An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Christophe Mallet,1 Jules Desmeules,2 Rassa Pegahi,3 Alain Eschalier1 1Université Clermont Auvergne, INSERM, NEURO-DOL Basics & Clinical Pharmacology of Pain, Clermont-Ferrand, France; 2Faculty of Medicine and The School of Pharmaceutical Sciences, Faculty of Sciences, Geneva University, Geneva, Switzerland; 3Medical Affairs Department, UPSA, Paris, FranceCorrespondence: Alain Eschalier, Faculté de Médecine, UMR Neuro-Dol, 49 Bd François Mitterrand, Clermont-Ferrand, 63000, France, Email alain.eschalier@uca.frAbstract: Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/p-aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio.Keywords: paracetamol, acetaminophen, AM404, analgesia, molecular targets