Paracetamol and Caffeine Combination in Pain Management: A Narrative Review

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.