Jerusalem, Israel – A groundbreaking study from the Hebrew University of Jerusalem has finally answered a decades-old question: how does paracetamol (also known as acetaminophen, Tylenol®, or Panadol®) actually relieve pain? Published in the June 2025 issue of the prestigious journal Proceedings of the National Academy of Sciences USA (PNAS), the research reveals that paracetamol doesn’t just act in the brain—it also blocks pain at its source, in the body’s nerve endings.
New Mechanism for Paracetamol’s Pain Relief
Led by Prof Alexander Binshtok (Faculty of Medicine, Center for Brain Sciences) and Prof Avi Priel (School of Pharmacy), the Hebrew University team discovered that paracetamol’s active metabolite, AM404, is produced directly in pain-sensing nerve endings. This compound works by shutting down specific sodium channels in these neurons, effectively stopping pain signals before they ever reach the brain.
“For the first time, we’ve shown that AM404 acts directly on nerves outside the brain,” said Prof. Binshtok. “This discovery fundamentally changes our understanding of how paracetamol fights pain.”
Safer, More Targeted Painkillers on the Horizon
Unlike traditional painkillers and local anaesthetics, which can cause numbness and side effects, AM404 targets only the nerves that transmit pain. This breakthrough opens the door to developing new pain treatments that are both safer and more precise.
“If we can create new drugs based on AM404, we may finally have painkillers that are highly effective without unwanted side effects,” added Prof Priel.
About the Study
The research, titled “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels,” is available in PNAS and can be accessed at: https://www.pnas.org/doi/10.1073/pnas.2413811122.
Research Team:
Yossef Maatuf, Yishai Kushnir, Alina Nemirovski, Mariana Ghantous, Ariel Iskimov, Alexander M. Binshtok, Avi Priel
Institutions:
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem
- Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem
- The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem
- Mass Spectrometry Unit, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem