Suzetrigine as Part of Multimodal Therapy Enables Opioid-Free Recovery after Laparoscopic or Arthroscopic Procedures

Abstract

Introduction

Suzetrigine, a non-opioid voltage-gated sodium channel 1.8 (Na_V1.8) pain signal inhibitor with no addiction potential, is approved in the USA for moderate-to-severe acute pain.

Methods

In this phase 4, single-arm study, suzetrigine (100 mg preoperatively, then 50 mg every 12 h) was administered as part of multimodal therapy (MMT) for ≤ 14 days. Participants (N = 47) underwent arthroscopic or laparoscopic procedures wherein opioids are commonly used ≥ 72 h postoperatively for pain management. Pre- and postoperative MMT was prespecified as suzetrigine, acetaminophen, and ibuprofen. Oxycodone or hydromorphone were permitted as opioid rescue. The primary endpoint was the proportion of participants reporting good/very good/excellent on a patient global assessment (PGA) for pain control after treatment. Opioid rescue and safety were also assessed.

Results

Participants had various surgeries, the most common being arthroscopic knee procedures (38.3%) or rotator cuff repair (17.0%), and laparoscopic hernia repair with mesh (29.8%). Most participants (90.9%) rated suzetrigine as part of MMT as good/very good/excellent on a PGA for pain control at end of treatment; results were consistent across surgeries. A majority of participants (76.1%) did not require opioid rescue; those who did received 2.2 tablets (mean) after surgery (mean: 1.7 days). Suzetrigine was generally safe and well tolerated. One participant had a serious adverse event (aspiration) considered unrelated to suzetrigine. Adverse events were consistent with postoperative settings.

Conclusions

Suzetrigine demonstrated effective pain management and enabled opioid-free recovery for most participants when initiated preoperatively and as part of MMT in arthroscopic or laparoscopic procedures wherein opioids are commonly used postoperatively for pain management. In studies of similar surgeries, < 50% did not require opioids.

Graphical abstract available for this article.

Trial Registration

NCT06887959.

Graphical Abstract

Supplementary Information

The online version contains Supplementary Material available at https://doi.org/10.1007/s40122-026-00865-4.

Key Summary Points

Why carry out this study?

There is an unmet need for effective and safe non-opioid analgesics to improve pain management and reduce reliance on opioids, which remain a key component of multimodal therapy (MMT) despite significant safety and tolerability concerns such as addiction, opioid use disorder, and gastrointestinal side effects.

Suzetrigine, an oral non-opioid analgesic approved in the USA for moderate-to-severe acute pain in adults, selectively inhibits the voltage-gated sodium channel 1.8 (NaV1.8) on peripheral nociceptors, avoiding the addiction potential and tolerability issues of centrally acting opioids.

This phase 4, single-arm study evaluated the effectiveness of suzetrigine, including rescue opioid use, when initiated preoperatively and administered as part of MMT for treatment of acute pain in laparoscopic or arthroscopic procedures wherein historically opioids are commonly used for ≥ 72 h postoperatively for pain management.

What was learned from this study?

Suzetrigine demonstrated effective pain management and enabled opioid-free recovery for most participants (76.1%) when initiated preoperatively as part of MMT after a variety of laparoscopic and arthroscopic procedures for which opioids are commonly used postoperatively for pain management; although cross-study comparisons should be interpreted cautiously, published literature suggests that fewer than 50% of patients undergoing similar arthroscopic or laparoscopic procedures remained rescue opioid-free.

These findings support the potential for suzetrigine to alter pain management practices across broad clinical settings by helping to reduce reliance on opioids while maintaining effective pain control; interpretation of these findings should take into account the single-arm design and small sample size (N = 47).

Digital Features

This article is published with digital features, including a Graphical Abstract, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.32848454.

Introduction

Management of moderate-to-severe acute pain remains a significant challenge across clinical settings. Opioids continue to be a mainstay in multimodal analgesia regimens despite serious safety concerns (e.g., addiction, opioid use disorder, and respiratory depression) and tolerability issues (e.g., nausea, vomiting, constipation, and dizziness) [1]. To overcome the limitations of current multimodal analgesia approaches, there is a critical need for effective and safe non-opioid analgesics to improve pain management and reduce opioid reliance.

Suzetrigine is an oral, non-opioid analgesic approved in the USA for managing moderate-to-severe acute pain in adults. It is a highly selective pain signal inhibitor of the voltage-gated sodium channel 1.8 (Na_V1.8) that is selectively expressed on nociceptors within peripheral sensory nerves and dorsal root ganglia but absent from the human brain. On the basis of this targeted mechanism of action, suzetrigine avoids the addiction risks and tolerability challenges commonly associated with centrally acting opioids [2–8]. In two of the largest phase 3, randomized, controlled trials in established models of acute pain (abdominoplasty/bunionectomy; N = 2191, combined), postoperative administration of suzetrigine demonstrated both statistically significant and clinically meaningful pain relief compared with placebo, with efficacy similar to moderate opioid therapy [9]. Since multimodal therapy (MMT) is a widely used strategy for managing moderate-to-severe acute pain, it is important to evaluate the role of suzetrigine within this framework. The key objective of this phase 4, single-arm study, was to evaluate the effectiveness of suzetrigine, including rescue opioid use, when initiated preoperatively and administered as part of MMT for treatment of acute pain in laparoscopic or arthroscopic procedures wherein historically opioids are commonly used for ≥ 72 h postoperatively for pain management [10].

Methods

Study Oversight

This study was sponsored by Vertex Pharmaceuticals Incorporated (Vertex) and was designed by the sponsor in collaboration with the steering committee. All participant-facing study procedures were conducted by independent investigators and site study staff, and there was no direct contact between the sponsor and study participants. Site study staff and participants received formal bias training, and key study data were reported directly by participants, helping to limit potential bias in data collection. Data were collected by the investigators and analyzed by the sponsor according to the prespecified statistical analysis plan, with procedures in place to maintain data integrity throughout collection and handling. The investigators were responsible for study conduct at their respective sites, including data accuracy and adverse event reporting. The sponsor and investigators vouch for the fidelity of the study to the protocol. All authors had access to the relevant study data, participated in data interpretation, critically reviewed the manuscript, and approved it for submission.

Ethical Approval

The study protocol was approved by a central institutional review board (Advarra, Inc.; Pro00081432) and conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All participants provided written informed consent before screening. All study sites accepted the approval of the central institutional review board (IRB) except that of Ashraf S. Habib, which used their local IRB: Duke University Health Systems Institutional Review Board ([Pro00117274]; 2200 West Main St.; Campus Box 104026; Erwin Square, Ste 900; Durham, NC, 27705, USA).

Study Design and Participants

An overview of the study design is shown in Fig. 1. Eligible participants were adults (≥ 18 years) with a body mass index (BMI) of ≥ 18.0 to ≤ 40.0 kg/m² who were scheduled to undergo a laparoscopic intraperitoneal or retroperitoneal procedure or arthroscopic orthopedic procedure that would typically be treated with opioid therapy for at least 72 h postoperatively as the standard of care (at the discretion of the investigator) [10].

Fig. 1.

Study design. ^aA participant for whom ibuprofen was contraindicated could participate in the study and take acetaminophen alone instead of the acetaminophen and ibuprofen regimen. ATC, around the clock; pre-op, preoperative; prn, as needed; q6h, every 6 h; q12h, every 12 h

Approximately 50 participants were planned to be enrolled to receive suzetrigine (100 mg first dose, then 50 mg every 12 h [q12h]) for 14 days or until their pain resolved, whichever occurred first.

On day 1, participants received the first dose of suzetrigine (100 mg) approximately 1 h prior to the surgical procedure (Supplementary Table S1). In addition to suzetrigine, preoperative MMT was prespecified as acetaminophen (1000 mg, oral or intravenous [IV]) for all participants and ibuprofen (600 mg, oral) for all participants except those undergoing arthroscopic rotator cuff repair (who received an interscalene nerve block, celecoxib [200 mg, oral] and dexamethasone [4 mg, IV] instead). Participants for whom ibuprofen was contraindicated could take acetaminophen alone instead of the acetaminophen and ibuprofen regimen.

Postoperative analgesic protocols were standardized across study sites. During the first 72 h after surgery, postoperative MMT was prespecified as acetaminophen (650 mg every 6 h [q6h], oral) and ibuprofen (400 mg q6h, oral) around the clock. Oral opioids (i.e., oxycodone or hydromorphone at a dose prescribed by the participant’s physician) were permitted as first-tier rescue medication during the initial 72-h postoperative period. After 72 h, acetaminophen and ibuprofen together were taken as the first tier of rescue medication, before taking an orally administered opioid (i.e., oxycodone or hydromorphone) as the second tier of rescue medication. Participants were encouraged to wait at least 60 min after taking a dose of acetaminophen and ibuprofen before use of the opioid rescue. Rescue opioid use was evaluated continuously, as participants recorded their use in an electronic diary.

Outcomes

Study endpoints are listed in Supplementary Table S2. The effectiveness of suzetrigine was evaluated on the basis of the primary endpoint, which was the proportion of participants reporting good, very good, or excellent on a patient global assessment (PGA; evaluated on a 5-point Likert scale [poor, fair, good, very good, or excellent]) for pain control at the end of treatment; this endpoint has been used in numerous acute pain studies, and positive patient-reported ratings are associated with lower pain intensity as well as satisfaction with pain relief, thus providing a more global assessment of the patient’s impression of their pain control [11]. The effectiveness of suzetrigine was also evaluated on the basis of the other endpoints, including the proportion of participants reporting good, very good, or excellent on a PGA for pain control over time; proportion of participants who remained rescue opioid-free through 72 h after the end of surgery and through the end of treatment; opioid rescue medication usage through 72 h after the end of surgery and through the end of treatment; number of days of opioid rescue medication usage through the end of treatment; time to first opioid rescue medication use; and incidence of vomiting, nausea, or constipation through the end of treatment. Safety was also assessed as an other endpoint and was based on the incidence of adverse events (AEs).

Statistical Analysis

All analyses included participants who received at least one dose of suzetrigine, unless otherwise specified. Participants recorded PGA in an electronic diary after the first dose of suzetrigine on that day. The proportion of participants reporting good, very good, or excellent on a PGA at the end of treatment was summarized descriptively with 95% exact confidence intervals (CIs) using Clopper Pearson method. PGA at end of treatment was defined as either the PGA collected on day 14 or within 48 h after the last dose for participants who completed or discontinued suzetrigine; PGA was also measured on day 3 and day 7. Missing PGA assessments at end of treatment were imputed using the last available PGA assessment. Participants without any PGA were excluded from the analysis. Safety and other endpoints were summarized descriptively.

Results

Demographics and Baseline Clinical Characteristics

The study enrolled a diverse group of participants who underwent a broad range of minimally invasive laparoscopic abdominal or gynecologic, as well as arthroscopic orthopedic surgical procedures (Table 1). A total of 47 participants received at least one dose of suzetrigine. The mean ± standard deviation (SD) age was 51.9 ± 14.8 years, with 17.0% of participants ≥ 65 years of age. Participants were balanced by sex (male: 48.9%; female: 51.1%). Most participants (85.1%) were white, 10.6% of participants were Black or African American, and 8.5% of participants were Hispanic or Latino. The majority of participants (57.4%) had orthopedic surgery (knee, rotator cuff repair, or other), 29.8% had abdominal surgery (hernia repair with mesh), and 12.8% had gynecologic surgery (hysterectomy or other). The mean duration of suzetrigine treatment was 10.4 days and maximum duration of treatment was 15 days; given availability of extra tablets of suzetrigine, some participants continued to take suzetrigine beyond the 14-day study period (Supplementary Table S3).

Table 1.

Demographics and baseline clinical characteristics

	Suzetrigine N = 47
Age (years)
Mean (SD)	51.9 (14.8)
Min, max	22, 76
≥ 65, n (%)	8 (17.0)
Sex, n (%)
Male	23 (48.9)
Female	24 (51.1)
Race, n (%)
White	40 (85.1)
Black or African American	5 (10.6)
Asian	1 (2.1)
American Indian or Alaska Native	1 (2.1)
Ethnicity, n (%)
Hispanic or Latino	4 (8.5)
Not Hispanic or Latino	43 (91.5)
BMI (kg/m2), mean (SD)	28.54 (4.67)
Surgical procedure, n (%)
Orthopedic	27 (57.4)
Kneea	18 (38.3)
Rotator cuff	8 (17.0)
Otherb	1 (2.1)
Abdominal	14 (29.8)
Hernia repair with mesh	14 (29.8)
Gynecologic	6 (12.8)
Hysterectomy	2 (4.3)
Otherc	4 (8.5)

^aOrthopedic knee procedures included knee arthroscopy with or without meniscectomy, with or without chondroplasty, with or without synovectomy

^bOther orthopedic procedure was a shoulder arthroscopy with biceps tenodesis and capsular shift/labral repair

^cOther gynecologic procedures by participant included laparoscopic salpingectomy; laparoscopy, lysis of peritoneal adhesions, and right salpingectomy; diagnostic laparoscopy with peritoneal biopsy; and laparoscopy, surgical salpingectomy (partial/total salpingectomy), and removal of intrauterine device

Table includes all participants who received at least one dose of suzetrigine

BMI, body mass index; SD, standard deviation

Disposition

Most participants (91.5%) completed treatment with suzetrigine (Fig. 2). Overall, 23 (48.9%) participants completed treatment before day 14 owing to pain resolution, and 20 (42.6%) participants completed treatment through day 14. Four participants discontinued suzetrigine; none were due to lack of efficacy or AEs related to suzetrigine. One participant (knee procedure) discontinued treatment owing to a mild AE of right lumbar back pain, which was considered unrelated to suzetrigine. Additional reasons for treatment discontinuation included loss to follow-up, participant not meeting eligibility criteria, and other (i.e., participant inadvertently submitted that their pain resolved on day 1).

Fig. 2.

Participant disposition. ^aParticipant (knee procedure) discontinued treatment owing to mild right lumbar back pain, which was considered not related to suzetrigine. ^bParticipant inadvertently submitted that their pain resolved on day 1 in the e-diary. Study drug was discontinued per protocol; the discontinuation occurred on day 6

Effectiveness Outcomes

Patient Global Assessment

Most participants (90.9%; 95% CI: 78.3%, 97.5%) rated suzetrigine as part of MMT for pain control on a PGA as good, very good, or excellent at the end of treatment (primary endpoint; Fig. 3). By response category, 47.7% of participants reported excellent, 29.5% reported very good, and 13.6% reported good on the PGA (Supplementary Table S4).

Fig. 3.

Patient global assessment. ^aThree participants at the end of treatment and day 7 without any PGA data were excluded from the analysis. ^bFive participants at day 3 without any PGA data were excluded from the analysis. ^cOnly surgical procedures with N ≥ 5 are presented. CI, confidence interval; PGA, patient global assessment

The proportion of participants reporting good, very good, or excellent on a PGA for pain control was 83.3% by day 3 and 93.2% by day 7 (Fig. 3). Results were consistently high across surgical procedures; the proportion of participants reporting good, very good, or excellent on a PGA for pain control through the end of treatment for individual surgical procedures ranged from 84.6% (hernia repair with mesh) to 100.0% (rotator cuff repair and gynecologic procedures).

Proportion of Participants Remaining Rescue Opioid-Free

The majority of participants (76.1%) remained rescue opioid-free both through 72 h after the end of surgery and through the end of treatment (Fig. 4). Results were generally consistent across surgical procedures; the proportion of participants who remained rescue opioid-free through the end of treatment ranged from 60.0% (gynecologic procedures) to 87.5% (rotator cuff repair).

Fig. 4.

Proportion of participants who remained rescue opioid-free. Rescue opioids were defined as opioid analgesics that were taken orally between the end of surgery and the last dose of suzetrigine. ^aOnly surgical procedures with N ≥ 5 are shown

Opioid Rescue Medication Usage

Total and number of days of opioid rescue medication usage among all participants are presented in Supplementary Table S5. Median time to first use of rescue opioid medication was not estimable. Owing to the low percentage of participants requiring opioid rescue medication (23.9%), we performed a post hoc analysis to evaluate average total rescue medication usage and number of days of opioid rescue medication usage in the subset of participants who used opioid rescue medications. Among the 11 participants who utilized opioid rescue medication, the mean number of tablets used per participant was 2.2, the mean total opioid rescue medication usage was 16.7 morphine milligram equivalents (MME) per participant, and the mean number of days of opioid rescue medication usage was 1.7 days (Table 2). All participants with rescue opioid use initiated rescue opioids within 72 h post-surgery; one participant had additional rescue opioid use after 72 h post-surgery (Fig. 5). Among these 11 participants, 10 received oxycodone (5 mg) and 1 received oxycodone/APAP (5/325 mg). In addition, 8 of the 11 participants with rescue opioid use took the first dose prior to discharge (Supplementary Table S6).

Table 2.

Opioid rescue medication usage among participants with rescue opioid use

		Surgical procedure
	Overall N = 11	Knee N = 4	Hernia repair with mesh N = 4	Rotator cuff repair N = 1	Gynecologic N = 2
Total opioid rescue medication usage through 72 h after the end of surgery, MME per participanta
n	11	4	4	1	2
Mean (SD)	14.7 (15.8)	12.2 (7.1)	20.6 (26.3)	15.0 (–)	7.5 (0.0)
Total opioid rescue medication usage through the end of treatment, MME per participanta
n	11	4	4	1	2
Mean (SD)	16.7 (17.2)	12.2 (7.1)	20.6 (26.3)	37.5 (–)	7.5 (0.0)
Total opioid rescue medication usage through the end of treatment, number of tablets per participant
n	11	4	4	1	2
Mean (SD)	2.2 (2.3)	1.6 (0.9)	2.8 (3.5)	5.0 (–)	1.0 (0.0)
Number of days of opioid rescue medication usage through the end of treatmentb
n	11	4	4	1	2
Mean (SD)	1.7 (1.3)	1.5 (0.6)	1.5 (1.0)	5.0 (–)	1.0 (0.0)

^aSum of all opioid rescue medication usage, where opioid rescue medication usage (MME) = concentration (mg) × tablets (or units) × morphine ratio

^bNumber of days with rescue opioid usage was calculated from the end of surgery through the end of treatment

The table includes participants with rescue opioid use. Rescue opioid was defined as opioid analgesics that were taken orally between the end of surgery and the last dose of suzetrigine

MME, morphine milligram equivalents; SD, standard deviation

Fig. 5.

Participant study journey. Only surgical procedures with N ≥ 5 are shown

Incidence of Nausea, Vomiting, and Constipation

Overall, seven (14.9%) participants had nausea or constipation through the end of treatment (Supplementary Table S7); no participants experienced vomiting. All AEs of nausea or constipation were mild or moderate in severity. The median time to first onset of nausea or constipation was within 1.0 day of surgery, and the median duration of nausea or constipation events was 2.0 days (Supplementary Table S8).

MMT Usage

Observed usage of pre-, intra-, and postoperative analgesic medications is summarized in Table 3. Pre- and intraoperatively, the majority of participants received opioids (89.4%), acetaminophen (97.9%), nonsteroidal anti-inflammatory drugs (NSAIDs) (95.7%), and/or local anesthetics (89.4%). In the initial 72-h postoperative period, the majority of participants (70.7%) used suzetrigine with acetaminophen and/or ibuprofen only. Among the 38 participants who continued suzetrigine after the initial 72-h postoperative period, 50.0% used only suzetrigine, and 47.4% used suzetrigine with acetaminophen and/or ibuprofen.

Table 3.

Pre/intraoperative and postoperative medication use

	Suzetrigine N = 47 n (%)
Pre/intraoperative medicationsa
Suzetrigine	47 (100.0)
Opioidsb	42 (89.4)
Acetaminophen	46 (97.9)
NSAIDsc	45 (95.7)
Local anestheticsd	42 (89.4)
Steroidse	17 (36.2)
Immediately postoperative IV opioidsf	10 (21.3)
Postoperative multimodal therapy within initial 72-h postoperative period
Participants who continued dosing suzetrigine postoperatively	41
Suzetrigine only	2 (4.9)
Suzetrigine and ibuprofen and/or acetaminophen only	29 (70.7)
Suzetrigine and rescue opioids
Rescue opioids, ibuprofen and/or acetaminophen	10 (24.4)
Postoperative multimodal therapy after initial 72-h postoperative period through the end of treatment
Participants who continued dosing suzetrigine after the initial 72-h postoperative period	38
Suzetrigine only	19 (50.0)
Suzetrigine and ibuprofen and/or acetaminophen only	18 (47.4)
Suzetrigine and rescue opioids
Rescue opioids, ibuprofen and/or acetaminophen	1 (2.6)

^aProtocol-mandated preoperative medications included suzetrigine, acetaminophen, and either celecoxib and dexamethasone (rotator cuff repair) or ibuprofen (all other procedures; if not contraindicated). As part of general anesthesia, short-acting parenteral opioids were allowed

^bPre/intraoperative opioids: fentanyl, hydromorphone

^cNSAIDs: ibuprofen, celecoxib, ketorolac

^dLocal anesthetics (via nerve blocks and/or infiltration): lidocaine (with or without epinephrine), bupivacaine, ropivacaine (with or without epinephrine)

^eSteroids: dexamethasone

^fIV opioids (permitted for the first 30 min after surgery completion): fentanyl, pethidine, hydromorphone

The table includes all participants who received at least one dose of suzetrigine

IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs

The most common other concomitant medications (used by $\ge$ 5 participants) used from day 2 onward were aspirin, lisinopril, and vitamins not otherwise specified (Supplementary Table S9).

Safety

Suzetrigine was generally safe and well tolerated (Table 4). All AEs were mild or moderate in severity. The most common AEs (occurring in ≥ 5% of participants) were constipation (8.5%) and nausea (6.4%). One (2.1%) participant had a mild AE of right lumbar back pain that led to treatment discontinuation and was assessed by the investigator as not related to suzetrigine. One (2.1%) participant (knee procedure) had a serious adverse event (SAE; aspiration) that was considered by the investigator to be unrelated to suzetrigine.

Table 4.

Summary of adverse events

	Suzetrigine N = 47 n (%)
Participants with any AEs	19 (40.4)
Participants with AEs by maximum severity
Mild	10 (21.3)
Moderate	9 (19.1)
Participants with SAEsa	1 (2.1)
Participants with AEs leading to treatment discontinuationb	1 (2.1)
AEs occurring in ≥ 2 participants
Constipation	4 (8.5)
Nausea	3 (6.4)
Blood bicarbonate decreased	2 (4.3)
Post-procedural swelling	2 (4.3)
Pruritus	2 (4.3)
Rashc	2 (4.3)
Urinary tract infection	2 (4.3)
Vulvovaginal mycotic infection	2 (4.3)

^aOne participant (knee procedure) had an SAE (aspiration) that was considered unrelated to suzetrigine

^bOne participant (knee procedure) discontinued treatment owing to mild AE of right lumbar back pain that was considered unrelated to suzetrigine

^cThe two AEs of rash were localized (i.e., abdomen and under the breast) and were not considered to be related to suzetrigine

The table includes all participants who received at least one dose of suzetrigine

AE, adverse event; SAE, serious adverse event

Discussion

Multimodal analgesia is a widely used approach for managing moderate-to-severe acute pain, often including opioids despite the well-documented safety concerns (e.g., addiction, opioid use disorder, and respiratory depression) and tolerability issues (e.g., nausea, vomiting, constipation, and dizziness) [1]. There remains an unmet need for effective and safe pain management strategies that minimize opioid use, particularly in the context of postoperative recovery.

The findings from this single-arm, open-label study suggest that suzetrigine, when initiated preoperatively and as part of MMT after a variety of laparoscopic and arthroscopic orthopedic surgical procedures, provides effective pain management as a non-opioid treatment option. A majority of participants (90.9%) rated suzetrigine as part of MMT as good, very good, or excellent in managing their postoperative pain. These results were consistently high across a broad range of surgical procedures.

This single-arm study also showed that most participants (76.1%) were rescue opioid-free through the end of treatment; these results were also consistent across surgical procedures. To contextualize these results, a literature review (details provided in Supplementary Material) was conducted to assess rescue opioid use among patients undergoing similar procedures without the use of suzetrigine. Across multiple studies in the literature, < 50% of patients who underwent similar arthroscopic or laparoscopic surgical procedures were rescue opioid-free, with reported rates ranging from 17.6% to 46.0% (Fig. 6) [12–16]. Although cross-study comparisons should be interpreted cautiously, the proportion of participants who were rescue opioid-free in the present study was numerically higher than rates reported in the literature [12–16]. This study also provided valuable insights into specific surgical contexts. For instance, 87.5% of participants who underwent rotator cuff repair remained opioid-free postoperatively compared with the 28% reported in the literature [16]. Similarly, 77.8% of participants undergoing orthopedic knee procedures achieved opioid-free recovery compared with the reported ranges of 17.6–37.0% in prior studies [13, 14]. Lastly, 71.4% of participants who underwent hernia repair with mesh were rescue opioid-free compared with the approximately 46% of patients who had opioid-free recovery in the literature [12, 15]. The rescue opioid-free recovery rate in the present analysis is also consistent with a retrospective, observational drug utilization study of suzetrigine in a diverse patient population (N = 3288), including nearly one-third of patients (N = 1009) who underwent diverse surgical procedures, from the Merative™ MarketScan^® Commercial Claims and Medicare databases. In that study, suzetrigine was the only analgesic filled for 82.8% of patients; the remaining 17.2% of patients were co-prescribed other analgesics (i.e., opioids, NSAIDs, or acetaminophen), indicating that > 80% of suzetrigine-treated patients remained opioid-free [17]. Among the 23.9% of participants who required rescue opioid use in this study, the mean total opioid consumption was minimal (16.7 MME), with an average of only 2.2 tablets used over 1.7 days. Collectively, these findings suggest that suzetrigine may have utility as part of MMT in supporting postoperative pain management and reducing rescue opioid use across diverse laparoscopic or arthroscopic procedures.

Fig. 6.

Proportion of participants who remained rescue opioid-free within context of literature. ^aLiterature-based data from different studies

In addition, suzetrigine demonstrated a favorable safety profile. No SAEs related to the drug were reported, and all AEs were mild to moderate in severity, and consistent with the postoperative setting [18]. Notably, none of the participants had an AE of vomiting. Overall, these findings indicate that suzetrigine was generally safe and well tolerated.

A major limitation of this study is its single-arm design, as the absence of a placebo or active control group prevents direct comparisons of suzetrigine’s effectiveness against other pain management approaches. Furthermore, pain scores using the visual analog scale (VAS) and the numeric pain rating scale (NPRS) were not assessed in this study; however, in two large randomized, controlled phase 3 trials in abdominoplasty and bunionectomy (N = 2191, combined) evaluating the efficacy of suzetrigine using NPRS, suzetrigine demonstrated statistically significant and clinically meaningful pain relief versus placebo [9]. Another limitation is the small sample sizes across different surgical procedures, which warrants cautious interpretation, particularly for subgroup analyses. Although we did not conduct formal statistical hypothesis testing comparing the effectiveness of suzetrigine in the different surgical models, the results are generally consistent across surgeries and with findings from other suzetrigine acute pain trials suggesting the outcomes are valid for a wide variety of surgical procedures [3, 9, 19]. A final limitation is that most participants are white; however, in the two large randomized, controlled phase 3 trials in abdominoplasty and bunionectomy, there was no difference in pain relief between white participants and participants of other races [20].

Conclusions

Suzetrigine demonstrated effective pain management and enabled opioid-free recovery for most participants (76.1%) when initiated preoperatively and as part of MMT after a variety of laparoscopic abdominal or gynecologic, as well as arthroscopic, surgeries for which opioids are commonly used postoperatively for pain management. By enabling opioid-free recovery for most participants, suzetrigine may help reduce reliance on opioids within current multimodal analgesia regimens across a broad range of clinical settings.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Daneshvari Solanki, Darin J. Correll, and Scott G. Weiner contributed to study conception and design. Data acquisition was carried out by Ashraf S. Habib, Daneshvari Solanki, Jeremy Hoff, Dominick D’Aunno, George Konis, and Jeffrey Moore. Data analysis was performed by William Bortcosh, Lanju Zhang, and Darin J. Correll. Daneshvari Solanki, William Bortcosh, Lanju Zhang, Jaideep Mehta, Darin J. Correll, Richard Scranton, and Scott G. Weiner contributed to the interpretation of the data. The initial draft of the manuscript was prepared by Darin J. Correll and Richard Scranton. All authors critically reviewed the manuscript and approved the final version for publication.

Funding

This study and the journal’s Rapid Service Fee were funded by Vertex.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Vertex is committed to advancing medical science. This includes the responsible sharing of data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact ctds@vrtx.com if you would like to submit a proposal or need more information.

Declarations

Conflict of Interest

Ashraf S. Habib has reported grants or contracts from Vertex and Pacira Biosciences. Scott G. Weiner has reported consulting fees from Vertex and Cessation Therapeutics. William Bortcosh, Lanju Zhang, Jaideep Mehta, Darin J. Correll, and Richard Scranton are employees of Vertex and may hold stock/stock options in the company. Daneshvari Solanki, Jeremy Hoff, Dominick D’Aunno, George Konis, and Jeffrey Moore have nothing to disclose.

Ethical Approval

The study protocol was approved by a central institutional review board (Advarra, Inc.; Pro00081432) and conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All participants provided written informed consent before screening. All study sites accepted the approval of the central IRB except that of Ashraf S. Habib, which used their local IRB: Duke University Health Systems Institutional Review Board ([Pro00117274]; 2200 West Main St.; Campus Box 104026; Erwin Square, Ste 900; Durham, NC, 27705, USA).