain management. The incidence of serious adverse events was comparable among suzetrigine, placebo, and HB/APAP groups, indicating no increased risk of severe complications with suzetrigine use. Similar results were observed in another study.[19]

The gastrointestinal side effects of opioids include nausea and vomiting. When suzetrigine was compared with HB/APAP for nausea and vomiting, it was found that suzetrigine is associated with less incidence of nausea [RR = 0.58 (95% CI 0.48-0.69), I² = 0%; P < 0.00001] and vomiting [RR = 0.42 (95% CI 0.25-0.70), I² = 0%; P = 0.001] as compared to HB/APAP. This is a positive finding as episodes of nausea and vomiting affect the patient’s compliance and subsequently delay the patient’s pain relief and recovery process.

In the present meta-analysis, all the included trials evaluated suzetrigine either for 2 days or maximum for 14 days. This short duration of trials fails to demonstrate the long-term efficacy and safety of suzetrigine. Hence, long-term safety studies would be required to assess the potential for tolerance or dependence with prolonged use. Additionally, studies comparing suzetrigine to other nonopioid analgesics and investigating its efficacy in different types of acute pain (e.g., non-surgical pain) could further elucidate its place in pain management strategies. Last, we could not assess the publication bias because of the lesser number of studies (<10) included in the final analysis.

Conclusion

In conclusion, suzetrigine appears to be an effective and well-tolerated option for acute pain management, showing superiority to placebo and comparable efficacy to HB/APAP, with a potentially better safety profile. Nevertheless, future studies are warranted as most of trials were of short duration and carried out only in surgical settings.

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1

SPID 48 (Suzetrigine Vs HB/APAP)

Supplementary Figure 2

Proportion of Participants with ≥30%, ≥ 50% and ≥ 70% reduction in NPRS score at 48 hours (Suzetrigine Vs HB/APAP)

Supplementary Figure 3

Participants with Serious Adverse Events (AEs)

Supplementary Figure 4

Participants Experiencing Vomiting (Suzetrigine vs Placebo)

Funding Statement

Nil.