Isobolographic analysis of the dual-site synergism in the antinociceptive response of tramadol in the formalin test in rats

Tramadol is an atypical opioid with a complex mechanism of action including a synergistic interaction between the parent drug and an active metabolite. The local action of the parent drug is poorly documented. This study was designed to evaluate the site–site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of intraplantar (i.pl.) and intraperitoneal (i.p.) tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In both first and second phases of the formalin test, tramadol was active not only by the systemic (ED50 10.2 ± 2.1 and 7.1 ± 0.5 mg/kg i.p.) but also by the local route (ED50 171.0 ± 44.8 and 134.6 μg/paw i.pl.). The isobolographic analysis revealed a “self-synergism” in the antinociceptive effect between the two routes of administration, as the experimental ED50 (211.1 ± 13.6 and 45.9 ± 3.9 “dose units” phase 1 and 2, respectively) of the combination was significantly lower than the theoretical ED50 (422.2 ± 50.5 and 138.5 ± 9.2 “dose units”). The mechanism underlying this self-synergism appears to be partially opioid since systemic but not local naloxone reversed the potentiation. The observed dual-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.