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

Christophe Mallet; Jules Desmeules; Rassa Pegahi; Alain Eschalier

doi:10.2147/JPR.S393809

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

J Pain Res. 2023 Mar 29:16:1081-1094. doi: 10.2147/JPR.S393809. eCollection 2023.

Authors

Christophe Mallet¹, Jules Desmeules², Rassa Pegahi³, Alain Eschalier¹

Affiliations

¹ Université Clermont Auvergne, INSERM, NEURO-DOL Basics & Clinical Pharmacology of Pain, Clermont-Ferrand, France.
² Faculty of Medicine and The School of Pharmaceutical Sciences, Faculty of Sciences, Geneva University, Geneva, Switzerland.
³ Medical Affairs Department, UPSA, Paris, France.

Abstract

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: AM404; acetaminophen; analgesia; molecular targets; paracetamol.

Publication types

Review

Grants and funding

Medical writing and editorial support in preparing this paper were provided by Content Ed Net, France, and funded by UPSA. All authors take complete responsibility for the integrity and accuracy of the data presented in the review. All authors met the International Committee of Medical Journal Editors (ICMJE) authorship criteria and approved the final version of the manuscript. UPSA is funding the open access fees of the journal.