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.
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.
Ellinwood
E
E
Duke University Medical Center, Durham, North Carolina 27710.
Linnoila
M
M
Marsh
G
G
D000328:Adult; D001143:Arousal / Q000187:drug effects*; D001288:Attention / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005479:Flurazepam / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009483:Neuropsychological Tests; D011597:Psychomotor Performance / Q000187:drug effects; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood / Q000188:drug therapy*; D012894:Sleep Stages / Q000187:drug effects*
C033473:didesethylflurazepam; C040081:1-hydroxymethylmidazolam; D005479:Flurazepam; D008874:Midazolam