Kasturi Shikshan Sanstha College of pharmacy, Shikrapur, Tal. Shirur, Dist. Pune 412208
Acute pain is a common clinical condition that greatly affects patient comfort and recovery. Current pain management mainly depends on opioids, which, though effective, have major drawbacks such as dependence, tolerance, and adverse effects. Therefore, there is a strong need for safer and more effective non-opioid alternatives. Suzetrigine is a novel nonopioid analgesic that selectively inhibits the NaV1.8 sodium channel in peripheral nociceptors. This mechanism blocks pain transmission without causing central nervous system side effects or addiction risk related to opioids. The present study aims to characterize the role of Suzetrigine as a non-opioid analgesic for acute pain management, emphasizing its mechanism of action, safety, and therapeutic efficacy. This research can provide important insights for developing safer alternatives to opioids, reducing dependence, and improving pain management outcomes. Although many analgesic agents are available, opioids remain the main treatment for moderate to severe pain. However, their prolonged use leads to several adverse effects such as respiratory depression, sedation, constipation, tolerance, dependence, and risk of addiction. The growing opioid crisis highlights the urgent need for effective non-opioid analgesics that can provide similar pain relief without these limitations. Suzetrigine, a new investigational compound, shows promise in this field. Its mechanism of action does not involve opioid receptors but targets specific ion channels and neural pathways linked to nociceptive signaling. This study aims to thoroughly evaluate Suzetrigine’s role as a non-opioid analgesic for acute pain through pharmacological, preclinical, and clinical studies.
An analgesic is a drug or medication used to relieve or reduce pain without causing a loss of consciousness. These substances, commonly known as painkillers, work on the central and/or peripheral nervous systems to alleviate pain. Examples include acetaminophen, ibuprofen, and aspirin. An analgesic is a drug that relieves pain without causing loss of consciousness. Also called painkillers, they work by acting on the peripheral or central nervous system to reduce or eliminate the sensation of pain. Examples include common over-the-counter medications like acetaminophen and ibuprofen, as well as prescription drugs like opioids for more severe pain. In pharmacy, an analgesic is a type of medication used to relieve pain without causing a loss of consciousness or significantly altering sensation. These drugs are commonly referred to as painkillers or pain relievers.
Types and examples
1. Non-opioid analgesics:
Description: These are often available over the counter and are used for mild to moderate pain. Examples: Aspirin: Also used to reduce inflammation. Acetaminophen (Paracetamol): Used for pain and to reduce fever. Ibuprofen: A nonsteroidal anti-inflammatory drug (NSAID) also used for inflammation.
2. Opioid analgesics:
Description: Stronger pain relievers that are available by prescription only and act on the central nervous system. Examples: Morphine: Used for severe pain. Oxycodone: A potent pain reliever. Codeine: Also, an example of a narcotic analgesic.
Introduction of non-opioid analgesic
Non-opioid analgesics are a type of painkiller that does not use opioids (e.g., morphine), so they are not addictive. These medications are used to treat mild to moderate pain and fever, and include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetaminophen (paracetamol). A non-opioid analgesic is a type of pain reliever that is not an opioid, commonly used for mild to moderate pain and often with anti-inflammatory and fever-reducing effects. Examples include acetaminophen, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs), which work by inhibiting the production of pain-mediating prostaglandins A non-opioid analgesic is a pain-relieving medication that does not belong to the opioid class, and they are effective for mild to moderate pain. Examples include acetaminophen (Tylenol) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and aspirin. These drugs are widely available, are less likely to cause addiction, and can be used alone or with stronger painkillers.
Types of non-opioid
Non-opioid analgesics are divided into two main groups: nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. NSAIDs reduce inflammation, while acetaminophen is used primarily to reduce pain and fever.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Mechanism of action: These drugs work by reducing the production of prostaglandins, which play an important role in pain and inflammation. Example: Aspirin, Ibuprofen, Naproxen. Type: Non-selective NSAIDs: Inhibit both COX-1 and COX-2 enzymes. This can cause stomach problems (gastrointestinal side effects) and other side effects. Selective COX-2 inhibitors: Inhibit only the COX-2 enzyme, which reduces the risk of gastric side effects. 2. Acetaminophen Mechanism of action: It is an analgesic and antipyretic drug. Example: Paracetamol. Function: Does not reduce inflammation. Remember: Excessive use can be harmful to the liver.
Introduction of suzetrigine Structure:
Molecular formula C21H20F5N304
Molecular weight 473.39 g/mol
History of suzetrigine
Suzetrigine is emerging as a potential non-opioid oral pharmaceutical agent for abating moderate-to-severe acute pain, carrying no risk of addiction or opioid-like complications. It is highly selective and improves overall patient outcomes. Its clinical development includes rigorous Phase 2 and Phase 3 randomized, double-blind, placebo- and active-controlled trials. In the NAVIGATE-1 and NAVIGATE-2 trials, patients undergoing abdominoplasty or bunionectomy received either suzetrigine, placebo, or hydrocodone/ acetaminophen. Suzetrigine significantly reduced pain over 48 hours with a faster onset of relief (median 2–4 hours vs. 8 hours for placebo). In pooled analyses of double-blind studies (total n ≈ 874), the most common adverse events on suzetrigine were mild to moderate—pruritus, muscle spasms, CPK elevation, and rash—with no serious treatment-related events. In a separate Phase 2 trial for chronic lumbosacral radiculopathy, suzetrigine met its within-group endpoint (mean NPRS change – 2.02 at Week 12, P < 0.001 vs. baseline), but placebo patients improved almost identically (– 14 1.98), showing no statistically significant difference between groups. In short, suzetrigine’s pain reduction did not outperform placebo. Currently, there is an increased need for multicentric, randomized, controlled trials to establish its efficacy further. To assess safety and effectiveness, more research with pregnant and lactating women is required. The company continues to progress its peripheral neuropathic pain (PNP) clinical program and has initiated Phase 3 pivotal trials in patients with painful diabetic peripheral neuropathy (DPN). Additionally, results from Phase 2 studies in painful lumbosacral radiculopathy (LSR) are expected soon.
Uses
1. Acute pain management – Effective in treating acute pain such as post-operative pain, dental pain, or pain due to injury.
2. Non-opioid analgesic – Provides strong pain relief without causing addiction or dependence like opioids.
3. Peripheral nociceptor blockade – Acts on peripheral Nav1.8 sodium channels to block pain signals without affecting the central nervous system.
4. Fewer side effects – Does not cause respiratory depression, sedation, nausea, or constipation that are common with opioid drugs.
5. Short-term pain relief – Safe and effective for short-duration pain management. 6. Dental pain – for pain after tooth extraction or dental procedures.
7. Musculoskeletal pain – such as sprains, strains, or muscle injury.
8. Trauma-related pain – in cases of fractures or wounds.
9. Back or joint pain – short-term pain management.
10. Soft tissue injury pain – like swelling or bruising.
11. Headache or migraine-related acute pain (under study).
12. Acute neuropathic pain – being researched for this use.
13. Pain from minor surgical procedures – for quick recovery.
14. Alternative to opioids – when opioid drugs are risky or unsuitable.
Ideal Characteristics of Suzetrigine
1. Non-opioid analgesic – Provides strong pain relief without acting on opioid receptors, so it avoids addiction and dependence.
2. Peripheral action – Works mainly on peripheral sodium channels (NaV1.8), reducing pain at its source with minimal effects on the brain or central nervous system.
3. Effective for acute pain – Gives fast and long-lasting relief (up to 12 hours) in moderate to severe acute pain.
4. Fewer side effects – Causes less sedation, respiratory depression, or euphoria compared to opioids.
5. Convenient oral dosage – Available as oral tablets; easy to take, no need for injections.
6. Safe alternative to opioids – Reduces the need for opioid medications and helps prevent opioid-related addiction problems.
7. Predictable pharmacokinetics – Has a clear and consistent dose–response, making it easier to manage pain effectively.
Common / expected side effects
1. Itching (pruritus) and skin rash.
2. Muscle spasms.
3. Elevated creatine phosphokinase (CPK) levels (a lab test abnormality) indicating possible muscle stress or damage.
4. Nausea and vomiting.
5. Constipation.
6. Headache.
Less common / more serious side-effects & special-concerns
1. Hypotension (low blood pressure), tachycardia or irregular heartbeat in rare cases.
2. Decrease in estimated glomerular filtration rate (eGFR) – i.e., some effect on kidney function noted in trials (though rare/transient).
3. Use in patients with moderate to severe liver impairment: in moderate hepatic impairment exposure is higher and risk may increase; in severe impairment (ChildPugh Class C) it should be avoided.
4. Allergic reactions: e.g., swelling of face/ lips/ tongue, hives, difficulty breathing. Requires emergency care.
5. Interaction issues: Because Suzetrigine is metabolized by CYP3A4, drugs that strongly inhibit or induce this enzyme can increase risks or reduce efficacy. It may also reduce the effectiveness of some hormonal contraceptives.
6. Long-term safety is still uncertain: Most trials were short (≈ up to 14 days) and chronic/long-term use has limited data.
Advantages / Benefits
1. Non-opioid pain relief – It provides strong pain relief without acting on opioid receptors, so it avoids addiction and respiratory depression risks seen with opioids.
2. Effective for acute pain – Proven effective for moderate to severe acute pain, such as after surgery, injury, or dental procedures.
3. Novel mechanism – Works by blocking NaV1.8 sodium channels in peripheral nerves, directly targeting pain signals at their source.
4. Reduced CNS side effects – Since it acts mainly on peripheral nerves, it causes less drowsiness, confusion, or sedation compared to traditional painkillers.
5. Lower risk of dependency or abuse – Does not cause euphoria or psychological dependence like opioids.
6. Oral tablet form – Easy to take and convenient; does not require injections or hospital administration.
MECHANISM OF ACTION
Suzetrigine acts through a new mechanism that selectively inhibits the Nav1.8 sodium channel isoform, which is mainly found in peripheral pain-sensing neurons (nociceptors). Unlike general sodium channel blockers, suzetrigine precisely attaches to the voltage-sensing domain 2 (VSD2) of the Nav1.8 channel, keeping the channel in its closed position through allosteric modulation.
This mechanism provides several therapeutic benefits:
1. Peripheral restriction – It shows minimal entry into the central nervous system (CNS) (brain-plasma ratio < 0.1), preventing opioid-like central side effects.
2. High selectivity – It has about 31,000 times stronger affinity for Nav1.8 compared to other sodium channel types (Nav1.1, Nav1.7, Nav1.9).
3. Functional selectivity – It reduces pain transmission without fully blocking nerve activity.
Suzetrigine (VX-548) is a next-generation, highly selective small-molecule inhibitor specifically targeting the NaV1.8 voltage-gated sodium channel, which is predominantly expressed in peripheral nociceptive neurons and plays a central role in propagation of pain signals from peripheral tissues towards the central nervous system. Scientific evidence demonstrates that suzetrigine shows approximately >31,000-fold greater selectivity for NaV1.8 compared to other sodium channel isoforms such as NaV1.1, NaV1.7, NaV1.9, etc., thereby significantly reducing off-target ion-channel blockade-related adverse effects. Unlike conventional sodium channel blockers that act non-selectively and cause complete neuronal suppression, suzetrigine exhibits a unique and novel allosteric mechanism of action.
ROUTE OF ADMINISTRATION
Suzetrigine is administered orally in the form of tablets. The tablets should be swallowed whole and not chewed or crushed. The dosing schedule is as follows: Initial dose: A starting dose of 100 mg is taken orally on an empty stomach (at least 1 hour before or 2 hours after food) to ensure faster absorption. Subsequent doses: Starting 12 hours after the initial dose, a 50 mg tablet is taken orally every 12 hours. These subsequent doses can be taken with or without food.
Dosage schedule:
• Initial dose: Take 100 mg orally on an empty stomach (at least 1 hour before or 2 hours after food) for better absorption.
• Subsequent doses: After 12 hours of the initial dose, take 50 mg every 12 hours. These later doses can be taken with or without food.
Clear liquids like apple juice, vegetable broth, tea, or black coffee may be taken during this fasting period. Suzetrigine should be used for the shortest possible duration according to the patient’s treatment plan. The use of suzetrigine for acute pain has not been studied for more than 14 days. Refer to the full prescribing information for dosage recommendations in patients with liver impairment and those taking CYP3A inhibitors, as well as instructions for missed doses. Avoid consuming grapefruit or grapefruit-containing products during treatment with suzetrigine.
CONCLUSION
Suzetrigine is a highly selective oral Nav1.8 sodium channel inhibitor that marks one of the most significant advancements in acute pain management in more than two decades. It addresses a critical need for safe and effective non-opioid analgesics in the midst of the ongoing opioid crisis, where traditional opioids—despite their efficacy—are burdened with serious risks such as respiratory depression, sedation, tolerance, dependence, and addiction. Unlike opioids, suzetrigine exerts its action peripherally by selectively inhibiting Nav1.8 sodium channels found on nociceptive neurons, which play a pivotal role in transmitting pain signals. This targeted mechanism allows it to provide meaningful pain relief without activating central opioid receptors, thereby avoiding common central nervous system side effects and eliminating the risk of opioid use disorder. Clinical trials, including pivotal Phase 3 studies, have demonstrated that suzetrigine produces rapid analgesia with an onset of action of approximately two hours and significantly improves pain scores compared to placebo. It has shown efficacy in both surgical and non-surgical acute pain conditions and displays comparable outcomes to NSAIDs and low-dose opioids while causing fewer gastrointestinal and neurological adverse effects. Most side effects, such as pruritus and muscle spasms, were mild to moderate, and serious treatment-related complications were rare, reinforcing its strong safety and tolerability profile.
REFERENCE
Shraddha Ghadage*, Snehal Kadbhane, Dr. Vijaykumar Kale, Shweta Mahajan, Shweta Dandawthe, Characterizing the Role of Suzetrigine Drug as A Non-Opioid Analgesic for Acute Pain Management, Int. J. Sci. R. Tech., 2025, 2 (11), 693-698. https://doi.org/10.5281/zenodo.17732027
10.5281/zenodo.17732027
