Effect of caffeine on antinociceptive action of ketoprofen in rats

Background. To assess a possible synergistic antinociceptive interaction, t he antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administ ered either separately or in combinations were determined in a model of art hritic pain. Methods. Antinociceptive activity was assayed using "... pain- induced functional impairment in the rat" (PIFIR model). The antinociceptiv e efficacies were evaluated using several dose-response curves and time cou rses. The antinociceptive effects from the combination that produced the gr eater effect were compared with the maximal antinociceptive effect of eithe r morphine, acetylsalicylic acid (ASA), or KET alone. The animals were admi nistered with 0.05 mt intra-articular (i.a.) of uric acid to induce nocicep tion. Groups of six rats received orally either ASA, morphine (MOR), KET, C AF, or a combination KET + CAF (24 combinations). Results. ASA (ED50 465.2 +/- 1.5 mg/kg), MOR (ED50 71.0 +/- 1.6 mg/kg), and KET (ED,, 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinatio ns showed various degrees of potentiation (p <0.01), while the remainder ex hibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest a ntinociceptive potentiations. For example, antinocicepctive effect was 125. 6 <plus/minus> 21.4 area units (au) with KET (3.2 mg/kg) alone, but the com bination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effecti ve dose (ED,,) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED50 of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was appr oximately 18 times more potent than the analgesic drug without CAF, Conclusions. These results showed that CAF was able to potentiate the analg esia of KET, but only at selected dose combinations: CAF in the doses of 10 .0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the m ost efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive e ffects than the analgesic drug alone. This knowledge will permit the select ion of the therapeutically most effective combination ratio of drugs, emplo ying lower doses of each drug. (C) 2001 IMSS. Published by Elsevier Science Inc.