• Klaus Schiene, Jean De Vry, and Thomas M Tzschentke.
• Global Preclinical Research and Development, Department of Pharmacology, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany. klaus.schiene@grunenthal.com
• J. Pharmacol. Exp. Ther. 2011 Nov 1;339(2):537-44.

AbstractThe novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

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