Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs

Abstract

ObjectiveTo evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs. Study designProspective part-randomized pre-clinical research trial. AnimalsFifteen male Beagle dogs (HsdCpb:DOBE), aged 12–15 months. MethodsOn different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg−1), tapentadol (2.15, 4.64, 6.81 mg kg−1) or morphine (0.464, 0.681, 1.0 mg kg−1) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1). ResultsTapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg−1 and 0.71 mg kg−1, respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociptive effect of tramadol in this experimental pain model in dogs. Conclusions and clinical relevanceDifferent breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states.