Why acetaminophen works: New discovery ends longstanding mystery

edited by Lisa Lock, reviewed by Robert Egan

A study from the Hebrew University of Jerusalem, published this week in Proceedings of the National Academy of Sciences reveals a previously unknown peripheral mechanism by which paracetamol (also known as acetaminophen, Tylenol, or Panadol) relieves pain.

The study was led by Prof. Alexander Binshtok from the Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof. Avi Priel from its School of Pharmacy. Together, they uncovered a surprising new way that paracetamol—one of the world’s most common painkillers—actually works.

For decades, scientists believed that paracetamol relieved pain by working only in the brain and spinal cord. But this new research shows that the drug also works outside the brain, in the nerves that first detect pain.

Their discovery centers on a substance called AM404, which the body makes after taking paracetamol. The team found that AM404 is produced right in the pain-sensing nerve endings—and that it works by shutting off specific channels (called sodium channels) that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.

“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” said Prof. Binshtok. “It changes our entire understanding of how paracetamol fights pain.”

This breakthrough could also lead to new types of painkillers. Because AM404 targets only the nerves that carry pain, it may avoid the numbness, muscle weakness, and side effects that come with traditional local anesthetics.

“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” added Prof. Priel.

Examining the mechanisms and clinical potential of a promising non-opioid pain therapy candidate