A landmark study from the Hebrew University of Jerusalem challenges long-held beliefs about acetaminophen’s mode of action, showing that its metabolite, AM404, halts pain signals in peripheral nerves by inhibiting specific sodium channels. This discovery, published in PNAS on 10 June 2025, marks a pivotal shift in pain management science.
Historically, acetaminophen was thought to work primarily in the brain and spinal cord. The new research uncovers a peripheral mechanism: AM404 is generated in pain-sensing nerve endings and blocks voltage-gated sodium channels — specifically NaV1.7 and NaV1.8 — preventing pain signals from ever firing.
The study was led by Professor Alexander Binshtok and Professor Avi Priel, combining expertise from the Faculty of Medicine and School of Pharmacy. Their team demonstrated that AM404 is synthesised locally in nociceptors and directly inhibits sodium currents, significantly reducing pain behaviours in both normal and inflamed rat models.
This peripheral action mirrors the effect of local anaesthetics but targets only the nerves responsible for pain perception. As a result, AM404-based interventions could preserve motor and sensory functions, avoiding numbness or weakness commonly associated with traditional local anaesthetics.
Prof. Binshtok stated, “This is the first time we’ve shown that AM404 works directly on the nerves outside the brain. It changes our entire understanding of how acetaminophen fights pain”. Prof. Priel added that exploiting AM404’s selectivity could lead to safer, more precise analgesics that bypass the side effects of existing medications.
Published on 10 June 2025, the paper titled “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels” identifies the compound’s mechanism as state-dependent binding to the local anaesthetic site on NaV1.7 and NaV1.8 channels. These findings correct the incomplete understanding of acetaminophen as primarily a central nervous system agent and highlight a dual mechanism involving both central and peripheral pathways.
Other experts in neuroscience are welcoming the breakthrough. Commentary in Medical Xpress noted that this “ends a longstanding mystery” about how acetaminophen relieves pain. IFL Science emphasises the therapeutic promise: AM404’s ability to selectively silence pain neurons could inspire local anaesthetics without typical side effects.
From a pharmacological perspective, this discovery aligns with earlier theories by researchers like Stephen Waxman, who posited that peripheral sodium channels are viable targets for analgesia. NaV1.7 and NaV1.8 are central to pain signalling in peripheral neurons, a fact that has spurred generations of drug discovery efforts.
Beyond academic significance, this insight opens a new paradigm for drug development. AM404’s specific action suggests that chemists could design molecules that mimic or enhance its peripheral blocking properties, potentially offering pain relief without impairing motor function or causing dependency.
The clinical implications are substantial. Opioids and traditional local anaesthetics carry risks of addiction, motor impairment, and systemic side effects. AM404-inspired drugs could provide non-addictive, nerve-targeted alternatives with fewer adverse effects, particularly in postoperative and chronic pain management.
Next steps centre on translating these findings into human studies. Researchers must investigate whether AM404 concentrations in human peripheral tissues reach effective levels and evaluate long-term safety, metabolism, and efficacy across diverse patient populations. As Prof. Binshtok and Prof. Priel note, the journey has begun but much work remains to assess clinical potential.
The discovery adds to a growing trend of re-evaluating old medications with modern techniques, uncovering their hidden benefits. It comes one month after Indiana University researchers pointed to acetaminophen’s influence on endocannabinoid metabolism — another central mechanism — suggesting that the drug’s effects may be multifaceted.