Indomethacin, caffeine and prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine.

The combination of indomethacin, caffeine, and prochlorperazine (hereinafter IndoProCaf) represents an effective antimigraine drug available on the Italian market. The aim of this study was to test the efficacy of the three active principles alone and in combination in reverting hyperalgesia. Hyperalgesia was induced by morphine withdrawal in mice treated with morphine for 15 days and then made hyperalgic by morphine substitution with water. This study showed that indomethacin 0.3 mg kg(-1), i.p.; caffeine 0.1 and 0.3 mg kg(-1), i.p.; and prochlorperazine 0.1 mg kg(-1), i.p.; as well as the combination of the three active principles, were able to revert morphine withdrawal induced hyperalgesia, causing a statistically significant increase of pain threshold in hyperalgic mice. In a second model, hyperalgesia was induced by the i.p. injection of a 0.3% solution of acetic acid in mice and was evaluated counting the number of abdominal constrictions. Indomethacin (0.1 mg kg(-1), i.p.), caffeine (0.3 mg kg(-1), i.p.), and prochlorperazine (0.1 mg kg(-1), i.p.) reduced the number of abdominal constrictions, while the combination of the three active principles was able to abolish almost completely the abdominal constrictions, with a significantly higher efficacy compared to the single active principles. In both models, indomethacin, caffeine, and prochlorperazine reverted hyperalgesia at dosages 10 times lower than the corresponding analgesic ones. These data provide the pharmacologic evidence of the efficacy of IndoProCaf in reverting hyperalgesia, a condition of reduction of pain threshold similar to that occurring in migraine.