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 (AS A), a nonsteroidal anti-inflammatory drug (NSAID), and morphine, a mu- 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 mu mol/k g p.o.), morphine (3.1, 5.5, 9.8, 77.5, 31.1, or 55.2 mu mol/kg s.c.), or a combination of ASA and morphine (24 different combinations). Thi s allowed us to detect the profile of analgesic interaction of the com binations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs b y means of the ''surface of synergistic interaction'' of the combinati ons. The ED(50) values for ASA and morphine were 1,167.9 +/- 6.7 and 1 8.4 +/- 3.7 mu mol/kg, respectively. Eleven combinations of ASA and mo rphine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each ana lgesic drug alone (P < 0.01). The combination of ASA (3,121.3 mu mol/k g) and morphine (31.1 mu mol/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 mu mol/kg, respectively) produced the highest potentiation effects (P < 0.01). The surface of synergistic interactio n clearly showed which combination of these analgesic drugs produced t he highest degree of potentiation in the rat. This study showed that i t is possible to rationally predict the specific combinations of analg esic drugs and their dosages which will provide either maximal levels of analgesia or the highest potentiation effect in the rat. (C) 1995 W iley-Liss, Inc.