A Randomized, Controlled Trial Validates a Peripheral Supra-Additive Antihyperalgesic Effect of a Paracetamol–Ketorolac Combination

Authors

  • Kuntheavy Ing Lorenzini,

    1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva, Geneva, Switzerland
    2. Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Marie Besson,

    1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva, Geneva, Switzerland
    2. Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Youssef Daali,

    1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva, Geneva, Switzerland
    2. Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Denis Salomon,

    1. Faculty of Medicine, University of Geneva, Geneva, Switzerland
    2. Division of Dermatology and Venerology, University Hospitals of Geneva, Geneva, Switzerland
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  • Pierre Dayer,

    1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva, Geneva, Switzerland
    2. Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Jules Desmeules

    1. Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva, Geneva, Switzerland
    2. Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Author for correspondence: Jules Desmeules, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland (fax +41 22 382 99 45, e-mail jules.desmeules@hcuge.ch).

Abstract

Abstract:  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 (< 0.014). The combination performed better than paracetamol (< 0.001) and placebo (< 0.042), increasing heat pain threshold by 1.5°C. The combination radically reduced primary hyperalgesia to mechanical stimulation (39%) compared with placebo (< 0.002) and single agents (paracetamol < 0.024 and ketorolac < 0.032). The combination also reduced, slightly although significantly, the intensity of pain (10%) for the cold pressor test (versus placebo: < 0.012, paracetamol: < 0.019 and ketorolac < 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.

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