Suzetrigine: Is this what we've been waiting for, or just beginningni

The opioid prescribing crisis is largely behind us, and what other non-opioid drug therapy options are to help patients suffering from chronic pain due to the ongoing illegal opioid crisis that leads to tens of thousands of deaths each year? Although recent estimates are lacking, it is estimated that the economic impact of pain will cost the US nearly $1 trillion, in line with inflation greater than the total of heart disease, diabetes and cancer.¹ Despite this incredible number, pain research remains underfunded, which could have led to an overall decline in new therapies reaching the market. The latest non-opioid painkillers approved by US Food and Drug Administration (FDA) celecoxib went on the market in 1998, followed by a recall of similar drug therapy, rofecoxib, as cardiovascular events increased several years later.² Naturally, public and healthcare providers continue to be cautious about new drugs coming into the market.

In 2018, the Healing (End Long-Term Addiction) initiative was launched to better understand the mechanisms of pain, encourage the development of non-opioid medications, strengthen current pain modalities, and induce safer interventions for those with pain.³ The annual budget is $500 million a year, and the HEAL Initiative funds more than $2.5 billion in research.³ Although this initiative is still in its early stages, given the impact of pain on society, continuing funding by Congress should be advocated to further pursue new treatments.

January 30, 2025, first non-opioid NA_v1.8 inhibitor (suzetrigine) was approved by the FDA. Based on previous research, Na_v1.8 Sodium channels are selectively expressed in peripheral nociceptive neurons of the dorsal root ganglia, and inhibition is thought to relieve pain without opioid-related side effects.⁴ To provide the context for the need for a long pipeline from ongoing clinical research and discovery to clinical use, selective sodium channel inhibitors have been the proposed target for analgesia for nearly 20 years.^5,6 In two randomized controlled trials involving patients undergoing abdoplasty and aponeurectomy, the group receiving a loading dose of 100 mg received 50 mg every 12 hours relieves greater pain over the postoperative period of 48 hours compared to placebo.⁴ Compared to the placebo and opioid groups, total adverse events were lower in this group, with no severe or life-threatening events occurring. Overall, there are fewer opioid-related side effects associated with suzetrigine, suggesting its safety when compared to opioids.

As physicians involved in pain management, we recognize the importance of expanding our non-opioid treatment options. Pain is a complex condition with multiple contributing factors, and a single drug does not serve as a universal solution. Effective pain management requires a multimodal, interdisciplinary approach, and it is important to critically assess both the potential benefits and risks of new treatments developed and approved. Suzetrigin's approval is a promising step, but concerns and reactions in the medical community must be addressed along with countering misinformation.

Despite the obvious safety of Suzetrigine, criticisms remain about the lack of advantage over the opioid group, which is valid, but given the different mechanisms of action, it is necessary to understand that comparisons with opioids are disproportionate. First, opioids act centrally and can produce a systemic effect of analgesia, whereas suzetrigine acts peripherally. Opioids are less selective and may target multiple pathways, while suzetriggin is more selective. Opioids provide a faster and more potent onset, hydrocodone concentration has a time to peak plasma concentrations of 1-2 hours, and suzetrigine is 4-6 hours. Non-opioid drugs tend to have ceiling effects at high doses that do not necessarily cause better analgesia, but analgesia with opioids often leads to greater analgesia with escalating doses that are limited by adverse events. Given some concerns in the medical community, both suzetrigine are structurally different from opioids and are not known to interact with MU-opioid receptors, suggesting that it has no effect on the mesolinebic dopamine pathway, which is not supported by the lack of reported signs of dependence or addiction.⁴ Given the short-term data on suzetrigine, post-market post-phase research is needed to better understand long-term impacts, tolerability and safety profiles.

To address these concerns, long-term and follow-up studies are required to fully characterize the efficacy and safety profile of a drug. Proper pain control after surgery is key to improving outcomes and preventing progression to chronic pain. By assessing results over 48 hours, investigators can see whether recovery is improved and progression to chronic pain is reduced. Further studies focusing on conditions related to the mechanism of action of suzetrigine, such as neuropathy and acute exacerbation of chronic pain conditions, may provide some relief for people suffering from chronic pain. It is important to frame Suzetrigin's approval as an addition to the armor of a multimodal, interdisciplinary approach to pain management, rather than a panacea to replace all other drugs. Suzetrigine's approval may be renewed interest in developing oral pain medications, and increasing interest will provide those who feel scrutiny and comfort in concern.^7,8 Suzetrigine's approval is welcome. This is because people treating pain do so with limited options.

Disclosure

Dr. Michael Shatman is a senior medical advisor to Aplano Pharma outside of the work submitted. Dr. Matthew Chong reports personal expenses from Saldaemdicals other than the work submitted. Dr. Trent Emerick owns shares/subsidy of Vanish Therapeutics, Inc. outside of the work submitted. The authors report no other conflicts of interest in this work.

reference

1. Gaskin DJ, Richard P. The economic costs of pain in the US. J Pan. 2012;13(8):715–724. doi:10.1016/j.jpain.2012.03.009

2. COX-2-selective (including Bextra, Celebrex, and Vioxx) and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) | FDA. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-nformation-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-non-selective-non-steroidal-anti-inflammatory. access February 112025.

3. Helps to end addiction in the long term^® Initiative (NIH HEAL Initiative)^®) – National Institute of Mental Health (NIMH). Available from: https://www.nimh.nih.gov/research/research-funded-by-nimh/research-initiatives/helping-to-addiction-long-termr-initiative-nih-heal-initiative-. access February 112025.

4. Jones J, Correll DJ, Lechner SM, and others Selective inhibition of Na v 1.8 by VX-548 for acute pain. n engl j with. 2023; 389(5): 393–405. doi:10.1056/nejmoa2209870/suppl_file/nejmoa2209870_data-sharing.pdf

5. Eagles DA, Butterfly, King GF. 15 years of NAV 1.7 channels as a target for painkillers: Why is good in vitro pharmacology not translated into in vivo analgesic effects? Br J Pharmacol. 2022; 179(14): 3592–3611. 2:10.1111/BPH.15327

6. McGowan E, Hoyt SB, Li X, Lyons KA, Abbadie C. Peripheral action Na(V) 1.7 sodium channel blocker reverses hyperalgesia and allodynia in rat models of inflammatory and neuropathic pain. Anesthesia anal. 2009;109(3):951–958. doi:10.1213/ane.0b013e3181b01b02

7. A novel non-opioid multimodal painkiller from Xgene Pharmaceutical reduces the need for pain and opioid consumption in surgical pain testing | Business Wire. Available from: https://www.businesswire.com/news/home/20241231349875/en/a-novel-non-opioid-multimodal- analgesic-from-xgene-pharmaceutical-reduces-and-a-consumption-consumption-in-post-surgical-trial. access February 112025.

8. Recent advances in small molecule NAV 1.7 inhibitors for cancer pain management, Yu X, Zhao X, Li L, and others. Bioorg Chem. 2024:150. doi: 10.1016/j.bioorg.2024.107605