Dose-Dependent Interaction Between Caffeine and Morphine in Analgesia in the Hot-Plate in Mice

Combination analgesic therapy is a widely employed strategy for pain management worldwide. This study investigated the potential synergistic interaction between caffeine and morphine using the hot-plate test and isobolographic analysis in male NMRI mice. The interaction between caffeine and morphine in pain modulation was evaluated, and it was determined whether the combination produces a synergistic effect.

Mice were treated with morphine (0.135, 1.25, 5, and 20 mg/Kg, s.c.) or caffeine (20, 40, 80, and 160 mg/Kg, i.p.) to obtain the ED50 values of each agent in the hot-plate test, then, an isobolographic analysis was used to evaluate the nature of interaction between the two drugs in mice.

Morphine significantly increased pain thresholds in a dose-dependent manner (ED₅₀=2.49 mg/kg; P<0.001). Caffeine at a lower dose (46.13 mg/kg) potentiated morphine's analgesic effect, indicating a synergistic interaction (P<0.001). In contrast, a higher caffeine dose (138.3 mg/kg) reversed this effect, demonstrating an antagonistic interaction (P<0.001) in the mouse hot-plate test.

A low dose of caffeine synergistically enhanced morphine-induced analgesia in the mouse hot-plate test; this effect was absent at a higher dose. Consequently, only low-dose caffeine administration effectively reduced the required dosage of morphine for acute pain management in the mouse hot-plate test.