Episode #265 The Breakthrough Drug Changing Perioperative Pain Management

Hello and welcome back to the Anesthesia Patient Safety Podcast. My name is Alli Bechtel, and I am your host. Thank you for joining us for another show. We are so excited to be talking about the excellent articles from the June 2025 APSF Newsletter. Last week, we talked about considerations for specialized advanced cardiac life support training and protocols for when these critical events occur in the operating room. This week, we are opening the anesthesia drug drawer and talking about a new medication. So, grab your headphones because here we go.

Before we dive further into the episode today, we’d like to recognize Blink, a major corporate supporter of APSF. Blink has generously provided unrestricted support to further our vision that “no one shall be harmed by anesthesia care”. Thank you, Blink – we wouldn’t be able to do all that we do without you!”

Our featured article today is “Suzetrigine: A Novel, Peripherally Acting Analgesic” by Paul Lee, Michael Kim, Joseph Szokol and Michael Bottros. To follow along with us, head over to APSF.org and click on the Newsletter heading. The first one down is the current newsletter. Then, scroll down until you get to our featured article today. I will include the link in the show notes as well.

We have exclusive content from one of the authors to help kick off the show today. Let’s take a listen now.

[Szokol] “ My name is Joseph Szokol, and I’m a professor of Clinical Anesthesia, Department of Anesthesiology and perioperative medicine at UCLA Health in Los Angeles, California. Most recently, I was the professor of clinical anesthesiology at the Keck School of Medicine in USC, where I served as the Executive Director of Mentorship and physic development, as well as the co-director of Quality and Patient Safety.

We chose to write this article with the importance of, uh, approved pain control in the perioperative period. On January 30th, 2025, the US Food and Drug Administration approved the drug Suzetrigine, a first in class non-op analgesic to treat moderate to severe pain in in adult patients having surgery. Sutro Gene is a novel small molecule that binds tightly to the NAV1.8 channel with 31,000. To one selectivity over other nav channels. Despite approval of numerous analgesic agents throughout the 20th century, greater than half the surgical patients still will  experience moderate to severe postoperative pain. Rogen and non-op opiate, non-addictive, selective, non potent, 1.8 pain signal inhibitor holds the potential to be the first treatment for mod to zero pain in a new pharmacologic class in over two decades. Suzetrigine in first non-op analgesic to receive FDA of approval since 2004 when the FDA A approved pregabalin, we know that poorly treated pain can lead to chronic pain, so does vial to treat pain preemptively.”

[Bechtel] Thank you so much to Szokol for helping to introduce this exciting article and more importantly, this new medication. And now it’s time to get into the article.

Do you remember what you were doing on January 30^th, 2025? That is the day that the US Food and Drug Administration approved the drug Journavx or Suzetrigine to treat moderate to severe pain in adult patients. This is a first in-class nonopioid analgesic medication. We are not the only ones excited about this new medication. Jacqueline Corrigan-Curay, the acting director of the FDA’s Center for Drug Evaluation and Research states that this an important public health milestone in acute pain management by providing a non-opioid treatment option for pain management.

This article highlights two of the APSF Patient Safety Priorities: Medication Safety and Opioid-Related Harm. We need to learn all about this new medication. Suzetrigine is the first drug to be approved in a new class of pain management medications. That’s right, it is not an opioid medication and it will likely have a big impact on perioperative pain management and help to mitigate opioid-related harm going forward. Did you know that over half of surgical patients still experience moderate to severe postoperative pain? We have work to do in this area.

Let’s meet the newcomer in the medication drawer. Suzetrigine is a non-opioid, non-additive, selective pain signal inhibitor. This may be the first treatment for moderate to severe acute pain in a new pharmacologic class in over 20 years. The mechanism of action is inhibition of the voltage-gated sodium channel, NaV1.8, by binding to the protein’s second voltage sensing domain, VSD2, to stabilize the closed state of the channel. This novel allosteric mechanism leads to tonic inhibition of NaV1.8 and reduces pain signals in the primary human dorsal-root ganglion sensory neuron. The pain signals are blocked in the nociceptive C-fibers before they are allowed to reach the brain. This opioid alternative is safe without the risk of addiction or organ toxicity.

Researchers have learned that acute, neuropathic, or inflammatory pain is caused by excessive firing of dorsal-root ganglion, or GRD, neurons or trigeminal ganglion neurons. In addition, different sodium channel genes have been identified. Then, the search was on for a “peripheral” sodium channel that was involved in DRG neuron firing, but not in the brain or in the heart. It was a sodium channel scavenger hunt and three such channels were identified, NaV1.7, NaV1.8, and NaV1.9 that regulate peripheral pain-signaling in nociceptive C-fibers. NaV1.8 was found to be responsible for more than 70% of the current allowing propagation of the action potential. As the main contributor, this channel became the primary target.

Check out Figure 1 in the article to see the voltage-gated sodium channels that are involved in generation and propagation of pain signals. There are 9 of these channels, that are named NaV1.1-NaV1.9, and each channel has a unique cell type specific expression pattern and function. Non-selective voltage gated sodium channels blockers can affect multiple systems, but NaV1.7, NaV1.8, and NaV1.9 are highly expressed in peripheral sensory neurons and are essential for initiation and propagation of pain signals in peripheral nociceptive neurons. Let’s focus on our new medication, Suzetrigine, which inhibits depolarization in peripheral pain-signaling neurons without an effect on the brain or heart. This is great news since it means there is a reduction in pain with few central nervous system or cardiac side effects. In vitro studies have revealed a greater than 31,000-fold selectivity for NaV1.8 channels for Suzetrigine unlike nonselective sodium channel blockers.

Figure 2 in the article highlights future NaV1.8 molecules that are being studied and evaluated in different phases from research to phase 3 with different formulations including oral and intravenous for the treatment of acute pain and peripheral neuropathic pain.

Vertex pharmaceuticals tested the safety and efficacy of Suzetrigine with two large randomized clinical trials that include over 1,100 patient undergoing abdominoplasty and over 1,000 patient undergoing bunionectomy. There were three groups of patients: a placebo, a combination of acetaminophen and hydrocodone, or suzetrigine. Suzetrigine is administered with 100mg oral loading dose followed by 50mg every 12 hours. Patient received the randomized treatment and anyone who experienced breakthrough pain were permitted to use ibuprofen for rescue analgesia. The results from both trials revealed statistically significant superior reduction in pain with suzetrigine compared to placebo. Superiority compared to hydrocodone and acetaminophen was not demonstrated, but a responder’s analyses at 12hours, 24 hours, and 48 hours showed similar reductions in numeric pain rating scale of 30%, 50%, and 70% respectively with suzetrigine compared to hydrocodone/acetaminophen.

Suzetrigine side effects were similar to placebo. Additional considerations include:

• An increased risk of adverse reactions with the concomitant use of moderate to strong CYP3A inhibitors
• Risk for drug interactions with certain hormonal contraceptives. Thus, patients taking suzetrigine should use nonhormonal contraceptives or use alternative contraceptives containing levonorgestrel and norethindrone.
• Patients with moderative to severe hepatic impairment may have higher systemic levels of suzetrigine and its active metabolites.
• This medications should be avoided for patients with severe renal impairment and a GFR less than 15mL/min.
• Patients should avoid food and drink containing grapefruit when taking suzetrigine.

The most common adverse effects were:

• Itching
• Muscle spasms
• Increased blood levels of creatine phosphokinase
• Rash

The good news is that Suzetrigine is safe and well-tolerated with a lower incidence of adverse events compared to placebo and acetaminophen/ hydrocodone combination.

Have you ever evaluated a patient with moderate to severe postoperative pain and thought, “I wish there was another non-opioid option available for treatment?” Well, Suzetrigine might be the answer we have been looking for to help with improved pain management and recovery.

Let’s run through the facts about this new medication one more time.

• It is a safe, effective, and non-addictive medication that can provide a new option for patients at high risk for opioid-related adverse events or when nonsteroidal anti-inflammatory drugs are contraindicated.
• May be an important component for future ERAS protocols.
• FDA approval occurred on January 30^th, 2025 for the oral treatment of moderate to severe pain
• It works as a selective sodium channel blocker that works at the voltage-gated sodium channel NaV1.8 which can be found in the peripheral dorsal root ganglion neurons. Notably, it is the first sodium blocker to be approved in the US for this indication and it it the first nonopioid drug to be approved for the treatment of pain in more than 25 years.
• Suzetrigine has no abuse potential and no known organ toxicity.

This is a very exciting development for perioperative pain management and the treatment of acute pain.

Before we wrap up for today, I also asked Szokol what he envisions for the future when it comes to this novel medication. This is what he had to say.

[Szokol] “Post-operative Pain control is a vital component to proper recovery for surgical patients. One major component of successful programs such as the Enhanced Recovery After Surgery UES protocols is optimizing pain control through the entire perioperative period. This starts with preoperative loading acetaminophen and NSAIDs and now Suzetrigine acts synergistically with other analgesics. Intraoperatively postoperative pain is additional minimized with regional ANS techniques, which include single shot blocks and catheters. There’s a large pipeline of future NAV1.8 molecules, both oral IV by Vertex and other pharma companies, which hopefully lead to additional non-addictive, safe and effective treatment for postoperative pain.”

[Bechtel] Thank you so much to Szokol for contributing to the show today and helping to highlight this exciting new medication. We are looking forward to learning more about Suzetrigine and using this medication option to help improve pain control during the perioperative period. We will also need to watch this space for the development of new medications in the class, especially once an IV formulation is available.

If you have any questions or comments from today’s show, please email us at [email protected]. Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. We hope that you will visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.

The APSF is delighted to announce the inaugural Digital Editor Program. This is a paid, one year program for an anesthesia professional or anesthesia professional in training with a talent for medical communications and digital media. Grow your skills in medical journalism and launch your career with networking and mentorship from the APSF. The deadline is August 1! Check out the link in the show notes or head over to APSF.org for more information.

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2025, The Anesthesia Patient Safety Foundation