Babette-Yvonne Kögel

196 TAPENTADOL, A NOVEL CENTRALLY ACTING ANALGESIC: PRECLINICAL EVIDENCE FOR A DUAL MODE OF ACTION UNDERLYING ITS BROAD EFFICACY PROFILE

Background and Aims: Tapentadol [(−)-(1R,2R)-3-(3-Dimethylamino-1ethyl-2-methyl-propyl)-phenol] is a novel analgesic with a dual mode of action, m opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition, and a broad analgesic efficacy. Methods: Tapentadol was tested in a range of in vitro and in vivo experiments to characterize its dual mode of action. Results: Tapentadol binds to MOR with a Ki = 0.1 mM, and has an efficacy of 88% in a [35S]GTPgammaS binding assay, relative to morphine. In addition, it has a Ki = 0.5mM for synaptosomal NA reuptake inhibition. The functional relevance of NA reuptake inhibition was supported by in vivo brain microdialysis studies showing that tapentadol, in contrast to morphine, produces dose-dependent increases in extracellular levels of NA in the analgesic dose range (up to 450% at 10mg/kg). A pronounced noradrenergic contribution to the analgesic efficacy was demonstrated in a rat neuropathic pain model, where the analgesic effect of tapentadol (10mg/kg) was strongly antagonized by the a2-NA receptor antagonist yohimbine (2.15mg/kg), but was only weakly affected by the MOR antagonist naloxone (0.3mg/kg), whereas the opposite was the case for morphine (6.81mg/kg). In the mouse writhing model, the analgesic effect of morphine (0.681mg/kg) was much more susceptible to antagonism by naloxone (0.001−1mg/kg) than that of an equipotent dose of tapentadol (3.16mg/kg). Conclusions: Tapentadol’s dual mode of action is based on MOR agonism and NA reuptake inhibition. There is clear evidence that both mechanisms of action contribute to its analgesic effects.