Introduction

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The FDA approval of Suzetrigine (Journaux) marks a significant advancement in the field of pain management, particularly in the realm of non-opioid alternatives for acute pain relief [1]. For over two decades, no novel drug class has emerged to challenge the dominance of opioids in treating acute pain, despite the pressing need for safer options. Suzetrigine’s unique mechanism of action, favorable safety profile, and potential role in acute and neuropathic pain make it a game-changer in clinical practice. This commentary explores the significance of Suzetrigine’s approval, its integration into pain management, and the broader implications for patients and healthcare providers.

Suzetrigine’s Role in Addressing Unmet Needs

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Acute pain is a widespread issue affecting over 80 million Americans annually, and its management remains a critical concern in emergency and surgical settings. Historically, opioids have been the cornerstone of acute pain treatment, but their use has raised concerns about its contributions to an opioid crisis characterized by dependency, misuse, and overdose-related deaths. Suzetrigine offers a promising alternative by providing effective pain relief without the risks associated with opioids.

Acute Pain Management

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Suzetrigine provides rapid relief for moderate-to-severe acute pain, making it a valuable addition to postoperative pain protocols and emergency care [2,3]. The ability to manage acute pain effectively is crucial, as inadequate pain control can lead to prolonged recovery times, increased hospital stays, and a higher likelihood of transitioning to chronic pain.

In surgical settings, Suzetrigine has demonstrated efficacy in reducing pain intensity following procedures such as abdominoplasty and bunionectomy. Its inclusion in multimodal pain management strategies could help minimize opioid exposure while maintaining adequate pain control, particularly in orthopedic, dental, and trauma-related pain scenarios.

Potential in Neuropathic Pain Treatment

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While primarily positioned for acute pain, Suzetrigine’s selective inhibition of voltage-gated sodium channel NaV1.8 suggests potential efficacy in neuropathic pain conditions. Chronic neuropathic pain, often resistant to conventional analgesics, represents a significant clinical challenge. Early evidence indicates that NaV1.8 plays a critical role in neuropathic pain pathways, and further research could establish Suzetrigine as a viable treatment option for conditions such as diabetic neuropathy, postherpetic neuralgia, and chemotherapy-induced neuropathy. If confirmed, this expanded application would further increase its value in pain management.

Unique Mechanism of Action

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Suzetrigine’s novel mechanism of action sets it apart from existing pain medications [4]. Unlike traditional analgesics, which often target broad receptor systems leading to significant side effects, Suzetrigine selectively inhibits NaV1.8, a key sodium channel involved in pain signal transmission.

By blocking NaV1.8, Suzetrigine effectively reduces repetitive nerve firing in sensory neurons without affecting other sodium channels essential for normal physiological function. This selectivity minimizes the risk of common side effects associated with non-selective sodium channel blockers, such as dizziness, sedation, and cognitive impairment. The result is a potent yet tolerable analgesic that preserves neural function while suppressing pathological pain signaling.

Safety Profile: A Key Differentiator

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One of the most compelling aspects of Suzetrigine is its favorable safety profile. In Phase 3 clinical trials, the drug was well-tolerated, with most adverse events (AEs) being mild to moderate. Importantly, the overall incidence of AEs was comparable to or lower than that of placebo and hydrocodone-acetaminophen, a commonly prescribed opioid combination.

Unlike opioids, Suzetrigine does not pose a risk of respiratory depression, dependence, or misuse, addressing a major concern in pain management. This makes it a particularly attractive option for populations at high risk for opioid-related complications, including older adults, individuals with a history of substance use disorder, and patients requiring long-term pain management strategies.

Efficacy and Patient Outcomes

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Clinical trials have demonstrated Suzetrigine’s robust efficacy across a range of surgical and non-surgical pain models [5]. In pivotal studies, patients receiving Suzetrigine reported significantly greater pain relief compared to placebo, with a faster onset of action. Notably, 83% of patients rated their pain relief as “good” to “excellent,” highlighting its real-world effectiveness.

The rapid onset of pain relief is particularly valuable in acute pain scenarios, where timely intervention can prevent pain from escalating and improve overall patient comfort. Furthermore, its potential to reduce opioid consumption in postoperative settings underscores its role in enhancing recovery and reducing the burden of opioid-related side effects, such as nausea, constipation, and sedation.

Cost-Effectiveness and Accessibility

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Suzetrigine’s approval aligns with policy initiatives aimed at expanding access to non-opioid pain management options. The NOPAIN Act, set to take effect in January 2025, facilitates Medicare coverage for FDA-approved non-opioid pain therapies in outpatient surgical settings. This legislation is expected to help broader adoption of Suzetrigine by reducing financial barriers and incentivizing healthcare providers to incorporate it into pain management protocols.

From a cost-effectiveness standpoint, reducing opioid use has substantial economic benefits. Opioid-related complications contribute to increased healthcare costs through prolonged hospital stays, readmissions, and addiction treatment expenses. By offering a safer and equally effective alternative, Suzetrigine has the potential to lower these costs while improving patient outcomes.

Challenges and Future Directions

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Despite its promise, several challenges remain in the widespread adoption of Suzetrigine.

1. Physician and Patient Education

The transition from opioid-centric pain management to non-opioid alternatives requires significant education and advocacy. Healthcare providers must be informed about Suzetrigine’s benefits, dosing strategies, and potential applications beyond acute pain. Additionally, patients accustomed to opioid prescriptions may need reassurance regarding the efficacy of non-opioid alternatives.

2. Long-Term Safety and Real-World Data

While clinical trials have demonstrated a strong safety profile, long-term real-world data will be essential to confirm Suzetrigine’s effectiveness and tolerability across diverse patient populations. Post-marketing surveillance will be critical in monitoring for any unforeseen adverse effects or potential off-target interactions.

3. Expanding Indications

Further research is needed to explore Suzetrigine’s potential applications in chronic and neuropathic pain. If ongoing studies validate its efficacy in these conditions, its clinical utility will expand significantly, offering relief to patients with limited treatment options.

Conclusion

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The FDA approval of Suzetrigine represents a pivotal moment in pain management, offering a long-overdue non-opioid alternative for acute pain relief. Its selective NaV1.8 inhibition provides a novel and targeted approach to pain control, minimizing side effects while maintaining efficacy. With a strong safety profile, rapid onset of action, and potential for broad clinical applications, Suzetrigine is poised to redefine acute pain treatment and reduce reliance on opioids.

As healthcare systems continue to grapple with the opioid crisis, the introduction of innovative analgesics like Suzetrigine is a welcome development. By integrating this groundbreaking medication into multimodal pain management strategies, clinicians can enhance patient care, improve outcomes, and contribute to a future where effective pain relief does not come at the cost of addiction and dependency. Moving forward, continued research, education, and policy support will be essential to maximize the impact of this promising new therapy.

COI Statement

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No conflict of interest to disclose.

Funding

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Supported by the following grants:

NIH/NINDS/1UG3NS127258-01A1 UG3/UH3 (Jianguo Cheng)

NIH/NIAMS 3R01AR077452-04S1, 09/15/2013 - 04/30/2025 (Xiaojuan Li and Jianguo Cheng)

Lisa Dean Moseley Foundation (LDMF 0920JC, 1909JC, 1812JC, and 1709 Jianguo Cheng)

Cleveland Clinic Pain Management Innovations Fund #T56629 (Jianguo Cheng).

References

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1. Dolgin E. US drug agency approves potent painkiller - the first non-opioid in decades. Nature. 2025.
2. Hang Kong AY, Tan HS, Habib AS. VX-548 in the treatment of acute pain. Pain Manag. 2024;14(9):477-486.
3. Mullard A. Vertex's non-opioid painkiller passes phase III tests. Nat Rev Drug Discov. 2024;23(3):162.
4. Osteen JD, Immani S, Tapley TL, Indersmitten T, Hurst NW, et al. Pharmacology and mechanism of action of suzetrigine, a potent and selective Na(V)1.8 pain signal inhibitor for the treatment of moderate to severe pain. Pain Ther. 2025.
5. Jones J, Correll DJ, Lechner SM, Jazic I, Miao X, et al. Selective inhibition of Na(V)1.8 with VX-548 for acute pain. N Engl J Med. 2023;389(5):393-405.