Quantitative design of optimal analgesic combination of acetaminophen, caffeine, and butalbital

AIM: To quantitatively seek an optimal analgesic combination of acetaminoph en (Ace), butalbital (But), and caffeine (Caf), and to characterize the pha rmacodynamics of interaction among the three drugs. METHODS: The models of acute inflammatory pain in carrageenin-injected rats were applied to measur e the vocalization threshold to paw pressure. Six groups with different rat ios and doses were set to seek an optimal combination of Ace, Caf, and But, analyzed by the weighted modification method. Based on the ratio and doses in the optimal combination, four continuous doses were set to analyze the interactions of therapeutic effects by the reflection method. The interacti on of the acute toxicity was evaluated by the parameter method. RESULTS: Ac cording to the degree of importance to the combined analgesic effect, Ace > Caf > But; Ace showed a significant dose-response relationship, whereas in Caf and But, this relationship was not apparent. A new combination was obt ained by the theoretical analysis and confirmed further by experimentation. Namely, at a ratio of 8.6: 1: 1.5 Ace + Caf + But (240 + 28 + 42 mg/kg, ig ) was an optimal combination. Both Caf and But had a synergism to Ace, but Caf was a stronger synergist in contrast to But. Such synergism increased t he therapeutic effects in the range of Ace 153.6 - 300 mg/kg combined with Caf 17.9 - 35 mg/kg and But 26.8 - 52.5 mg/kg (8.6: 1: 1. 5). However, the dose of Ace + Caf + Bul at 300 + 35 + 52.5 mg/kg resulted in sedation in ra ts. The peak latency was approximately 1 h for all four continuous doses, b ut the peak amplitude was dose-related, and the duration of the therapeutic effect was less than 2 h. The acute toxicity of the three drugs in combina tion remained the same. CONCLUSION: Ace + Caf + But at a dose of (240 + 28 + 42) mg/kg (ig) results in an optimal combination. The therapeutic window of the combination is located in the range of Ace (153.6 - 240 mg/kg) + Caf (17.9 - 28 mg/kg) + But (26.8 - 42 mg/kg) (8.6: 1: 1.5). Caf has a stronge r synergism with Ace than But.