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.

Background: Paracetamol is one of the most commonly used analgesic and antipyretic drug, available as a single or a combined formulation. Caffeine is an adjuvant analgesic to several drugs such as paracetamol. The goal of combining paracetamol with caffeine is to achieve a higher analgesic efficacy of paracetamol while lowering its dose and thus reducing side effects. Objective: This narrative literature review aims to provide an overview of the cumulative analgesic effects of this combination and the mechanisms underlying the potentiation by caffeine of the antinociceptive effect of paracetamol. Methods: The search was conducted in PubMed, MEDLINE, ClinicalTrials.gov , and Cochrane Database. For the clinical efficacy and safety, only randomized controlled trials and meta‐analysis assessing paracetamol 1000 mg in combination with caffeine 130 mg were considered. Results: As emphasized by the data presented in this review, there is a potentiation of paracetamol‐induced analgesia by caffeine with synergistic interactions observed in preclinical and clinical studies. Caffeine enhances the antinociceptive effect of paracetamol and accelerates the absorption of associated paracetamol, which explains the significant faster analgesics’ effect with the combination. In clinical trials in patients with mild to moderate acute pain, the combination demonstrates a higher pain relief compared with paracetamol alone with a significant improvement of pain relief in patients with primary headaches without added safety issues. Conclusions: This combination is effective and safe in the treatment of acute mild and moderate pain. Prescribing physicians might consider using paracetamol and caffeine combination among other options in treating these types of pain.