ABSTRACT
Preclinical Research The use of drug combinations to achieve a desired effect is a common practice in pharmacological reaserch and in clinical practice. The present study was designed to evaluate the potential synergistic antinociceptive interactions between tizanidine, an α-2-adrenoceptor agonist and tramadol on formalin-induced nociception in rat using isobolographic analyses. Tramadol (0.1-100 µg/paw) and tizanidine (0.01-10 µg/paw) were injected into the paw prior to formalin injection (1%). Both drugs produced a dose-dependent antinociceptive effect. The EC50 values were estimated for individual drugs, and isobolograms were constructed. Tizanidine (EC50 = 0.125 ± 0.026 µg) was more potent than tramadol (EC50 = 16.45 ± 6.4 µg). The combination of tramadol-tizanidine at fixed ratios of 1:1 (EC50exp = 67.43 ± 11 µg; EC50teo = 8.28 ± 3.2 µg) and 3:1 (EC50exp = 31.25 ± 9.49 µg; CE50teo = 12.36 ± 4.8 µg) generated subadditivity (antagonism). On the basis of the current preclinical data, the pharmacological profile of the combination of tramadol-tizanidine produced antagonism. Thus, the utmost caution is required during the use of this combination in clinical practice, due to their antagonistic interaction.
