Breakthrough Study Reveals Acetaminophen's True Mechanism, Paving Way for Safer Painkillers
June 21, 2025
In experiments, injecting AM404 into the paws of rats resulted in decreased sensitivity to pain stimuli, highlighting its localized effect without impacting other areas.
Researchers plan to create more stable versions of AM404 and investigate its potential for treating chronic and nerve-related pain, as well as assessing its safety and distribution in the body.
Previous theories suggested that acetaminophen works by inhibiting the production of prostaglandins, but new findings indicate that AM404 blocks sodium channels in sensory neurons, preventing pain signals from reaching the brain.
The implications of this research could lead to the development of next-generation painkillers that are more effective and safer than current options, including acetaminophen and opioids.
The study primarily involved experiments on rats, leading researchers to emphasize the importance of confirming these findings in human subjects.
Scientists have made a significant breakthrough in understanding how Tylenol, or acetaminophen, works in the body, despite its long history as a pain relief medication that dates back over 50 years.
A recent study published in the journal PNAS highlights that the drug's mechanism of action has remained unclear, but it focuses on a metabolite called AM404.
Acetaminophen is metabolized by the liver into 4-aminophenol, which is then converted into AM404, affecting both the central and peripheral nervous systems where pain originates.
AM404 appears to interact with the nervous system to block pain signals, providing a new perspective on how acetaminophen reduces pain.
This research is significant as it may change the overall understanding of acetaminophen's effects on the body, addressing long-standing questions about its mechanism.
Study co-authors Alexander Binshtok and Avi Priel from the Hebrew University of Jerusalem emphasized that these findings fundamentally change the understanding of acetaminophen's mechanism of action.
Summary based on 2 sources
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Sources

Live Science • Jun 19, 2025
We may finally know how Tylenol works — and it's not how we thought
InsideHook • Jun 21, 2025
Scientists Just Had a Breakthrough In Understanding Tylenol