Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs

The anesthetic interactions of midazolam and fentanyl were determined in terms of enflurane MAC reduction in dogs. In part 1, 8 animals received an intravenous (iv) loading dose of fentanyl followed by a constant infusion at 0.05 μg·kg^-1·min^-1 to produce a stable enflurane MAC reduction of approximately 20%. Midazolam was then administered in a series of three incremental loading doses and infusions (2.4, 9.6, and 28.8 μg·kg^-1·min^-1) previously determined to produce enflurane MAC reductions of approximately 30, 45, and 60%, respectively. Enflurane MAC was determined for each infusion. Then fentanyl was discontinued; naloxone 1 mg/kg was administered; and enflurane MAC was determined. In part 2, six dogs received a loading dose and a continuous infusion of fentanyl (0.2 μg·kg^-1·min^-1) designed to produce a stable enflurane MAC reduction of approximately 40%. A series of two incremental loading doses and infusions of midazolam (2.4 and 28.8 μg·kg^-1·min^-1) were added, and MAC determinations were repeated at each infusion rate. Then midazolam was discontinued; flumazenil (RO 15-1788) 1.5 mg/kg was administered; and enflurane MAC was determined. The fentanyl concentrations in plasma remained stable at 1.0 ± 0.3 ng/ml (mean ± standard deviation [SD], part 1) and 3.1 ± 0.5 ng/ml (part 2) throughout the study and, in the absence of midazolam, reduced enflurane MAC by 28 ± 11 and 44 ± 5%, respectively. The addition of midazolam produced significant further reductions in enflurane MAC, but the reductions were less than those predicted on the basis of an additive interaction. Naloxone returned enflurane MAC reduction to that expected for midazolam alone (part 1). The degree of enflurane MAC reduction after administration of flumazenil and in the presence of the continuing infusion of fentanyl was significantly less than predicted (part 2). We conclude that there is a less than additive interaction between fentanyl and midazolam with respect to enflurane MAC reduction.