09 Jun Hebrew University Study Sheds Light on How Paracetamol (Acetaminophen) Works

Dr. Binshtok

MedicalResearch.com Interview with:
Prof. Alexander Binshtok PhD
Cecile and Seymour Alpert Professor in Pain Research
Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC)

MedicalResearch.com: What is the background for this study?

Response: Paracetamol (also known as acetaminophen) is one of the world’s most commonly used pain relievers and fever reducers, yet for decades, its precise biological mechanism has remained something of a mystery. Traditionally, scientists believed its analgesic effect stemmed from central nervous system activity—specifically through the action of its metabolite, AM404, on cannabinoid and TRPV1 receptors in the brain.

MedicalResearch.com: What are the main findings?

Response:  Our study challenges and expands that understanding. We have discovered that AM404 is also synthesized in peripheral sensory neurons—specifically in nociceptors, the cells responsible for detecting pain. Most importantly, we found that AM404 directly inhibits the sodium channels NaV1.7 and NaV1.8. These channels are crucial for transmitting pain signals from the body to the brain. This previously unrecognized peripheral action appears to significantly contribute to the drug’s pain-relieving properties.

MedicalResearch.com:  How does AM404 act to decrease pain sensitivity?

Response:  We found that AM404, a metabolite of paracetamol, reduces pain by directly blocking two key sodium channels—NaV1.7 and NaV1.8—found in peripheral nociceptors, the nerve cells responsible for detecting and transmitting pain signals. These channels are essential for the electrical activity that allows pain signals to travel from the body to the brain.

AM404 appears to act in a way similar to local anesthetics. It binds to the same internal site on these sodium channels and does so in a use- and state-dependent manner—meaning it targets active, pain-transmitting neurons more selectively. This prevents the nerves from firing in response to painful stimuli, effectively quieting the pain at its source.

Significantly, the study also found that AM404 inhibits sodium channels in pain-sensing neurons more effectively than those in other types of tissue. This suggests a high degree of selectivity, which could make it a promising template for safer painkillers—ones that target only pain pathways without broadly impairing nervous system function. 

MedicalResearch.com: What should readers take away from your report?

Response: Our study sheds light on a previously overlooked aspect of how paracetamol works. While the drug has long been associated with effects in the brain and spinal cord, the researchers have now identified a peripheral mechanism: AM404, a metabolite of paracetamol, directly inhibits pain-specific sodium channels outside the central nervous system.

This insight significantly broadens our understanding of paracetamol’s mode of action. It also opens the door to a new generation of painkillers—drugs that could replicate or amplify AM404’s targeted effect in the peripheral nervous system. Such treatments could offer powerful pain relief with fewer risks of side effects commonly linked to drugs that act on the brain.

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: This discovery is just the beginning. Future studies should explore the therapeutic potential of AM404 as a peripherally acting pain reliever. Because it targets pain at its source without heavily involving the central nervous system, AM404-based treatments could offer a safer alternative to current analgesics. 

However, further research is needed to fully understand the safety profile of AM404—particularly with long-term use and in diverse patient populations. Establishing both its efficacy and safety will be critical steps toward developing it as a viable clinical option.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: We believe these findings significantly advance our understanding of how paracetamol works, particularly by identifying a novel peripheral target for pain relief. This opens up exciting possibilities for developing more targeted and safer analgesics.

We have no conflicts of interest to disclose.

Citation:

Maatuf, Y.Kushnir, A. Nemirovski, M. Ghantous, A. Iskimov, A.M. Binshtok, & A. Priel
The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels, Proc. Natl. Acad. Sci. U.S.A. 122 (23) e2413811122, https://doi.org/10.1073/pnas.2413811122 (2025).

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Last Updated on June 9, 2025 by Marie Benz MD FAAD