The effectiveness and value of suzetrigine for moderate to severe acute pain: A summary from the Institute for Clinical and Economic Review’s Midwest Comparative Effectiveness Public Advisory Council

Most definitions of acute pain include pain lasting no more than weeks to a few months, after which pain is considered subacute and then chronic. In the United States, approximately 80 million individuals experience acute pain in a given year, and more than 80% of surgical patients report acute postoperative pain, with most rating their pain intensity as moderate, severe, or extreme. ¹ Fewer than half of patients report adequate pain relief, which can impair daily function and increase the risk of chronic pain. ²

Currently, opioid analgesics are the primary treatment of acute postoperative pain and are often combined with nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen) or acetaminophen. Concerns regarding opioid use center on key side effects (eg, sedation, respiratory depression, and confusion) and most notably the risk of opioid use disorder (OUD). ³ OUD is defined as an opioid dependence that causes significant impairment and distress, and affects approximately 2 million Americans. ^{1 , 4} In 2022, it is estimated that 108,000 people died of opioid overdoses in the United States, with roughly 15,000 of those deaths reportedly caused by opioids that had been prescribed (though not necessarily for the person who died). ⁵ Although NSAIDs can relieve pain without a risk for OUD, there are still potential adverse events associated with their use (eg, gastrointestinal, renal, or cardiovascular events). ⁶ Acetaminophen has a favorable safety profile when appropriate doses are not exceeded, but as a monotherapy it is often inadequate for moderate to severe pain. Altogether, the annual US economic burden of pain (eg, health care costs and work-related productivity losses) is estimated at $560-$635 billion (in 2010 dollars; $823-$933 billion when adjusted for inflation), with $95 billion (in 2023 dollars; $101 billion when adjusted for inflation) from OUD-related emergency department visits alone. ^{1 , 7}

Given the current treatment landscape for pain, there is a great need for nonopioid analgesics to help address the issues of inadequate pain relief and risk of OUD in the treatment of acute pain. Suzetrigine (Journavx; Vertex Pharmaceuticals) is an oral small-molecule inhibitor of the voltage-gated sodium channel Na_v1.8 for the treatment of adults with moderate to severe acute pain. The US Food and Drug Admin-istration (FDA) approved the drug on January 30, 2025.

The Institute for Clinical and Economic Review (ICER) evaluated suzetrigine for acute pain. This report presents the summary of our systematic literature review and cost-effectiveness analyses and highlights the key policy recommendations discussed at the Midwest Comparative Effectiveness Public Advisory Council’s public meeting on February 28, 2025. The ICER Final Evidence Report on suzetrigine for acute pain is available at https://icer.org/wp-content/uploads/2025/03/ICER_Acute-Pain_Final-Report_For-Publication_033125.pdf.

Summary of Findings

CLINICAL EFFECTIVENESS

We evaluated the efficacy and safety of suzetrigine in adults with moderate to severe acute pain against 4 treatment modalities: no systemic therapy, as represented by a placebo arm; low-dose opioids (hydrocodone bitartrate 5 mg/acetaminophen 325 mg [HB5/APAP325], commonly known as Vicodin); high-dose opioids; and NSAIDs.

We looked at direct evidence from 2 pivotal trials, NAVIGATE-1 and 2. ⁸ Adult patients in these trials reported moderate to severe pain following bunionectomy and abdominoplasty procedures, as indicated by a self-reported score of 4 or greater on the 0-10 Numeric Pain Rating Scale (NPRS). On average, patients had a baseline NPRS score of 6.8 in the bunionectomy trial and 7.4 in the abdominoplasty trial. ⁸ In both trials, participants were randomized to receive suzetrigine (50 mg every 12 hours after an initial 100 mg dose), HB5/APAP325 every 6 hours (ie, low dose), or placebo.

The primary outcome was the time-weighted Sum of Pain Intensity Difference over 48 hours of follow-up (SPID48) with pain intensity assessed using the NPRS. A higher SPID48 value indicates greater pain reduction. Suzetrigine demonstrated superior pain relief compared with placebo in both trials; the least squares mean difference (LSMD) in SPID48 between suzetrigine and placebo was 48.4 (95% CI = 33.6-63.1; P < 0.0001) following abdominoplasty, and 29.3 (95% CI = 14.0-44.6; P = 0.0002) after bunionectomy. ⁸ Suzetrigine achieved a median NPRS decrease of at least 2 points, a change considered to be clinically meaningful, within approximately 2 hours in abdominoplasty patients and 4 hours in bunionectomy patients, significantly faster than the placebo group’s median 8-hour duration. ⁸ In the bunionectomy trial, rescue medication (ibuprofen 400 mg) use across 48 hours of follow-up was similar between suzetrigine (85.4%) and placebo groups (85.6%) (P = 0.9143), whereas in the abdominoplasty trial, significantly fewer suzetrigine patients (81.0%) required rescue medication compared with placebo (87.9%) (P = 0.0237). ⁸

Suzetrigine demonstrated a numerical advantage over HB5/APAP325 on the SPID48 in the abdominoplasty trial, but this difference was not statistically significant (LSMD = 6.6; 95% CI = −5.4 to 18.7; P = 0.2781). In the bunionectomy trial, suzetrigine treatment resulted in less pain relief than HB5/APAP325 on the SPID48 (LSMD = −20.2; 95% CI = −32.7 to −7.7; P = 0.0016). Patients in the bunionectomy trial experienced clinically meaningful pain reduction (median NPRS decrease of ≥2 points) faster with HB5/APAP325 (median 1.5 hours) than with suzetrigine (median 4 hours). ⁹ However, in the abdominoplasty trial suzetrigine provided pain relief significantly more quickly (median 2 hours) than HB5/APAP325 (approximately 8 hours). ⁹

We also sought indirect evidence of the relative efficacy of suzetrigine compared with other commonly used analgesics. We conducted a network meta-analysis (NMA) comparing suzetrigine with high-dose opioids (greater than HB5/APAP325) and NSAIDs on SPID48. The results showed that the relative treatment effect size on SPID48 compared with placebo was 0.42 (95% credible interval [CrI] = 0.24-0.61) for suzetrigine, 0.56 (95% CrI = 0.37-0.76) for high-dose opioids, and 0.34 (95% CrI = 0.15-0.52) for NSAIDs. These effect sizes suggest that these analgesics had a small to medium benefit when compared with no systemic therapy. None of the comparisons between the active treatments were statistically significant.

Suzetrigine was well-tolerated and had less than a 1% discontinuation rate owing to adverse events. ⁸ The most frequently reported adverse events were mild or moderate in severity and included pruritus, muscle spasms, elevated creatine kinase levels, and rash. ⁹ Notably, nausea or vomiting occurred less frequently in the suzetrigine group vs HB5/APAP325 in both the abdominoplasty (20.3% vs 33.5%, P < 0.0001) and bunionectomy (9.2% vs 16.5%, P = 0.0014) trials. ⁸ These differences were statistically significant. Given the short-term duration of the trials (approximately 14 days), we have limited information on the long-term safety of suzetrigine.

UNCERTAINTIES BECAUSE OF LIMITATIONS IN THE CLINICAL EVIDENCE

Patients receiving suzetrigine after bunionectomy showed delayed pain relief (longer time to a drop of ≥2 points on the NPRS) than observed in the abdominoplasty trial. This discrepancy may exist because of the use of ropivacaine (another sodium channel blocker) during bunionectomy surgery but not during abdominoplasty, which resulted in lower baseline pain scores in bunionectomy patients, or that suzetrigine works better in some pain models (bone vs soft issue) than others. Another concern is that patients given suzetrigine after bunionectomy had similar rates of rescue medication (ibuprofen) use as those given placebo, raising questions about its comparative efficacy. ⁸

The clinical trials used a lower dose and frequency of hydrocodone/acetaminophen than what doctors typically prescribe after surgery, making it difficult to properly compare efficacy. Our indirect comparison of suzetrigine against higher dose opioids via NMA showed inconclusive results, with large CrIs suggesting high uncertainty. Our comparison of suzetrigine against NSAIDs is limited by similar constraints.

Because suzetrigine has a new mechanism of action in this disease space, we do not fully understand its potential short and long-term risks. Although its FDA label permits use for any moderate to severe acute pain, additional side effects may emerge with widespread use. Finally, we still do not know enough about how suzetrigine compares with opioids in terms of addiction risk or with NSAIDs in terms of specific complications after surgery.

COST-EFFECTIVENESS

A 2-phase decision analytic model was developed to estimate the cost-effectiveness of suzetrigine compared with HB/APAP for moderate to severe acute pain, informed by key clinical trials and previous relevant economic models. Use of acute pain medication was modeled using an upfront short-term decision tree (<3 months) to estimate differences in health-related quality of life owing to pain intensity between suzetrigine and HB/APAP after one 7-day prescription, followed by a Markov model with an annual cycle to account for lifetime outcomes from adverse effects of HB/APAP between treatment arms. The Markov model consisted of the following 4 health states: no OUD, OUD, opioid abstinence, and death. The OUD health state was characterized by high costs, reduced survival, and decreased quality of life. The abstinence health state included the ongoing cost of medication-assisted therapy and was associated with an improved quality of life and a better mortality rate than the OUD health state, although both quality of life and mortality remained worse than those of the general population without OUD.

The economic model included several assumptions. The proportion of patients in the suzetrigine arm assumed to develop OUD within 3 years of short-term treatment was 0%, in contrast to the 0.43% of patients treated with HB/APAP, which was derived from a claim analysis of patients. No further transitions to OUD occurred after 3 years. Transition to the abstinence state was permitted during the first 8 years of the model, with 5.2% of patients transitioning from OUD to abstinence over a 5-year period. After this, we assumed no relapse from the abstinent state to OUD occurred, based on previous evidence of sustained abstinence. Adverse effects from OUD were modeled over a lifetime to account for the delayed risk that can occur after initial treatment and can affect patients’ long-term outcomes.

We used the wholesale acquisition cost (WAC) of $15.50 per 50-mg pill for suzetrigine, as announced by the manufacturer, and assumed an initial dose of 100 mg followed by 50 mg every 12 hours for 1 week. For HB/APAP, we identified the median spending per dosage unit in RedBook and assumed a dosage of 5 mg/325 mg every 6 hours for 1 week. In the short-term decision tree component of the model, there were no differences in quality-adjusted life-years (QALYs) gained (Table 1). In the lifetime Markov model, treatment with suzetrigine resulted in a total discounted cost of $197,500 with discounted equal values of life-years gained (evLYs), QALYs, and LYs of 18.65, 18.65, and 21.92, respectively. In comparison, HB/APAP had a total discounted cost of $197,900 with discounted evLYs, QALYs, and LYs of 18.61, 18.61, and 21.89, respectively. The total discounted cost for suzetrigine was approximately $400 less than HB/APAP, whereas suzetrigine gained 0.039 evLYs, 0.039 QALYs, and 0.032 LYs compared with HB/APAP. Suzetrigine was associated with 429 fewer cases of OUD per 100,000 people than HB/APAP. These results suggested that suzetrigine was dominant (less costly and more effective) across all health outcomes (Table 2). The results of cost-effectiveness estimates were sensitive to the risk of OUD from a short course of HB/APAP, the annual mean excess costs of OUD, and the excess mortality related to OUD.

TABLE 1.

Results for the Base Case for Suzetrigine Compared With HB/APAP

Treatment	Intervention acquisition costs	Intervention-related costs a	Total costs	OUD cases (per 100,000)	QALYs	evLYs	LYs
Suzetrigine	$232.50	N/A	$197,500	0	18.65	18.65	21.92
HB/APAP	$10.64	N/A	$197,900	429	18.61	18.61	21.89

^a Intervention-related costs include markup costs, administration costs, and monitoring costs required for the intervention, as specified in the clinical trials, guidelines, or package label.

evLY = equal value of life-years gained; HB/APAP = hydrocodone bitartrate/acetaminophen; N/A = not applicable; OUD = opioid use disorder; QALY = quality-adjusted life-year.

TABLE 2.

Incremental Cost-Effectiveness Ratios for the Base Case

Treatment	Comparator	Cost per QALY gained	Cost per evLY gained	Cost per life-year gained	Cost per OUD case averted
Suzetrigine	HB/APAP	Less costly, more effective	Less costly, more effective	Less costly, more effective	Less costly, more effective

evLY = equal value of life-years gained; HB/APAP = hydrocodone bitartrate/acetaminophen; OUD = opioid use disorder; QALY = quality-adjusted life-year.

KEY UNCERTAINTIES IN THE MODELING OF COST-EFFECTIVENESS

A key uncertainty in comparing suzetrigine with HB/APAP lies in the excess OUD incidence associated with short-term HB/APAP use as compared with suzetrigine. Because OUD risk from acute pain strongly influences model outcomes, future research should distinguish the effects of acute pain vs chronic pain and opioid vs nonopioid treatments on the risk of developing OUD. Additionally, further studies on suzetrigine are needed to better understand its potential risk for OUD associated with it. To address this limitation, we conducted a scenario analysis to determine the OUD incidence that would result in suzetrigine meeting the $100,000 per QALY and evLY cost-effectiveness threshold. At a WAC of $232.50 per week, suzetrigine reaches this threshold with a 3-year cumulative OUD risk of 0.02% (20 per 100,000). We acknowledge that the incidence of OUD following acute pain may be higher than the base case estimate of 0.43%, so we used an upper bound of 5.7% in a 1-way sensitivity analysis using existing evidence. ¹⁰ The health risks of OUD increase substantially after applying the higher cumulative incidence, leading to greater cost savings and health benefits for suzetrigine compared with those of HB/APAP. Recognizing that variability in inputs may yield alternative results, we expanded our parameters in our uncertainty analyses to include both higher and lower estimates. Results from our sensitivity and scenario analyses remained consistent with the base case.

Policy Discussion

The Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) convened on February 28, 2025, to publicly deliberate on the clinical effectiveness and cost-effectiveness of suzetrigine for acute pain not adequately controlled with nonsystemic therapies. The Midwest CEPAC is an independent appraisal committee composed of medical evidence experts, including clinicians, methodologists, and patient advocates. Their deliberations included input from clinical experts, patient representatives with expertise in pain, and formal comments from the public. Following the discussion, the Midwest CEPAC panel members deliberated on key questions raised by ICER’s report.

In our report, we evaluated the net health benefit of suzetrigine against nonsystemic therapies, opioid analgesics, and NSAIDs, assigning each a “Promising but Inconclusive” (P/I) rating. Midwest CEPAC panel members differed in their assessment of the evidence. Half of the panelists (7-7) found that the current evidence was adequate to demonstrate a net health benefit of suzetrigine plus nonsystemic therapies in comparison with nonsystemic therapies alone (Table 3). Most panelists (12-2) found that the current evidence was not adequate to demonstrate a net health benefit of suzetrigine plus nonsystemic therapies in comparison with oral opioid analgesics plus nonsystemic therapies. The panelists unanimously (14-0) found that the current evidence is not adequate to demonstrate a net health benefit of suzetrigine plus nonsystemic therapies when compared with oral NSAIDs plus nonsystemic therapies. Panel members cited the lack of direct evidence comparing suzetrigine with NSAIDs and the mixed results of the phase 3 trials when explaining their votes.

TABLE 3.

Votes on Comparative Clinical Effectiveness Questions

Question	Yes, n	No, n
For patients with acute pain, is the current evidence adequate to demonstrate that the net health benefit of suzetrigine in addition to nonsystemic therapies (eg, heat therapy or local anesthetic) is greater than that of nonsystemic therapies alone?	7	7
For patients with acute pain, is the current evidence adequate to distinguish the net health benefit of suzetrigine from that of oral opioid analgesics (with or without acetaminophen), each in addition to nonsystemic therapies?	2	12
For patients with acute pain, is the current evidence adequate to distinguish the net health benefit of suzetrigine from that of oral NSAIDs, each in addition to nonsystemic therapies?	0	14

Patient population for all questions: adult patients with acute pain that is not adequately controlled with nonsystemic therapies (eg, heat therapy or local anesthetic).

NSAID = nonsteroidal anti-inflammatory drug.

The Midwest CEPAC also voted on “benefits beyond health” and “special ethical priorities” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about the long-term value for money that are not adequately captured in analyses of clinical and/or cost-effectiveness (Table 4). Most of the panel (9 of 14) voted that suzetrigine at its current price has “intermediate long-term value for money at current pricing” compared with oral opioid analgesics (Table 5).

TABLE 4.

Votes on Benefits Beyond Health and Special Ethical Priorities

Benefits beyond health and special ethical priorities	Strongly disagree, n	Disagree, n	Neutral, n	Agree, n	Strongly agree, n
To help inform judgments of overall long-term value for money, please indicate your level of agreement with the following statements:
There is substantial unmet need despite currently available treatments.	0	1	2	6	5
This condition is of substantial relevance for people from a health/ethnic group that have not been equitably served by the health care system.	0	0	3	8	3
The treatment is likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life.	1	3	8	2	0
The treatment offers a substantial opportunity to improve access to effective treatment by means of its mechanism of action or method of delivery.	0	4	5	4	1

TABLE 5.

Votes on Long-Term Value for Money at the Current Price for Suzetrigine

Question	High long-term value for money at current pricing, n	Intermediate long-term value for money at current pricing, n	Low long-term value for money at current pricing, n
Given the available evidence on comparative clinical effectiveness and incremental cost-effectiveness, and considering benefits beyond health and special ethical priorities, what is the long-term value for money of suzetrigine compared with oral opioid analgesics (with or without acetaminophen) at current pricing?	1	9	4

Following the discussion of the evidence, a policy roundtable was convened to deliberate on how best to translate the evidence and additional considerations on this therapy into clinical practice, pricing, and insurance coverage. The full set of policy recommendations can be found on the ICER website: https://icer.org/wp-content/uploads/2025/03/ICER_Acute-Pain_Policy-Recommendations_Final_033125.pdf

Select key policy recommendations are as follows:

• •Payers, manufacturers, and the federal government should develop policies that enhance the use of therapies with higher upfront costs but greater long-term cost-effectiveness, whether these are gene therapies with very high initial prices or a therapy like suzetrigine where savings will likely be realized years in the future.
• •
  The large population of patients with acute pain, coupled with the higher cost of suzetrigine relative to generic opioid and nonopioid oral analgesics, may prompt payers to implement prior authorization requirements and other use constraints. Payers should consider the following when developing coverage policies:

  • •
    Step therapy: Step therapy is particularly problematic with medications for acute pain. Payers are likely to find that it will be difficult to implement step therapy for suzetrigine. The complication of OUD is one that will not be recognized in time to change to an alternative treatment. Although payers may wish to require that patients try to manage their pain with NSAIDs before filling a prescription for suzetrigine, given the course of acute pain it may be hard for most payers to expediently manage requests for suzetrigine owing to inadequate relief with NSAIDs. If payers wish to implement such policies, they may want to consider novel protocols or prescriptions (such as covering suzetrigine if a patient receives a prescription saying it can only be filled if a patient reports inadequate pain relief with NSAIDs) that can allow management of pain without further payer contact from a patient or provider.
  • •
    Clinical eligibility: We heard from clinical experts that there are no validated tools that are highly predictive of which patients will or will not develop OUD after a short course of opioids.
  • •
    Some payers are likely to develop eligibility criteria that initially allow treatment with suzetrigine only in patients who have previously been intolerant of opioids and NSAIDs or who are felt to be at particularly high risk of OUD (eg, those with prior OUD) or complications from treatment with opioids and/or NSAIDs (eg, older adults or debilitated patients).
• •Manufacturers should set prices that are aligned with net benefits. ICER’s analysis suggests that suzetrigine is priced well within a cost-effective price range, assuming that the risk of OUD after a short course of opioids is nonzero. Vertex deserves recognition for appropriately pricing suzetrigine.
• •The manufacturer should conduct additional research on suzetrigine to answer open questions. Questions remain about suzetrigine’s efficacy for various pain types and its potential synergistic effects when combined with medications like NSAIDs and acetaminophen. Addi-tional research is needed to compare suzetrigine with high-dose NSAIDs and determine its safety in younger populations.

Funding Statement

Drs McQueen, DiStefano, and Zemplenyi received funding from ICER for the work described in this summary.