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 (EC_50exp = 67.43 ± 11 μg; EC_50teo = 8.28 ± 3.2 μg) and 3:1 (EC_50exp = 31.25 ± 9.49 μg; CE_50teo = 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.