Coadministration of tramadol and tizanidine in an experimental acute pain model in rat

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.