Are Non-Opioid Therapies Finally Challenging Opioids in Acute Pain Management?

Acute pain remains one of the most common reasons patients seek medical care, this affects patients recovering from surgery, injury, and acute illness. Opioids have long served as the standard treatment for moderate-to-severe acute pain because of their potent analgesic effects, but concerns regarding adverse effects, misuse, and opioid-related harms have prompted ongoing efforts to optimize pain management strategies.¹

Multimodal pain management strategies, which combine therapies targeting different pain pathways, have emerged as an important approach to improving pain control while reducing opioid exposure.² Advances in non-opioid therapeutics have expanded the treatment landscape for acute pain in emerging data. The approval of suzetrigine (Journavyx; Vertex Pharmaceuticals) in 2025 marked the first new class of acute pain medication approved in more than 2 decades and renewed interest in the role of non-opioid therapies for the treatment of acute pain.³

While opioids remain an important component of pain management, evolving clinical practices and emerging therapies suggest that non-opioid approaches may play an increasingly crucial role in acute pain treatment.

The Intensified Search for Opioid Alternatives

Opioids remain among the most effective medications for treating moderate-to-severe acute pain and continue to play a central role in postoperative, emergency, and inpatient care settings.⁴ However, their use is associated with well-established adverse effects, including sedation, nausea, constipation, and respiratory depression.⁴

Beyond these immediate risks, opioid exposure following surgery has been linked to the development of persistent opioid use among previously opioid-naïve patients.⁵ In a widely cited analysis of more than 36,000 opioid-naïve surgical patients, the data revealed that emerging persistent opioid use occurred following both major and minor surgical procedures, showcasing how critical it is to minimize unnecessary opioid exposure whenever possible.⁵

Multimodal Analgesia Has Reshaped Acute Pain Management

One of the most significant developments in acute pain management has been the adoption of multimodal analgesia. Rather than relying on a single medication class, multimodal approaches combine therapies with complementary mechanisms of action to improve analgesia while reducing opioid requirements.²

Common components of multimodal pain management include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), local anesthetics, regional anesthesia techniques, and nonpharmacologic interventions.² Evidence suggests that these approaches can improve pain control and reduce opioid consumption compared with opioid-centered treatment strategies alone.²

Enhanced Recovery After Surgery (ERAS) protocols have further accelerated the integration of multimodal analgesia into perioperative care. These evidence-based pathways emphasize opioid-sparing strategies and have been associated with improvements in postoperative recovery, reduced hospital length of stay, and decreased opioid use.⁶

Existing Non-Opioid Options Remain Imperfect

Although non-opioid therapies are essential components of modern acute pain management, each approach has important limitations.

NSAIDs are effective for many types of acute pain but may not be appropriate for patients with renal dysfunction, gastrointestinal bleeding risk, or certain cardiovascular conditions.⁷ Acetaminophen is widely used because of its favorable safety profile but may provide insufficient analgesia when used alone in patients experiencing more severe pain.⁴

Regional anesthesia and peripheral nerve blocks can substantially reduce postoperative pain and opioid requirements, but these interventions require specialized expertise and resources that may not be available in all practice settings.⁸ Similarly, ketamine has emerged as an effective opioid-sparing option for select patients, although its use is generally limited to monitored clinical environments because of potential neuropsychiatric adverse effects.⁹

As a result, a need has persisted for novel non-opioid therapies capable of treating moderate-to-severe acute pain while avoiding many of the limitations associated with existing treatment options.

A New Era of Acute Pain Therapeutics

The approval of suzetrigine may represent one of the most important advances in acute pain management in recent years.³

Unlike opioids, which exert their effects through opioid receptors in the central nervous system, suzetrigine selectively inhibits NaV1.8 sodium channels located on peripheral pain-sensing neurons.³ These channels play a critical role in transmitting pain signals from injured tissues to the brain. By targeting pain signaling before it reaches the central nervous system, suzetrigine offers a novel mechanism for pain control without directly engaging opioid receptors.³

The FDA approval was supported by data from the phase 3 VX-548-302 bunionectomy trial and the phase 3 VX-548-303 abdominoplasty trial, both of which demonstrated statistically significant reductions in pain compared with placebo.¹⁰

The significance of suzetrigine extends beyond a single medication, and further provides evidence that targeting peripheral pain pathways may represent a viable strategy for future analgesic development and could help stimulate additional innovation in non-opioid pain management.

What Comes Next for Acute Pain Management?

Although non-opioid therapies are unlikely to completely replace opioids in the foreseeable future, their role in acute pain management is continuing to expand.

Many experts anticipate that future pain management strategies will increasingly rely on individualized multimodal regimens that incorporate both pharmacologic and nonpharmacologic interventions.² Novel therapies targeting sodium channels and other peripheral pain pathways remain under investigation and may further broaden treatment options in the coming years.¹¹

Rather than replacing opioids outright, these innovations may allow clinicians to reserve opioid therapy for situations in which it is truly necessary while reducing overall opioid exposure across larger patient populations.

Although opioids continue to play a critical role in acute pain management, the landscape is evolving. The growing emphasis on multimodal analgesia, coupled with the emergence of novel therapies such as suzetrigine, suggests that non-opioid approaches may play an increasingly important role in the future of acute pain treatment.

References

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2. Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surg. 2017;152(7):691-697. doi:10.1001/jamasurg.2017.0898

3. FDA approves JOURNAVX (suzetrigine) for the treatment of moderate-to-severe acute pain. News release. FDA. January 30, 2025. Accessed June 18th, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain

4. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008

5. Brummett CM, Waljee JF, Goesling J, et al. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg. 2017;152(6):e170504. doi:10.1001/jamasurg.2017.0504

6. Ljungqvist O, Scott M, Fearon KC. Enhanced Recovery After Surgery: A Review. JAMA Surg. 2017;152(3):292-298. doi:10.1001/jamasurg.2016.4952

7. Motov S, Masoudi A, Drapkin J, et al. Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2019;74(4):530-537. doi:10.1016/j.annemergmed.2019.05.037

8. Gabriel RA, Ilfeld BM. Use of Regional Anesthesia for Outpatient Surgery Within the United States: A Prevalence Study Using a Nationwide Database. Anesth Analg. 2018;126(6):2078-2084. doi:10.1213/ANE.0000000000002503

9. Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456-466. doi:10.1097/AAP.0000000000000806

10. Bertoch T, D'Aunno D, McCoun J, et al. Suzetrigine, a Nonopioid Na V 1.8 Inhibitor for Treatment of Moderate-to-severe Acute Pain: Two Phase 3 Randomized Clinical Trials. Anesthesiology. 2025;142(6):1085-1099. doi:10.1097/ALN.0000000000005460

11. Waxman SG, Dib-Hajj S, Cummins TR, Black JA. Sodium channels and pain. Proc Natl Acad Sci U S A. 1999;96(14):7635-7639. doi:10.1073/pnas.96.14.7635