Morphine and fentanyl anesthetic interactions with diazepam: relative antagonism in rats

The anesthetic effects of morphine-diazepam and fentanyl-diazepam combinations as characterized by abolition of the movement response to noxious stimulation were studied in rats to test the hypothesis of antagonistic interactions between the components of these combinations. Noxious pressure on the tail was used to induce the response. Dose-effect curves were constructed for the drugs given alone and in combination. With the use of probit procedure ED50 values for single drugs and their combinations were determined, and the interactions were analyzed with algebraic (fractional) and isobolographic methods. It was found that both morphine and fentanyl have a less than additive (antagonistic) interaction with diazepam. In combination the sum of fractional doses was higher than a single-drug fractional dose, 1.67 versus 1.00 (P less than 0.05) for morphine-diazepam and 1.61 versus 1.00 (P less than 0.05) for fentanyl-diazepam. The observed antagonism is a relative one that does not increase the requirement for one agent upon the addition of another agent.