¹Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 501, Centre Hospitalier Universitaire Clermont-Ferrand, Univ. Clermont, Unité de Formation et de Recherche Médecine, Equipe d'accueil 3848, Pharmacologie Médicale Laboratoire de Pharmacologie et de Toxicologie, Centre Hospitalier Universitaire Clermont-Ferrand, Clermont-Ferr and Assistance Publique-Hôpitaux de Paris, Biochemistry Department, European Georges Pompidou Hospital, Université Faculté de Médecine, Paris-Descartes, and Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherches 490, Paris.

Correspondence: Gisèle Pickering, MD, Clinical Pharmacology Centre, Bâtiment 3C, CHU, Hopital G. Montpied, 63001 Clermont-Ferrand Cedex, France. E-mail: gisele.pickering@u-clermont1.fr

Received 27 June 2005; Accepted 22 December 2005.

Abstract

Objectives: Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5-hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.

Methods: Twenty-six rapid metabolizers of tropisetron were included in this double-blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self-evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0-4 hours) (mean SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.

Results: The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time [% min]) (2145 2901 % min) was totally inhibited by both tropisetron (89 1747 % min, P = .007) and granisetron (45 2020 % min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).

Conclusion: These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.