Cite as: Machi A, Sondekoppam R, Ip VHY. Suzetrigine as a non-opioid analgesic: balancing promise with prudence. ASRA Pain Medicine News 2025;50. https://doi.org/10.52211/asra110125.009.

Introduction

Despite decades of progress, perioperative pain remains undertreated, reflecting the absence of an ideal analgesic that provides effective relief for acute pain while minimizing adverse effects, sedation, or addiction potential. This persistent therapeutic gap continues to drive the search for safer, more targeted non-opioid alternatives. Although the opioid epidemic has reshaped prescribing practices, the more enduring challenge lies in achieving adequate perioperative pain control without the liabilities of opioids. The field still lacks a truly effective non-opioid agent—one capable of delivering robust analgesia without sedation, organ toxicity, or dependence.

Chronic pain further compounds this landscape. Over 50 million adults in the United States, representing approximately 21% of the adult population, report chronic pain, and this number continues to rise (Centers for Disease Control and Prevention).¹ These trends have collectively steered clinical practice toward balanced, multimodal analgesia strategies that emphasize opioid minimization and the integration of effective non-opioid agents.

Against this backdrop, the search for safer alternatives has intensified. Suzetrigine, a selective sodium channel blocker, has recently emerged as a promising candidate. Approved by the U.S. Food and Drug Administration on January 30, 2025, for the treatment of acute postoperative pain,² suzetrigine offers a novel, orally administered, non-opioid option with an encouraging tolerability profile. These attributes position it as a potential addition to perioperative and acute pain management—and perhaps, with time and evidence, a future role in chronic pain care.

The ongoing national discourse on opioid stewardship and chronic pain management underscores a broader shift toward prescribing reform, patient education, and harm reduction. Encouragingly, recent Substance Abuse and Mental Health Services Administration data suggest that opioid-related deaths are beginning to decline.^3,4 New agents like suzetrigine could be viewed within this evolving narrative as tools to support rational, evidence-based multimodal care rather than replacements born of therapeutic optimism.

Still, history cautions against uncritical enthusiasm. Previous “non-opioid solutions” such as gabapentin, once widely adopted for its perceived opioid-sparing potential, failed to demonstrate consistent benefit⁵ and ultimately revealed associations with dependence and misuse.^6,7 Similarly, the liberal use of nonsteroidal anti-inflammatory drugs has been tempered by recognition of potential cardiovascular and renal risks,^8,9 while ketamine’s role in perioperative analgesia remains limited by inconsistent efficacy and tolerability.^10,11 Together, these examples highlight both the genuine need for well-tolerated, effective non-opioid options and the dangers of allowing enthusiasm to outpace evidence.

Although early data on suzetrigine appear promising, its long-term safety profile, real-world effectiveness, and potential off-label applications remain to be fully established. This article examines suzetrigine’s potential to bridge existing gaps in pain management, reviews the current evidence, and advocates for cautious optimism as the field welcomes a long-awaited addition to the non-opioid analgesic landscape.

Mechanism of Action

Suzetrigine is a selective blocker for the voltage-gated sodium channel Nav1.8, which is expressed in peripheral sensory neurons, such as dorsal root ganglion neurons. By stabilizing the closed state of the channel, suzetrigine inhibits the generation of action potentials that act as pain signals in the central nervous system. The promise of targeting nociceptor-specific sodium channels without the sedative or respiratory-depressant effects of opioids is appealing. Yet even here, a dose of humility is necessary. A recent report reminds us that the metabolite of acetaminophen, AM404, also inhibits Nav1.8 and Nav1.7, hinting that the pharmacologic concept of sodium-channel blockade in pain control is not as new as it seems.¹² Additionally, various other drugs target different sodium channels involved in pain transmission, such as Nav1.8, in a state-dependent manner. Several other drugs with similar properties are currently under investigation.^13-15 However, history has shown that novelty in mechanism does not always lead to novel clinical outcomes.

The drug has not, so far, been shown to cause addiction or dependence in human or animal studies.²⁶ Suzetrigine and its major active metabolite are CYP3A4 substrates and its inducer, which can decrease serum concentrations and the efficacy of sensitive CYP3A4 substrates, eg, midazolam. The extent to which suzetrigine may increase plasma levels of buprenorphine or methadone—both of which are CYP3A4 substrates—is unclear as are the effects on other substrates of CYP3A4.¹⁷

Clinical Evidence for its Use and Indication

The FDA approval of suzetrigine was based on the results of two phase-three, double-blind studies on its use for 48 hours, which showed suzetrigine to be more efficacious than placebo in two accepted pain research models: abdominoplasty (soft tissue) and bunionectomy (hard tissue, or bone).¹⁸ These studies also showed suzetrigine was comparable to hydrocodone/acetaminophen 5/325 mg in a total of 2,191 adults with moderate to severe pain: following full abdominoplasty (n=1,118) or bunionectomy (n=1,073). Patients were randomized to receive 48 hours of treatment with suzetrigine, hydrocodone/acetaminophen, or placebo. Suzetrigine was given as 100 mg loading dose followed by 50 mg every 12 hours while hydrocodone was given as hydrocodone 5 mg/acetaminophen 325 mg every 6 hours The primary outcome of least-squares mean time-weighted sum of pain intensity differences (SPID) from baseline over the first 48 hours of treatment was significantly greater with suzetrigine than placebo in both trials (118.4 vs 70.1; and 99.9 vs 70.6), but not against hydrocodone/acetaminophen (118.4 vs 111.8; and 99.9 vs 120.1). The median time to onset of pain relief was 30 minutes in trial 1 and 60 minutes in trial 2.¹⁸ While these trials reached statistical significance, the clinical meaning is less clear because there is no established, interpretable effect size for SPID. In addition, this was in the context of a preoperative Mayo block and continuous popliteal sciatic block until POD 1 in the bunionectomy study, fentanyl, acetaminophen and ropivacaine boluses perioperatively and ibuprofen as rescue medication. The magnitude of the effect of the variables other than ibuprofen, which was reported as negligible, remains unknown.

The only additional studies published thus far include the combination phase 2 study of Jones et al¹⁹ and a phase three single-arm study for surgical and non-surgical acute pain from McCoun et al.²⁰ As each related to the drug development process, all were funded by Vertex Pharmaceuticals.

Similar to the design of the Bertoch et al studies,¹⁸ the Jones studies involved two randomized, double-blind, placebo-controlled phase two trials of suzetrigine for acute postoperative pain after abdominoplasty and bunionectomy.¹⁹ Adults with moderate to severe pain were enrolled postoperatively and were randomized. As it was a dose finding study, there were three potential investigational regimens: high (100 mg load then 50 mg q12h), middle (60 mg load then 30 mg q12h) and low (20 mg load then 10 mg q12h). These were compared to hydrocodone/acetaminophen or placebo. The primary endpoint was the time-weighted sum of the pain-intensity difference from baseline (SPID48), while also evaluating the safety profile. As with the phase three study, “high” dose suzetrigine significantly reduced SPID48 compared to placebo and was comparable to hydrocodone-acetaminophen. In contrast, there was no difference with the “middle” and “low” dose of suzetrigine compared to placebo.

The final study published on suzetrigine to date is that of McCoun et al.²⁰ It is a phase three, open-label, single-arm, multicenter study designed to investigate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe surgical and nonsurgical options, thereby potentially broadening the clinical scope while assessing safety and tolerability. The participants included 256 adults, 222 after surgery (87%) and 34 (13%) with non-surgical acute pain. They received suzetrigine 100 mg oral loading dose and then 50 mg every 12 hours for up to 14 days or until resolution of pain. Rescue medication with acetaminophen 650 mg and ibuprofen 400 mg every 6 hours was permitted. The primary endpoint was safety and tolerability. A secondary endpoint included the participants’ perception of effectiveness on a five-point Likert scale. Almost 37% of participants experienced a mild adverse event (eg, headache 7.0%, constipation 3.5%). There were no drug-related serious adverse events, such as respiratory depression or sedation. Overall, 83.2% of subjects rated suzetrigine as providing “good” to “excellent” analgesia.

Comparative Effectiveness

While the data show that suzetrigine is effective as an analgesic, the degree of additional clinical impact to modern multimodal pain pathways that encompasses acetaminophen, NSAIDs, and regional anesthesia remains unclear. At this time, the evidence on the comparative effectiveness of suzetrigine is entirely lacking outside of its comparison to hydrocodone-acetaminophen in the two phase three trials and two phase two trials. Studies showing its efficacy are largely limited to patients undergoing abdominoplasty and bunionectomy. Thus, the recent enthusiasm in social media and preliminary systematic reviews must also be read with caution. The meta-analysis recently published on the analgesic efficacy of suzetrigine pooled only the few trials described above.²¹ It is premature to conduct or rely on a quantitative synthesis when the underlying data are so narrow. Systematic reviews are powerful when heterogeneity and numbers allow, but they can mislead when applied too early. For now, the data on suzetrigine are best viewed as encouraging but limited snapshots. Furthermore, it is unknown whether its efficacy remains in the presence of neuraxial analgesia or perineural blockade. There are more questions than answers with respect to comparative effectiveness.

Suzetrigine represents an important step in the quest for a safe and effective non-opioid analgesic for acute pain management.

Adverse Effects

Suzetrigine appears to be generally well tolerated in the short term, with most adverse effects being mild and self-limiting. Across phase three surgical trials and open-label studies, nausea, constipation, dizziness, and headache were the most common complaints, while reports of pruritus and rash were infrequent.^18-20 Interestingly, nausea, constipation, and pruritus are well-recognized adverse effects of opioids, and if future data confirm a higher-than-expected incidence of these symptoms with suzetrigine, its non-analgesic advantage over opioids could appear narrower than initially assumed. Creatine kinase elevations and mild, transient decreases in renal function were occasionally observed but not dose-limiting. Importantly, serious drug-related adverse events have not been reported to date, though long-term safety data are still limited. The recommended dosing regimen—an initial 100 mg followed by 50 mg every 12 hours—has been derived from acute pain studies of up to 48 hours, with safety data extending to a maximum of 14 days.²⁰ Beyond this period, efficacy and safety remain unknown, and the FDA approval explicitly restricts use to short-term management of acute pain. If there is no response to therapy, current data do not support dose escalation as higher doses have not shown consistent or clinically meaningful improvement.¹⁹ Non-response likely indicates that the underlying pain phenotype is less dependent on Nav1.8 pathways and should prompt reassessment of pain source, adequacy of multimodal analgesia, and consideration of short rescue opioid therapy when appropriate. There are no published data demonstrating that suzetrigine obviates the need for opioids altogether, and in most trials, opioid rescue was permitted and used in both placebo and suzetrigine arms.

Words of Caution and Future Directions

While suzetrigine is showing promise and there should be enthusiasm around innovation, the clinical effectiveness in the data and in our experience is modest. Moreover, the long-term safety profile is unknown, and the cost for a 14-day course is substantial—hundreds of dollars—if paid out-of-pocket, which is often necessary. Similar to other medications, adverse effects may only become apparent after long-term or widespread use. There are many areas of unknown which warrant further research, such as effectiveness in different patient populations, tolerance development with upregulation of other pathways in long-term use, adverse effects in much larger patient populations, other drug interactions, particularly with other medications that utilize CYP3A4, or withdrawal and rebound effects with abrupt discontinuation from medium/long-term use.

There is also a significant temptation for off-label use on this promising drug. In fact, the appeal to use for chronic neuropathic pain is very high given the lack of effective medication to treat this common, often profoundly painful condition; however, the classic example to learn from would be the gabapentin saga. Heralded as opioid-sparing agents and initially approved for use as an antiepileptic and postherpetic neuralgia, its use spiralled into a first-line postoperative analgesic option, which led to increasing evidence of harm outweighing its benefits, with over-sedation, increase use of naloxone and ventilatory support postoperatively especially in vulnerable population, such as the elderly or people with respiratory illness, or on concurrent sedatives and additional problems of dependency and cessation-related morbidity.^6,7,22,23

Quest for safer opioids and non-opioid adjuncts meant to minimize opioids is the right thing to do, but mechanistic precision rarely translates or guarantees better outcomes. On a similar note, oliceridine—a G protein-biased μ-opioid receptor agonist—was recently promoted as a “safer” opioid. While its mechanism suggested less respiratory depression, the current literature reveals only modest improvements: phase three trials did not demonstrate a clearly superior safety profile compared with standard opioids, and major risks, such as respiratory depression and QT prolongation, remain boxed warnings.^24-26 In short, progress in analgesia depends on balance—refining both non-opioids and opioids while learning when and how to use them wisely. While suzetrigine offers legitimate promise with its novel mechanism of action, there should be caution to monitor its effects as more robust and long-term evidence emerges, and patients are informed of the unknown risks. Suzetrigine deserves structured evaluation, not automatic adoption.

Conclusion

In the evolving landscape of pain medicine, suzetrigine is welcome but not yet a watershed. Cautious optimism, guided by evidence rather than enthusiasm, remains our best strategy. Suzetrigine represents an important step in the quest for a safe and effective non-opioid analgesic for acute pain management. While the purported mechanism of action of suzetrigine seems to be unique in that it selectively binds to Nav1.8, and early studies are encouraging for the safety and tolerability of suzetrigine in patients postoperatively, its efficacy, however, appears modest. Optimism for suzetrigine must be matched by prudence in its implementation and vigilance in its utilization. How judicious clinicians are with this new tool may determine whether it becomes a cornerstone of multimodal analgesia or another lesson in pharmaceutical overreach. Suzetrigine’s approval is a step forward, and it is encouraging to see the field continuing to diversify its pharmacologic toolkit. The safest and most responsible course is pragmatic curiosity—use it where evidence supports, collect data prospectively, and wait for the science to catch up before reshaping practice.

The authors used ChatGPT (OpenAI 2025) to assist in language editing; all substantive content and interpretations are the authors’ own.

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