For more than 100 years, acetaminophen, which is better known as Tylenol, has been a common way to relieve pain. Scientists have never fully understood how it works, even though it is used by a lot of people. A new study that changes everything says we might have been wrong about how it works all along. New research shows that acetaminophen’s main byproduct, AM404, may block pain signals at their source before they even reach the brain, rather than just dulling the brain’s perception of pain. This discovery could change what is taught in medical schools and lead to a new generation of painkillers that are safer and more effective.
The Century-Old Mystery of Acetaminophen
Acetaminophen has been a scientific mystery since it was first used in the late 1800s. The main theory said that it worked by stopping prostaglandins, which are chemicals that cause pain and inflammation in the brain. But this explanation never fully explained why it worked sometimes and why it didn’t work sometimes.
Researchers at the Hebrew University of Jerusalem have now found a completely different way for this to happen. Their research, published in PNAS, shows that when the liver breaks down acetaminophen, it makes 4-aminophenol, which then binds with a fatty acid to make AM404. This compound was already known to work in the brain, but it is now known to block pain signals in peripheral nerves.
Alexander Binshtok, a professor of pain research and co-author of the study, says, “These results fundamentally change our understanding of how paracetamol works.” If this is true in people, it could explain why acetaminophen works for some types of pain but not others, and why taking too much of it hurts the liver but not other organs.
How AM404 Acts Like a “Pain Gatekeeper”
The study found that AM404 doesn’t just hide pain; it stops it before it starts. This is how:
- Sodium Channel Blockade: AM404 blocked sodium channels in rat sensory neurons. These channels are important for sending electrical signals of pain. Pain signals don’t get to the brain if these channels don’t fire.
- Localized Relief: AM404 made rat paws less sensitive to heat and pressure when injected into them, but only in the treated paw. This suggests that it works directly at the site of pain rather than throughout the body.
- Faster than we thought: The strongest pain-blocking effects showed up within an hour, which is about the same amount of time that people say they feel better after taking Tylenol.
This goes against the long-held belief that acetaminophen only works in the brain. Instead, AM404 may work as a peripheral nerve silencer, stopping pain signals from ever starting.
Why This Changes Everything for Pain Treatment
If AM404 works the same way in people, it could change pain medicine in a number of ways:
- Safer Options than Opioids
- AM404 works on nerves in a specific area, which lowers the risk of overdose. Opioids, on the other hand, take over brain receptors and cause addiction.
- Acetaminophen overdoses send 56,000 people to the emergency room in the U.S. every year because they can damage the liver. However, a drug based on AM404 might not do this by avoiding harmful metabolic pathways.
- Painkillers for the Next Generation
- Scientists could make drugs that make AM404 more stable or make synthetic versions that work even better.
- Blocking sodium channels could lead to the creation of whole families of new drugs, says Nial Wheate, a pharmaceutical chemist at Macquarie University.
- Better ways to treat chronic pain
- Current treatments often don’t work for neuropathic pain, which is caused by nerve damage. AM404 works on peripheral nerves, so it might help where other drugs don’t.
The Catch: Rats Aren’t Humans
The findings are intriguing; however, a significant limitation exists: the study was performed on rats. AM404 might not work the same way in people because human biology is different in important ways.
- Differences in metabolism: Human livers break down drugs in different ways, which could affect how AM404 is made.
- No known side effects: It looks like AM404 is safe in rats, but we need to test it on people to make sure there are no hidden risks.
But the effects are too big to ignore. If future studies corroborate these effects, we may be on the verge of a revolution in pain alleviation.
Beyond Tylenol: The Future of AM404-Based Drugs
The finding that AM404 has peripheral effects has already led to the development of new drugs:
South Rampart Pharma’s SRP-001 is a new painkiller that increases the production of AM404 in the brain’s pain-control center (the periaqueductal grey) without harming the liver. It is already in Phase 2 trials for pain that is acute or neuropathic.
Targeted Sodium Blockers: Journavx™ (suzetrigine) is a new drug that the FDA just approved. It blocks sodium channels (Nav1.8) that are related to pain, just like AM404 does.
Dr. Hernan Bazan, CEO of South Rampart Pharma, says, “It is very important to find new ways to relieve pain.””Opioids and NSAIDs, which are already used to treat pain, can be addictive and toxic. That could change with AM404-based therapies.
What’s Next? Human Trials and Beyond
The scientists want to:
- Make AM404 variants that are more stable so that they last longer.
- Look into AM404 in models of chronic pain, especially those that involve nerve damage and inflammation.
- Find out if it can help with migraines or arthritis, both of which are conditions where peripheral nerve signaling is important.
If this works, we might soon have painkillers that are smarter, safer, and much stronger than Tylenol.
Conclusion: A New Era of Pain Science
AM404, acetaminophen’s secret weapon, was hiding in plain sight for 130 years. We now know that it might stop pain before the brain even feels it. This opens the door for a new wave of precise painkillers. More research is needed, but one thing is clear: the future of pain relief may not be in hiding pain, but in stopping it from happening in the first place.
Would you take an AM404-based painkiller of the next generation? Soon, the answer could be in your medicine cabinet.
Sources:
Jan loves Wildlife and Animals and is one of the founders of Animals Around The Globe. He holds an MSc in Finance & Economics and is a passionate PADI Open Water Diver. His favorite animals are Mountain Gorillas, Tigers, and Great White Sharks. He lived in South Africa, Germany, the USA, Ireland, Italy, China, and Australia. Before AATG, Jan worked for Google, Axel Springer, BMW and others.
