Many studies have been carried out to evaluate the effect of different premedications on the induction and maintenance dose of propofol using different end-points in both animals and human beings [1–3]. Melatonin has several functions, including regulation of circadian rhythms , regulation of the reproductive axis , antinociceptive effects , and anticonvulsant  and antioxidant activities . Autoradiographic studies and receptor assays have demonstrated the presence of melatonin receptors in various regions of the central nervous system and in other tissues in human beings . Different dosages of melatonin premedication were associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills and without prolonging recovery [10–14]. Based on these results, we hypothesized that melatonin might decrease the amount of propofol required to produce an adequate depth of hypnosis at induction.
After Ethics Committee approval, informed written consent was taken from 45 adult patients (American Society of Anesthesiologists Grade I–II) undergoing different surgical procedures. They were allocated randomly into three groups.
At 100 min preoperatively, premedication was given in the form of oral melatonin 3 mg (M3 group), oral melatonin 5 mg (M5 group) or no premedication (P group). Exclusion criteria for all groups included weight less than 50 kg or more than 90 kg and patients who were 25% less or more above ideal body weight, fever, pregnancy, cerebrovascular disease, seizure disorder, hepatic or renal diseases, history of substance abuse, current prescription of opioid or benzodiazepine use. On receiving patients in the operating room and before connection of monitoring, the anxiety level was evaluated by VAS ranging from 0 to 100 mm. Use of the VAS was explained to each participant during the preoperative evaluation.
In all patients, a standard bispectral index (BIS) monitor (BIS version 3.2, Aspect Medical Systems Inc., Newton, MA, USA) was placed on the forehead before induction of anaesthesia. After preoxygenation, an anaesthesiologist, who was blinded to the premedication, injected propofol 10 mg (1 mL) over 5 s every 15 s until the BIS score fell to 45. The total dose of propofol required was recorded. Response to verbal commands and eyelash reflex was evaluated and correlated to the BIS score and propofol dosage. All the previous measurements, namely verbal commands, eyelash reflexes and correlation to BIS reading, were evaluated before giving any opioids or muscle relaxants. Following attainment of a BIS score of 45, tracheal intubation was accomplished after administration of a narcotic and muscle relaxant as judged by the attending anaesthesiologist. Patients were deemed to meet the criteria for recovery room discharge when two consecutive Aldrete scores  of 9 or 10 were obtained. Time to be fit for recovery room discharge was recorded.
We determined the sample size according to a relevant previous investigation that studied the effect of different premedications on propofol dosages [1,16]. χ2-test was used for categorical data and the Kruskal–Wallis analysis of variance or Friedman test as appropriate for numerical data. Randomization to premedication with melatonin 3 and 5 mg or no premedication was done using a sealed-envelope technique. P < 0.05 was taken as significant.
There was no significant difference between the three groups regarding patient characteristics data (Table 1). The mean induction dose of propofol was significantly higher in Group P (134 ± 25 mg) than in the 3 and 5 mg melatonin groups 114 ± 20 and 115 ± 19, respectively (P < 0.05) (Table 2). The dose of propofol at which the eyelash reflex was lost was significantly higher in Group P than in the melatonin groups (P < 0.05). Although the dose of propofol that resulted in loss of response to verbal commands was more in Group P than in both melatonin groups, the difference was not statistically significant (Table 2). The BIS value at eyelash reflex and loss of response to verbal commands and the recovery room stay were comparable between the three groups (Table 2). Heart rate (HR) and mean arterial pressure (MAP) before induction of anaesthesia and after achieving a BIS score of 45 were comparable between all groups (Table 3).
A number of behavioural studies have shown that melatonin exerts an antinociceptive action against thermal, chemical and electrical stimuli in rodents [17,18]. Naguib and colleagues studied the electroencephalographic and pharmacologic effects of intravenous (i.v.) anaesthetic doses of melatonin in comparison with thiopental and propofol in animals. They concluded that melatonin exhibits antinociceptive and hypnotic effects and produces effects on processed electroencephalographic variables similar to those of thiopental and propofol [8,9].
The BIS monitor is a proprietary algorithm that translates electroencephalographic data into a numerical value, 100 (awake) to 0 (isoelectric electroencephalogram). Several studies have reported that BIS is a reliable predictor of the level of sedation, loss of consciousness and recall [19–21]. Glass and colleagues concluded that for a variety of clinically used anaesthetic agents, BIS values less than 50 indicated an adequate depth of anaesthesia . In other studies specifically relating BIS to sevoflurane, values less than 50 also reliably indicated an adequate depth of anaesthesia . Lallemand and colleagues studied BIS changes following etomidate induction of general anaesthesia and orotracheal intubation and concluded that a BIS value of 50 was associated with the absence of purposeful movement during tracheal intubation . Therefore, we determined the BIS value of 45 as reference to adequate hypnosis.
Propofol was administered in an incremental dose fashion in this study. Bolus administration of propofol needs a significantly smaller dose to abolish the eyelash reflex than incremental administration of propofol. The doses needed in this study, therefore, may not represent the dose required in bolus administration used in a usual clinical setting.
Propofol has a lag time to full effect of 90 s, but this may be after more rapid injection of propofol (100–200 mg min−1). By administering propofol more slowly, this time-lag should be shorter due to more efficient titration to effect. An administration rate of 50 mg min−1 has been suggested to be close to the optimal rate in human beings , yet our schedule of about 30 mg min−1 is unified in the three groups.
The purpose of our study was to determine the reduction of the induction dose of propofol to a BIS score of 45 by two different doses of melatonin premedication. To the best of our knowledge, this is the first study that has qualitatively measured the additive effect of melatonin on i.v. propofol for induction of anaesthesia in human beings as reflected by the BIS monitor. We found that melatonin premedication in an oral dose of either 3 or 5 mg reduced the required dose of propofol to achieve a BIS score of 45.
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