October 2000

The Comparative Dose-Response Effects of Melatonin and Midazolam for Premedication of Adult Patients: A Double-Blinded, Placebo Controlled Study
Naguib M, Samarkandi AH. Anesth Analg 2000;91:473-9.
[see abstract below]

Return to the Current Literature Review Front Page

Commentary by Katherine Grichnik, M.D.

This is an interesting study because it addresses the anxiolytic, sedative and amnesic effects of two different drugs against placebo. It is especially interesting because one of the drugs tested is melatonin, a non-prescription medication commonly used for treating jet lag.

The authors tested three different doses of sublingual midazolam versus the same doses of sublingual melatonin. The doses used were 0.05 mg/kg, 0.1 mg/kg, and 0.2 mg/kg. The placebo was normal saline. The study solution was given approximately 100 minutes before the induction of anesthesia and the subjects were instructed to hold the study solution under their tongues for 3 minutes before swallowing. Subjects were evaluated for anxiolysis, sedation, cognitive function and psychomotor performance on testing at 30 min, 60 min and 90 min after administration of the study solution. The subjects then underwent gynecological and laporascopic procedures under a prescribed anesthetic regimen. Sedation, amnesia and cognitive function were tested again postoperatively.

The authors found that the groups were similar in demographic and surgical variables. There were no differences in the amount of analgesics used intraoperatively or postoperatively between all groups.

There were no differences in anxiety between melatonin and midazolam with both drugs causing anxiolysis as compared to placebo. Patients receiving melatonin and midazolam both had increased levels of sedation at 60 and 90 minutes. The subjects given midazolam had significantly worse performance on cognitive digit symbol testing as compared to melatonin and placebo preoperatively. Interestingly, all groups were equally able to complete a dot test of psychomotor activity postoperatively. After surgery, the subjects given 0.2 mg/kg midazolam had increased levels of sedation and all three midazolam groups had impairment on the cognitive digit symbol test as compared to the 0.05 mg/kg melatonin group. Only the 0.2 mg/kg midazolam group had significant amnesia.

These results are interesting because they suggest that we can now tailor our premedication to the type of surgery and postoperative course that is expected. For longer, more complex surgeries in which an overnight hospital stay is expected in a monitored setting, the use of larger doses of midazolam can achieve the goals of anxiolysis, sedation and amnesia. In this situation, the decline in cognitive function before and after surgery does not matter, as the patient will be well cared for in the hospital. However, when anxiolysis and sedation are desired without amnesia or cognitive dysfunction, melatonin may be good choice for premedication. This may be an ideal drug for premedication in the outpatient surgical setting.

Another interesting point to consider is that melatonin is not a controlled substance. Is it possible that we will be asking our patients to take melatonin at home in anticipation of their outpatient surgery? Will this drug allow us to discharge a functional adult with no measurable mental impairment after surgery? This study may have determined a useful dose of melatonin to administer to a preoperative patient—but is this dose correct for the traveler as well? All of these questions need to be pondered and answered in future studies on this fascinating drug.

ABSTRACTS The Comparative Dose-Response Effects of Melatonin and Midazolam for Premedication of Adult Patients: A Double-Blinded, Placebo Controlled Study AUTHORS: Naguib M, Samarkandi AH SOURCE: Anesth Analg 2000;91:473-9 ABSTRACT: We designed this prospective, randomized, double-blinded, placebo-controlled study to compare the perioperative effects of different doses of melatonin and midazolam. Doses of 0.05, 0.1, or 0. 2 mg/kg sublingual midazolam or melatonin or placebo were given to 84 women, approximately 100 min before a standard anesthetic. Sedation, anxiety, and orientation were quantified before, 10, 30, 60, and 90 min after premedication, and 15, 30, 60, and 90 min after admission to the recovery room. Psychomotor performance of the patient was evaluated at these times also, by using the digit-symbol substitution test and Trieger dot test. Patients who received premedication with either midazolam or melatonin had a significant decrease in anxiety levels and increase in levels of sedation preoperatively compared with control subjects. Patients in the three midazolam groups experienced significant psychomotor impairment in the preoperative period compared with melatonin or placebo. After operation, patients who received 0.2 mg/kg midazolam premedication had increased levels of sedation at 90 min compared with 0.05 and 0. 1 mg/kg melatonin groups. In addition, patients in the three midazolam groups had impairment of performance on the digit-symbol substitution test at all times compared with the 0.05 mg/kg melatonin group. Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery. Implications: Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery.