A new direction in pain management?

While we all have our individual biases and practice preferences when working with patients with acute and chronic pain, complying with professional society, governmental, and institutional guidelines and social trends has been a roller-coaster ride. In “shared decision-making” with individual patients, I frequently find our decisions in disagreement with some or all of the above regulatory guidance. The frustration points are many, but our limited therapeutic armamentarium is a significant one.

In January 2025, suzetrigine was approved by the US Food and Drug Administration (FDA) for treatment of moderate to severe acute pain.¹ As discussed by Divito et al² in this issue of the Journal, suzetrigine is a novel orally active nonopioid selective inhibitor targeting a specific sodium channel predominantly expressed on peripheral nociceptive (pain-sensing) neurons. In part because the initial regulatory approval studies were in the perioperative setting of abdominoplasty and bunionectomy,³ there has been as yet little fanfare about the drug in the general medicine literature. Also, considering how sensitized the medical community and the pharmaceutical industry are to issues surrounding the marketing of pain medications based on prior experiences, this is no surprise. And it is by no means clear that this drug will provide a panacea for the many dilemmas we face in treating our patients who are coping with acute and, particularly, chronic pain.

As a result of increased awareness about suboptimal pain control in many patients with cancer or chronic conditions and during end-of-life care, the Veterans Health Administration in 1999 supported initiatives by the American Pain Society and designated “pain” as the fifth vital sign (joining heart rate, blood pressure, respiratory rate, and temperature). In the same time frame, new opioid compounds were marketed and the Joint Commission on the Accreditation of Healthcare Organizations mandated that pain must be addressed in all patients in accredited healthcare settings by 2001 in order for institutions to receive federal financial support. As discussed by Tompkins et al,⁴ there was also a loosening of concerns about physicians prescribing greater amounts of opioids and reduced potential for negative regulatory actions taken against physicians who were “overprescribing” them. These well-intentioned efforts to improve management of patients’ chronic pain were not uniformly successful⁵ and may well have contributed to the wider prescription of opioids that is now defined as a problem that needs to be constrained.

Nonetheless, the need to treat patients with both acute and chronic pain remains an ongoing challenge. Despite the regulatory scrutiny and bureaucratic red tape associated with prescribing opioids as well as some other medications, patients still seek our help. Perhaps creating some expectation for some patients that their pain can be totally relieved, and that pain medications may be escalated to deal with every pain, our medical assistants, as they bring patients back to their room in clinic, ask each of them, “Are you currently experiencing any pain?” and, if the response is yes, then ask them to rate its severity from 0 to 10. It would be nice to have another treatment option for pain that is less limited by metabolic or organ-targeted side effects, cognitive dysfunction, addiction potential, and red tape.

Suzetrigine is an oral, twice-daily tablet that selectively targets the Na 1.8 sodium transport channel that is expressed mainly in peripheral nociceptive nerve fibers. These channels are not expressed in the brain, and preclinical studies did not demonstrate behavioral changes or addictive potential in rodents and monkeys.^1,6 Other less subtype-specific sodium channel blockers like lidocaine have cardiac and central nervous system side effects when given systemically. Currently, suzetrigine is approved by the FDA for short-term use in patients with acute pain. Results from fairly small phase 3 trials demonstrated efficacy greater than placebo and comparable but not superior to hydrocodone 5 mg and acetaminophen 325 mg over 48 hours following abdominoplasty or bunionectomy. Studies predominantly included White women. In these and other short-term studies, suzetrigine was well tolerated, with a few patients experiencing muscle spasms, rash, or reversible elevations in creatine kinase. There is little information regarding postoperative opioid-sparing effects. Whether there will be wide acceptance of this new drug in the perioperative setting remains to be seen. For example, celecoxib, which unlike other nonsteroidal anti-inflammatory drugs does not adversely impact platelet function, decreased postoperative pain and opioid use in clinical trials,⁷ but has not apparently achieved widespread use for control of postoperative pain.

Given the many challenges of treating patients with chronic pain, undoubtedly suzetrigine will be tried off-label in those patients whose pain has not adequately responded to medications like gabapentin, duloxetine, nonsteroidal anti-inflammatory drugs, and so on. Very preliminary studies suggest that suzetrigine may have some efficacy in treating the pain of diabetic neuropathy, but had no greater effect than placebo in treating the pain associated with chronic radiculopathy.¹ Although other sodium channel blockers have not shown significant efficacy in treating fibromyalgia, I’m sure suzetrigine will also be tried in patients with this condition. Given that this is currently felt to be a syndrome associated with central sensitization and pain escalation,⁸ demonstration of efficacy of a peripherally acting neural channel antagonist could contribute to a better understanding of fibromyalgia. But at $15 per pill,² results of individual patients’ anecdotal experiences with suzetrigine may not rapidly accrue.

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