A randomized, controlled trial validates a peripheral supra-additive antihyperalgesic effect of a paracetamol-ketorolac combination

The combination of paracetamol with non-steroidal anti-inflammatory drugs (NSAIDs) is widely used; however, the nature and mechanism of their interaction are still debated. A double-blind, pharmacokinetic/pharmacodynamic, randomized, cross-over, placebo-controlled study was carried out in human healthy volunteers. The aim was to explore the existence of a positive interaction between paracetamol 1 g and ketorolac 20 mg administered intravenously on experimental pain models in human beings. The effects of the paracetamol-ketotolac combination were compared with similar doses of respective single analgesic and to placebo on the sunburn model (UVB-induced inflammation), cold pain tolerance and the nociceptive flexion reflex. The kinetics of the plasma concentrations of paracetamol and ketorolac were measured using 2D-liquid chromatography-mass spectrometry. Thirteen volunteers were screened, and 11 completed the study. Ketorolac significantly decreased primary hyperalgesia to heat stimuli compared with paracetamol (p < 0.014). The combination performed better than paracetamol (p < 0.001) and placebo (p < 0.042), increasing heat pain threshold by 1.5°C. The combination radically reduced primary hyperalgesia to mechanical stimulation (39%) compared with placebo (p < 0.002) and single agents (paracetamol p < 0.024 and ketorolac p < 0.032). The combination also reduced, slightly although significantly, the intensity of pain (10%) for the cold pressor test (versus placebo: p < 0.012, paracetamol: p < 0.019 and ketorolac p < 0.004). None of the treatments significantly affected the central models of pain at this dosage level. No pharmacokinetic interactions were observed. These results suggest a supra-additive pharmacodynamic interaction between paracetamol and ketorolac in an inflammatory pain model. The mechanism of this interaction could mainly rely on a peripheral contribution of paracetamol to the effect of NSAIDs.