Doses of acetyl salicylic acid and morphine in combination which provided either maximal levels of analgesia or the highest potentiation effect in the rat

The analgesic efficacy of the combination of acetyl salicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID), and morphine, a μ-opiate receptor agonist, was evaluated in the pain-induced functional impairment in the rat (PIFIR) model. Groups of 6 rats received either vehicle, ASA (175.4, 311.9, 555.1, 986.9, 1,755.2, or 3,121.3 μmol/kg p.o.), morphine (3.1, 5.5, 9.8, 17.5, 31.1, or 55.2 μmol/kg s.c.), or a combination of ASA and morphine (24 different combinations). This allowed us to detect the profile of analgesic interaction of the combinations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs by means of the “surface of synergistic interaction” of the combinations. The ED50 values for ASA and morphine were 1,167.9 ± 6.7 and 18.4 ± 3.7 μmol/kg, respectively. Eleven combinations of ASA and morphine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each analgesic drug alone (P < 0.01). The combination of ASA (3,121.3 μmol/kg) and morphine (31.1 μmol/kg) produced the maximum analgesic effect. However, three combinations of ASA + morphine (555.1 + 31.1, 986.9 + 9.8, and 1,755.2 + 9.8 μmol/kg, respectively) produced the highest potentiation effects (P < 0.01). The surface of synergistic interaction clearly showed which combination of these analgesic drugs produced the highest degree of potentiation in the rat. This study showed that it is possible to rationally predict the specific combinations of analgesic drugs and their dosages which will provide either maximal levels of analgesia or the highest potentiation effect in the rat. © 1995 Wiley-Liss, Inc.