title: Paracetamol and opioid pathways: a pilot randomized clinical trial.
abstract: Previous studies suggest that the antinociceptive action of paracetamol (acetaminophen, APAP) might involve descending inhibitory pain pathways and the opioidergic system: this study explores this issue in humans with naloxone, the opioid antagonist. After ethical approval, 12 healthy male volunteers were included in this randomized, controlled, double-blind, crossover, four-arm study. They were administered intravenous paracetamol (APAP 1 g) or saline (placebo, pl) followed at 100 min with IV naloxone (Nal 8 mg) or saline, every week for 4 weeks. The amplitude of cerebral potentials evoked by thermal/painful stimuli applied on the arm was recorded nine times over 150 min, witnessing of pain integration at central level. Amplitude changes as well as areas under the curve (AUCs) over 150 min were compared for the four treatments by repeated measures ANOVA (significance 0.05). Amplitude changes were significant for APAP/pl vs. pl/pl at t150: -44% (95%CI -58 to -30) vs. -27% (95%CI -37 to -17; P < 0.05) but not vs. APAP/Nal. AUC (0-150) of APAP/pl is significantly different from pl/pl (-3452%.min (95%CI -4705 to -2199) vs. -933% min (95%CI -2273 to 407; P = 0.015) but not from APAP/Nal (-1731% min (95%CI -3676 to 214; P = 0.08) and other treatments. AUC (90-150) is not significantly different. This pilot study shows for the first time in human volunteers that naloxone does not inhibit paracetamol antinociception, suggesting no significant implication of the opioid system in paracetamol mechanism of action: this needs be confirmed on a larger number of subjects.
authors.affiliation: CHU Clermont-Ferrand, Centre de Pharmacologie Clinique, F-63003 Clermont-Ferrand, France. gisele.pickering@u-clermont1.fr
authors.forename: Gisèle
authors.initials: G
authors.lastname: Pickering
authors.forename: Fares
authors.initials: F
authors.lastname: Moustafa
authors.forename: Stephanie
authors.initials: S
authors.lastname: Desbrandes
authors.forename: J Michel
authors.initials: JM
authors.lastname: Cardot
authors.forename: Delphine
authors.initials: D
authors.lastname: Roux
authors.forename: Claude
authors.initials: C
authors.lastname: Dubray
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000704:Analysis of Variance; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D010865:Pilot Projects; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D009292:Narcotic Antagonists; D000082:Acetaminophen; D009270:Naloxone