The emergence of the first promising new pain medication in a generation and a developing technology to curtail opioid use suggest progress that could be relevant to surgical practice. The emergence of suzetrigine (Journavx) and ongoing research into opioid vaccines both have ignited attention among surgeons, pain specialists, and scientists, although the full benefits of each new option remain unclear.
New Painkiller
Suzetrigine is the newest pain medication in the US, approved in January 2025, by the US Food and Drug Administration (FDA). This drug offers pain control via a somewhat novel mechanism: it is a highly selective inhibitor of the voltage-gated sodium channel NaV1.8, part of the peripheral nervous system.1
Because this target is not present in the brain or spinal cord, suzetrigine does not have the central nervous system effects that opioids and other drugs do, such as sedation and euphoria. As a result, the drug is considered to have no addictive potential.1 Suzetrigine therefore brings new hope to the longstanding conundrum facing physicians: opioid therapy for pain carries a risk of substance use disorder, especially for susceptible patients, but avoiding opioids can leave few options to adequately manage moderate to severe pain.
“Although the data are limited, the findings suggest that suzetrigine may provide analgesic efficacy comparable to opioids, raising the question of whether suzetrigine could be used to achieve similar pain control while potentially mitigating opioid-specific harms,” said Jay V. Karri, MD, MPH, an interventional pain medicine clinician and researcher at the University of Maryland Medical Center in Baltimore.
Gap Between Efficacy and Safety in Pain Treatment
The search for better pain management options has been lengthy, with novel pain drugs with sufficient efficacy, usability, and safety disappointingly rare.
The most famous setback may be rofecoxib (Vioxx), a cyclooxygenase-2 inhibitor (COX-2) selective nonsteroidal anti-inflammatory drug (NSAID) that the FDA approved for use in 1999. The manufacturer subsequently withdrew the drug from the market in 2004, after data showed significantly increased risks of heart attack and stroke in the patients who used it.
Other COX-2 NSAID drugs also have failed. These include valdecoxib (Bextra), which the FDA approved in 2001 and the manufacturer withdrew in 2005 after serious cardiovascular and skin reactions, and lumiracoxib (Prexige), which the FDA declined to approve in 2007 and several European countries abandoned after severe hepatotoxicity cases emerged.
Other painkillers have remained in use, demonstrating limited efficacy compared to opioids in terms of usability and/or safety. Celecoxib (Celebrex), a COX-2 inhibitor that entered the market in 1999, is commonly used but effective only for mild to moderate pain. Ziconotide (Prialt) won FDA approval in 2004, but is suitable for a niche patient population, largely because it requires intrathecal infusion via a surgically installed pump. Gabapentin (Neurontin), an oral anticonvulsant that emerged in the 1990s, is now widely used for neuropathic pain but also associated with misuse, as well as overdose risk in the context of polypharmacy.
Suzetrigine Use
In contrast, suzetrigine appears to offer safe, effective, easily usable pain control. In two randomized clinical trials (RCTs) assessing pain in patients after abdominoplasty and bunionectomy, the groups receiving a 100 mg oral loading dose of suzetrigine, followed by 50 mg doses every 12 hours, had superior pain relief over 48 hours compared to the group receiving a placebo and comparable relief (noninferiority) to a group given 5 mg of hydrocodone and 325 mg of acetaminophen.2 Suzetrigine also is marketed as suitable for multiple surgical and nonsurgical purposes, including orthopaedic, plastic, otorhinolaryngologic, general, and urologic surgery.3 In the media, private-practice plastic surgeon Luis A. Vinas, MD, FACS, has described it as a “significant advantage” for surgical practice.4
However, the efficacy for all these uses is somewhat questionable, as is its full impact. In RCTs, suzetrigine has outcomes similar to, not better than, those of the active comparison arm. Thus far, how much pain control it might offer at larger doses is unclear.5
For now, many surgeons cannot rely on experience to ascertain its clinical value. For example, Lourdes Castañón, MD, FACS, director of the Burn Program at Banner-University Medical Center in Tucson, Arizona, and a clinical associate professor of surgery in the Department of Surgery, Trauma, Surgical Critical Care, Burns, and Acute Care Surgery at The University of Arizona College of Medicine–Tucson, said, “I don’t have any experience with this medication, but it may be something we can start using.”
Dr. Karri, who has prescribed suzetrigine, said he finds it useful in practice, including for postsurgical patients. Mindful that adverse effects have been minimally explored, he administered the drug only at the dosage studied in the RCTs, often as part of multimodal analgesia. “This is a good option to include as part of a cocktail,” he said.
Steven P. Cohen, MD, the Edmond I. Eger Professor of Anesthesiology at Northwestern University in Chicago, Illinois, concurred. He said that opioid sparing in a diverse population may be possible, because the mechanism of action allows for additive effects with opioids or other drugs. Per manufacturer-affiliated scientists,1 this approach may include combinations with other nonselective NaV blockers, such as carbamazepine, perhaps enhancing the drug’s utility.
Like Dr. Karri, Dr. Cohen (who is Dr. Karri’s coauthor5) saw possible uses for the drug. “Opioid use disorder is pretty common, and when some of the affected patients have surgery, there are data from Veterans Affairs and the nonveteran populations that show they’re more likely to relapse, overdose, and die. So you want an alternative for these patients,” Dr. Cohen said.
Nonetheless, Dr. Cohen also saw cause for skepticism, estimating that blocking just one of many sodium channels would lead to a ceiling effect. “NaV1.8 is probably not going to have much of an effect on the affective and cognitive components” of pain, he noted.
Financial Limits
Dr. Cohen described payment bundling for postsurgical pain as decreasing the likelihood clinicians will choose suzetrigine, a pricey new medication, when cheaper NSAID or opioid options would suffice. Dr. Karri agreed, describing insurance coverage as favorable for the acute uses for which suzetrigine is on label, but less so for chronic pain. “It’s much easier to use this drug in the inpatient setting, given some of the reimbursement restrictions,” he said.
Drs. Castañón and Cohen also discussed other potential uses—albeit ones that may be limited by payment models. Dr. Castañón noted that using some management techniques, including administration of acetaminophen before surgery, may help reduce the intensity of pain at later points in time. Although acknowledging a lack of objective evidence to date, she theorized that suzetrigine “may be something we can preemptively give to reduce the activation of nerve endings, so the pain would be less than it would be without that drug.”
Another prospective use has been suggested by suzetrigine’s manufacturer, Vertex. Because local anesthetics block all sodium-gated voltage channels, including NaV1.8, they have conducted in vitro studies that combined two local anesthetics (bupivacaine and ropivacaine) with suzetrigine. They found simple additive pharmacological effects that suggest suzetrigine could provide continuous NaV1.8 inhibition as an anesthetic block wears off.1 This finding may make suzetrigine a worthwhile option for pain control after a patient with a regional block has been discharged.
But these uses will occur in clinical settings only if they make financial sense. “If you do a nerve block and you give people high-dose NSAIDs,” Dr. Cohen said, “Is it the same as giving them a systemic sodium channel blocker? I think that could make sense, but I don’t know if it’s better than drugs that you can get for pennies.”
Making Opioids Less Dangerous
While suzetrigine is a new option for those needing pain medication, other scientific inquiries are opening the door to another improvement in opioid-based pain management: supporting patients in discontinuing prescribed opioids at the right time. (Read “In Surgical Care, Opioid Use Is Complex” from the March 2024 issue of the Bulletin.)
One option under current research may assist with this: vaccines for opioid drugs.
The concept is similar to that of vaccines for infectious diseases. The aim is to activate the immune system to make antibodies, in this case targeting a specific drug rather than a microorganism. The idea of using immunotherapies for this purpose first emerged decades ago,6 and research has since found appropriate vaccine selectivity and safety for a variety of opioids (as well as other illicit drugs).7 Efficacy is variable but generally considered sufficient, with some opioid vaccines requiring multiple injections before sufficient immune response is reached.7
The vaccines can prevent a given opioid from entering the brain, thus removing its central antinociceptive, euphoric, and respiratory depressive effects, as well as lessening the compulsion toward using the drug that people with opioid use disorder (OUD) experience. This can help prevent overdoses and ensure patients in recovery from OUD maintain sobriety.
Specificity and Limitations
The perception that an opioid vaccine can remove population-wide risk of OUD, in the way that vaccines can reduce or even eliminate the risk associated with specific microorganisms, is incorrect.
“If we were giving them an honest name, we would call them ‘drug-stranding technologies,’” said Travis N. Rieder, PhD, an associate research professor at the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland, who served on an advisory committee for the National Institute on Drug Abuse. “It keeps the drug away from the central nervous system by keeping it floating around the bloodstream.”
This distinction can help clarify the use case for these vaccines: to help patients in recovery from OUD avoid relapse, including patients without established substance use disorders who struggle to end their postsurgical opioid use.
