Comparison of the sedative effects of butorphanol and midazolam

Abstract

Although kappa opioid agonists and certain agonist-antagonists are known to be sedating, this effect has not been well characterized in a drug-naive population. We compared the sedative properties of intravenous butorphanol with those of midazolam or the combination in 126 healthy preoperative patients. Subjects were randomly assigned to receive one of nine treatments in a double-blind fashion: 7.1, 22.5, or 71.4 μg/kg butorphanol; 4.3, 13.6, or 42.9 μg/kg midazolam; or 3.6 + 2.2, 11.3 + 6.8, or 35.7 + 21.5 μg/kg butorphanol and midazolam in combination. Eight visual analogue scales (VAS) were completed by the subject and an observer. The subject then performed two psychomotor tests (the Trieger dot test and the Halstead trail-making test) and was shown two playing cards in order to assess memory. The test drug was administered, and 5 min later the evaluations were repeated and two more cards were shown. On the following day the subjects were asked to recall the names of the playing cards. Butorphanol, midazolam, and their combination produced dose-related changes in VAS scores that were significant and qualitatively similar: subjects became sleepy, less nervous, weak, and less clear-thinking. There was no significant euphoria or dysphoria. The sedative and depressant effects on respiratory rate of the high-dose combination were significantly greater than those predicted by simple additivity: 14 of 14 subjects receiving the high dose of the butorphanol/midazolam combination had lid droop and marked sedation, and 2 of 14 subjects had respiratory rates of less than 4 breaths per min. All three drug treatments caused significant, dose-dependent impairment of psychomotor function. Subjects usually remembered cards seen prior to drug treatment, but not those seen afterward. The amnesic effects of midazolam were dose-related, profound, and much greater than those of butorphanol. In a 70-kg subject, a dose as low as 0.5 mg butorphanol (lower than the usual analgesic dose) provided clinically useful sedative effects. At this dose, however, butorphanol caused no significant amnesic effect or psychomotor impairment.