Suzetrigine (VX-548): Bidding goodbye to opioids: The latest oral non-opioid analgesic for acute pain

Abstract

Suzetrigine is the first and only FDA-approved non-opioid oral medication designed to be used for the treatment of moderate-to-severe acute pain. It represents a significant step forward in pain treatment by providing excellent relief without the hazards associated with opiate usage. Its approval transforms postoperative pain care, meeting a key public health need while lowering addiction concerns. While the adverse effect profile requires additional investigation, its distinctive mechanism and safety feature represent a game-changing potential in the area of analgesia.

Pain is almost universal, leading to a certain burden on the healthcare system. Acute pain causes a detrimental effect on lifestyle, which leads to an increase in morbidity. A wide range of analgesics, including both opioids and non-opioids, are available to treat acute pain.

Acute pain significantly contributes to increased morbidity and disability, resulting in a higher burden on society. Inadequate management of acute pain can negatively impact quality of life and may lead to the onset of chronic pain. Multimodal pharmacotherapy plays an integral part in the management of acute pain.

Suzetrigine, also known as VX-548, marketed under the brand name of JOURNAVX, was developed by Vertex Pharmaceuticals in January 2025. It is the first and only U.S. food and drug administration (FDA)-approved non-opioid oral medication designed to be used for the treatment of moderate-to-severe acute pain.[1] It is a potent and highly selective inhibitor of the voltage-gated sodium channel Na_V1.8.[2] The unique characteristic of Na_V1.8 receptors is that they are expressed only in the peripheral nervous system (PNS), which carries nociception, and not in the central nervous system (CNS). This special property avoids the development of serious neurological side effects.[3]

Urgent Need to Address Acute Pain

Acute pain can be caused by physical illnesses, traumas, accidents, and surgeries. Generation and persistence of acute pain can have various serious detrimental effects on brain cells, affecting memory, emotions, behaviour, and attention of the patient. This causes an immediate need to alleviate acute pain and prevent its progression to chronic pain. Multimodal pharmacotherapy is the mainstay of the management of acute pain in addition to supportive non-pharmacological techniques such as hot or cold massage, etc.

What’s New About Suzetrigine

Suzetrigine (VX-548) was introduced because there is a high unmet need for an efficient non-opioid pharmacological medication for treating acute pain that avoids the risk of physical dependence and addiction. Being a non-opioid selective Na_V1.8 inhibitor, suzetrigine avoids various adverse effects associated with opioids. In gene expression data, it was confirmed that Na_V1.8 is not expressed in any of the 190 regions in the human brain or spinal cord, thus avoiding adverse CNS consequences.[4] It has the properties of fast absorption and shows the phenomenon of “use dependence”.[4]

Jones et al.[3] did a clinical trial that showed that suzetrigine has clinically significant efficacy to alleviate moderate-to-severe acute pain, which was comparable to opioids. Their study showed that it has clinically insignificant addictive potential.

Another distinctive characteristic of suzetrigine is its novel allosteric mechanism of action, which stabilizes the closed state of NaV channel [Figure 1].[4]

Figure 1.

Depicting special characteristics of suzetrigine

Suzetrigine vs. Traditional Analgesics

Traditional analgesics include various categories such as non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and ketorolac, which inhibit cyclooxygenase (COX-1 and 2), acetaminophen, local anaesthetics, and N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. They are typically used as a first-line agent in pain management. To combat the severity of acute pain, opioids such as morphine, fentanyl, and pethidine have been traditionally used as a mainstay for moderate-to-severe pain. Suzetrigine avoids the various adverse effects that are typically associated with opioids, such as sedation, nausea, vomiting, constipation, respiratory depression, urinary retention, physical dependence, and tolerance. The non-selective sodium channel inhibitors such as lignocaine, mexiletine, and carbamazepine, have diverse adverse effects due to their action on other channels and organs, which are prevented with suzetrigine.

Pharmacology and Mechanism of Action

There are a total of nine subtypes of voltage-gated sodium channels, which range from Na_V1.1 to Na_V1.9 and are selectively expressed in dorsal root ganglia of peripheral nociceptive neurons.[3]

Na_V1.8 is a voltage-gated sodium channel that is selectively expressed in the dorsal root ganglion (DRG) and the trigeminal ganglion. When these neurons are stimulated, Na_V1.8 sodium channels open to allow a sudden influx of sodium, which causes depolarisation, leading to the perception of pain. Suzetrigine, being a selective Na_V1.8 sodium channel blocker, blocks this nociception in human DRG neurons, thus alleviating pain. The unique binding site of the Na_V1.8 receptor and its > 31,000 times selectivity for suzetrigine, make it distinguished from other NaV receptors.[4]

Zhang et al.,[5] developed a pharmacologic profile of suzetrigine using liquid chromatography tandem mass spectrometry and illustrated its fast absorption with an oral dose of 2 mg/kg. The peak plasma concentration was achieved at 1 hour after oral administration with 71% of oral bioavailability. The half-life was comparable for both oral (5.9 hours) as well as intravenous administration. Suzetrigine is metabolized by cytochrome (CYP) P450 enzymes (CYP 3A2 and CYP 2C11 in rats, human equivalent as CYP 3A4 and 3A5).[6]

Efficacy and Safety

Suzetrigine is currently undergoing phase III clinical trials after the completion of the phase II trial. In general, there are no serious adverse effects associated with it. A few common side effects include headache, constipation, itching, muscle spasms, elevated blood creatine phosphokinase levels, and rash.[1] It might temporarily reduce the fertility in females.

Future Prospects

Suzetrigine is emerging as a potential non-opioid oral pharmaceutical agent for abating moderate-to-severe acute pain, which carries no risk of addiction or opioid-like complications, is highly selective, and improves overall patient outcomes. Currently, an increased need for research and multicentric, randomized, controlled trials are to be done to establish its efficacy. To assess its safety and effectiveness, more research with pregnant and lactating women is required.

Further research should focus on the development of safe, efficient, and non-dependency drugs that can be used to alleviate acute pain.

Author contributions

All the authors contributed to the manuscript.

Conflicts of interest

None.

Funding Statement

Nil