Buccal Absorption of Midazolam: Pharmacokinetics and EEG Pharmacodynamics

Purpose: To determine whether buccal/sublingual administration of midazolam (MDL) would lead to detectable venous concentrations and EEG changes in 10 healthy volunteers. Methods: The study consisted of an open‐label and a double‐blind phases. Subjects held 10 mg MDL in 2 ml peppermint‐flavored fluid or peppermint‐flavored placebo in their mouth for 5 min and then spat it out. Cardiorespiratory and EEG monitoring was performed in all subjects. Results: Venous MDL concentrations measured on 10 occasions from 5 to 600 min after administration showed a rapid increase for the first 20–30 min. However, changes in the 8‐to 30‐Hz frequencies identified by spectral analysis of the EEG showed changes in ≤5–10 min in test but not in control subjects—more rapid than were expected from the venous absorption data. There were no significant adverse effects. Conclusions: Our data provide direct evidence of the speed of cerebral effect of a drug. Our results suggest that the buccal/sublingual route of administration should be tested in emergency treatment of seizures as an alternative to the rectal route, over which it has clear practical advantages.