THE PAIN PILL OF THE FUTURE?

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Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group

Richard Novak, MD is a Stanford physician board certified in anesthesiology and internal medicine.Dr. Novak is an Adjunct Clinical Professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, the Medical Director at Waverley Surgery Center in Palo Alto, California, and a member of the Associated Anesthesiologists Medical Group in Palo Alto, California.
emailrjnov@yahoo.com

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We live in a world of pain. In my previous career as an internal medicine doctor I saw countless patients with back pain, neck pain, knee pain, hip pain, pelvic pain, abdominal pain, or migraines. Our department at Stanford is called the Department of Anesthesiology, Perioperative and Pain Medicine. Of these three subgroupings, the practice of intraoperative Anesthesiology management has changed little in the past 25 years. Perioperative Medicine continues to fascinate, as the variety of patient comorbidities and the plethora of surgical procedures brings an almost infinite combination of medical circumstances to our specialty. But the third subgroup—Pain Medicine—is the vast frontier in our future. Treating pain without the use of narcotics is one of the most important goals in all of medicine. Anesthesiologists utilize needles to administer pain blocks and corticosteroid injections to relieve pain. These procedures have a role, but for long-term non-narcotic solutions to pain we’re left with relatively weak multimodal therapies including nonsteroidal anti-inflammatory drugs, acetaminophen, gabapentin or antidepressants. Narcotic therapy for pain carries the risks of opioid addiction and tolerance, and the risk of fatal respiratory depression due to overdose. On January 30, 2025, the Food and Drug Administration (FDA) approved a new pain pill named suzetrigine (Journavx), a non-opioid analgesic, to be marketed by Vertex Pharmaceuticals for the treatment of moderate to severe acute pain in adults. This drug may herald a game-changing treatment tool in the battle against pain. This month’s issue of Anesthesiology published two phase 3 randomized, double-blind, placebo-controlled trials utilizing suzetrigine to treat postoperative pain. Suzetrigine was studied in adults after abdominoplasty (1,118 patients) or bunionectomy (1,073 patients). Following surgery, participants were randomized to suzetrigine, Vicodin (hydrocodone bitartrate/acetaminophen 5/325 mg every 6 h), or placebo, for 48 hours. Suzetrigine demonstrated statistically significant reduction in pain versus placebo, although neither trial showed superiority of suzetrigine versus Vicodin. The advantages of suzetrigine over Vicodin were a) reduction in nausea and vomiting, and b) lack of the potential for addiction with suzetrigine. Both findings are encouraging and important.

Suzetrigine blocks a voltage-gated sodium channel named Na_V1.8. Na_V1.8 is a target for pain-relieving medication because this channel plays an important role transmitting pain signals in peripheral sensory nerves. Suzetrigine is a small molecule which is a potent and highly selective inhibitor at the Na_V1.8 channel. It binds tightly to the Na_V1.8 channel with 31,000:1 selectivity over other Na_V channels.

Na_V1.8 channels are present in peripheral visceral and somatosensory neurons. The Na_V1.8 channel is not found in the human brain or spinal cord, so suzetrigine should not have the central nervous system side effects or addictive potential associated with centrally acting opioids. Studies in animals suggest that suzetrigine lacks any addictive potential.

In the bunionectomy trial, most patients were women (85%) and White (71%). In the abdominoplasty trial, most patients were also women (98%) and White (70%). In both trials, midazolam, fentanyl, and propofol were permitted to induce general anesthesia. In the bunionectomy trial, popliteal sciatic nerve blocks using ropivacaine were placed prior to surgery. For postoperative supplemental analgesia, fentanyl, acetaminophen, and ropivacaine boluses/infusion rate changes (in the bunionectomy popliteal block patients) were permitted as needed. Those randomized to suzetrigine received a 100 mg loading dose followed by 50 mg every 12 hours. Those randomized to hydrocodone bitartrate/acetaminophen received one 5 mg/325 mg capsule every 6 hours. Questions remain regarding suzetrigine’s usefulness as a sole agent, because in both studies, patients were allowed ibuprofen 400 mg orally every 6 hours as needed as a rescue medication for pain relief upon the participant’s request any time after the first dose of the study drug. Eighty-one percent of participants in the suzetrigine group (vs. 87% in the placebo group) received one or more doses of ibuprofen during the first 48 hours.

In both trials, patients receiving suzetrigine had a greater reduction in their mean pain rating scale score compared to those taking placebo. Neither trial demonstrated superiority of suzetrigine compared to hydrocodone bitartrate/acetaminophen for pain relief. Note that the dose of hydrocodone/acetaminophen was 5 mg/325 mg given every 6 hours, a dose at the low end of the recommended range for adults, which is 1 to 2 tablets every 4 to 6 hours as needed. It’s possible the dose of suzetrigine may have had inferior analgesia potency if compared with higher doses of hydrocodone/acetaminophen. In both trials, the incidence of nausea or vomiting was lower with suzetrigine compared to hydrocodone bitartrate/acetaminophen. In the abdominoplasty trial, the incidence of nausea was 20.3% in the suzetrigine group and 33.5% in the hydrocodone bitartrate/acetaminophen group (P < 0.0001). In the bunionectomy trial, the incidence of nausea was 9.2% in the suzetrigine group and 16.5% in the hydrocodone bitartrate/acetaminophen group (P = 0.0014).

The median time to meaningful pain relief with suzetrigine was 2 hours for abdominoplasty patients and 4 hours for bunionectomy patients. This delayed onset may require suzetrigine to be preferably administered orally with a sip of water prior to anesthetic induction to effect significant postoperative pain relief.

The phase 3 trials had limitations. Participants were predominantly women, which was a limitation because acute pain also affects men, and we don’t know whether the findings of the studies will generalize to all patients. As part of the bunionectomy anesthetic model, a popliteal block with ropivacaine was used to extend analgesia into postoperative day one. As a result, ropivacaine—a nonselective sodium channel blocker—was active in the sciatic nerve after the removal of the popliteal catheter, and exerted analgesia and thereby resulted in a lower baseline pain score.

Suzetrigine is available only for oral administration, with a recommended initial dose of 100 mg followed by 50 mg every 12 hours for up to 14 days. The price of a 50-milligram tablet of suzetrigine is $15.50 per pill. Most people will need to take two pills per day. This adds up to a weekly cost of $217. In comparison, the cost of Vicodin is $1 to $2 per pill. It’s not yet known if insurance companies will pay for suzetrigine, and for what conditions it will pay for the drug.

WHAT ABOUT CHRONIC PAIN?

Suzetrigine is FDA-approved for the treatment of acute pain, and these initial studies were in the setting of post-surgical pain. Could the drug someday be useful for chronic pain? Let’s hope so. Fifty million adults in the United States experienced chronic pain (pain lasting at least 3 months) in 2016, which was tied to significant health care costs and lost productivity. Chronic pain has been linked with depression, suicide risk, and substance use. Patients with chronic pain present to internal medicine, family practice, neurology, orthopedic, and pain clinics, where doctors struggle to relieve the chronic pain complaints, while patients often leave frustrated by the lack of successful therapies.

At a suzetrigine cost of $15.50 per pill, with most people needing to take two pills per day, the total price will equal $930 per month, or $11,160 per year. Would insurance companies, Medicare, and/or Medicaid ever cover this cost? For patients in constant chronic pain, is there anything they are more interested in spending their money on?

We need an effective, non-addicting, non-narcotic pain pill for the masses. Will suzetrigine be the forerunner of future pills which block the Na_V1.8 channel to fill this need? Further studies of suzetrigine in chronic pain will likely follow. Hopefully suzetrigine will be the analgesic pill of the future, and once off-patent will lead to an affordable, low risk treatment for pain.