Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism.
OBJECTIVE
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 [% x min]) (2145 +/- 2901 % x min) was totally inhibited by both tropisetron (89 +/- 1747 % x min, P = .007) and granisetron (45 +/- 2020 % x min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).


CONCLUSIONS
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.
Institut National de la Santé et de la Recherche Medicale, Centre d'Investigation Clinique 501, Centre Hospitalier Universitaire Clermont-Ferrand, France. gisele.pickering@u-clermont1.fr
Gisèle
G
Pickering
Marie-Anne
MA
Loriot
Frédéric
F
Libert
Alain
A
Eschalier
Philippe
P
Beaune
Claude
C
Dubray
D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D017829:Granisetron / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077526:Tropisetron
D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D017829:Granisetron; D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D000077526:Tropisetron