Plasma Concentrations of Flurazepam and Midazolam in Chronic Insomniacs during 14-Day Use and Their Relationship to Therapeutic Effects and Next-Day Performance and Mood

Abstract

Blood samples were drawn from each of 99 chronic insomniacs twice during washout (days -20 and -6) and six times during the study (mornings after study nights -1, 1, 2, 7, 13, and 14) to examine the relationship between morning-after drug plasma levels, sleep efficiency, next-day mood, and performance. Patients in the four treatment groups received either flurazepam 30 mg, flurazepam 15 mg, midazolam 15 mg, or placebo. Plasma drug concentrations of N-desalkylflurazepam and midazolam were measured by electron-capture gas chromatography. Values of midazolam during the 14-day study were at or near the sensitivity limit of the assay and were not used in the calculations. Levels of N-desalkylflurazepam increased as expected during the 14 days. Mean level for the high-dose flurazepam group was approximately twice that of the low-dose group. The main consistency in the correlations, which were found on days 13 and 14, was that the high-dose desalkylflurazepam concentrations had a negative correlation with two independent measures of sleep latency. However, otherwise there was little or no relationship between N-desalkylflurazepam levels and sleep efficiency or next-day behavior. Issues of tolerance, individual variability in baseline and response, and their contribution to the findings are discussed.