Preclinical Research The aim of the present study was to evaluate the 
antinoceptive interaction between the opioid analgesic, tapentadol, and the 
NSAID, ketorolac, in the mouse orofacial formalin test. Tapentadol or ketorolac 
were administered ip 15 min before orofacial formalin injection. The effect of 
the individual drugs was used to calculate their ED50 values and different 
proportions (tapentadol-ketorolac in 1:1, 3:1, and 1:3) were assayed in the 
orofacial test using isobolographic analysis and interaction index to evaluate 
the interaction between the drugs. The combination showed antinociceptive 
synergistic and additive effects in the first and second phase of the orofacial 
formalin test. Naloxone and glibenclamide were used to evaluate the possible 
mechanisms of action and both partially reversed the antinociception produced by 
the tapentadol-ketorolac combination. These data suggest that the mixture of 
tapentadol and ketorolac produces additive or synergistic interactions via 
opioid receptors and ATP-sensitive K+ channels in the orofacial formalin-induced 
nociception model in mice. Drug Dev Res 78 : 63-70, 2017. © 2016 Wiley 
Periodicals, Inc.