[Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain. Preclinical overview]. / Tapentadol: mit zwei Mechanismen in einem Molekül wirksam gegen nozizeptive und neuropathische Schmerzen. Präklinischer Überblick.

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

In vitro and in vivo characterization of tapentadol metabolites.

Tapentadol is a novel, centrally acting analgesic combining micro-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. Nine metabolites, including the major metabolite tapentadol-O-glucuronide, had no analgesic effects in the tail-flick test in mice. In the phenylquinone writhing test in mice, only 5 of these metabolites showed analgesic effects. The absence or presence of analgesia correlated with moderate activity (0.5 microM < K(i) < 1.1 microM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.

The beagle dog as a predictor of gastrointestinal findings in humans caused by the prostacyclin analogue taprostene.

Beagle dogs were exposed orally to the prostacyclin analogue taprostene for four weeks. Dose levels of 200-3000 micrograms/kg body weight/day were used. Specific activity of taprostene on the digestive system compared to other species is reported. It is characterized by hypermotility of the gastrointestinal tract resulting in intestinal invagination in some animals. Gastrointestinal symptoms occurred also after intravenous administration indicating a systemic stimulating effect on smooth muscles. Concerning reversible gastrointestinal side effects in humans after intravenous infusion of prostacyclin the results of this subacute toxicity study indicated that the dog is an adequate and sensitive species for preclinical testing of prostacyclins.