Pharmacological bases of combining nonsteroidal antiinflammatory drugs and paracetamol

Paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs), particularly ibuprofen, are frequently administered together. A systematic review of clinical studies using combined or alternating regimes of NSAIDs was performed up to May 2023. Clinical evidence (77 studies) confirms that in many cases efficacy is enhanced by paracetamol + NSAID combinations, but quite a few studies show no added benefit. Synergism is more commonly found with combined regimens in analgesia for surgery, and with alternating regimes in antipyresis. In some instances the advantage may be related to the short duration of the effect of paracetamol. Mechanistically, central and peripheral actions associated with inhibition of cyclooxygenase have been documented for both paracetamol and NSAIDs, which are relevant for analgesia, antipyresis and closure of patent ductus arteriosus in neonates. In addition, paracetamol may achieve analgesia via different central pathways independently of cyclooxygenase. Hence, increased analgesia may result from NSAID and paracetamol acting at least partly via different mechanisms, while enhancement of antipyresis probably is explained simply by augmented or more prolongued inhibition of cyclooxygenase. Because of the inconsistencies found in the available evidence, added benefit should not be assumed for paracetamol/NSAID combinations. In addition, combining paracetamol and NSAIDs may lead to increased dosing errors, and may result in increased toxicity as a result of enhanced cyclooxygenase interference, a possibility that has barely been scrutinized. We conclude that combining paracetamol and NSAIDs may be justified in analgesia, but further studies are warranted to establish when and how an enhanced effect is achieved with this strategy.