Background: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and ami-triptyline on cutaneous orofacial inflammatory pain in rats. Methods: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline. Results: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED 50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2–33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0 –1.7 mg/kg) for amitripty-line and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED 50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. Conclusions: The current study suggests that systemic ami-triptyline and morphine synergistically inhibit cutaneous oro-facial inflammatory pain in rats.