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Anesth Analg 2006;103:1448-1452
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000244534.24216.3a

ANESTHETIC PHARMACOLOGY

Section Editor:
James G. Bovill

The Effects of Melatonin Premedication on Propofol and Thiopental Induction Dose–Response Curves: A Prospective, Randomized, Double-Blind Study

Mohamed Naguib, MB, BCh, MSc, FFARCSI, MD*, Abdulhamid H. Samarkandi, MB, BS, KSUF, FFARCSI{dagger}, Mohamed A. Moniem, MD{dagger}, Emad El-Din Mansour, MD{dagger}, Ahmad A. Alshaer, MD{dagger}, Hasan A. Al-Ayyaf, MB, BCh{dagger}, Awatif Fadin, MB, BCh{dagger}, and Saleh W. Alharby, MB, BS, FRCS (Glas){ddagger}

From the *Department of Anesthesiology and Pain Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and Departments of {dagger}Anesthesia and {ddagger}Surgery, King Saud University, Riyadh, Saudi Arabia.

Address correspondence and reprint requests to Mohamed Naguib, MB, BCh, MSc, FFARCSI, MD, Department of Anesthesiology and Pain Medicine, University of Texas M.D. Anderson Cancer Center, Unit 409, 1400 Holcombe Boulevard, Houston, TX 77030. Address e-mail to naguib{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The effect of melatonin on the intraoperative requirements for IV anesthetics has not been documented. We studied the effect of melatonin premedication on the propofol and thiopental dose–response curves for abolition of responses to verbal commands and eyelash stimulation.

METHODS: This prospective, randomized, double-blind study included 200 adults with ASA physical status I. Patients received either 0.2 mg/kg melatonin or a placebo orally for premedication (n = 100 per group). Approximately 50 min later, subgroups of 10 melatonin and 10 placebo patients were administered various doses of propofol (0.5, 1.0, 1.5, 2.0, or 2.4 mg/kg) or thiopental (2.0, 3.0, 4.0, 5.0, or 6.0 mg/kg) for anesthetic induction. The ability of each patient to respond to the command, "open your eyes," and the disappearance of the eyelash reflex were assessed 60 s after the end of the injection of propofol or thiopental. Dose–response curves were determined by probit analysis.

RESULTS: Melatonin premedication decreased thiopental ED50 values for loss of response to verbal command and eyelash reflex from 3.4 mg/kg (95%confidence interval, 3.2–3.5 mg/kg) and 3.7 mg/kg (3.5–3.9 mg/kg) to 2.7 mg/kg (2.6–2.9 mg/kg) and 2.6 mg/kg (2.5–2.7 mg/kg), respectively (P < 0.05). Corresponding propofol ED50 values decreased from 1.5 mg/kg (1.4–1.6 mg/kg) and 1.6 mg/kg (1.5–1.7 mg/kg) to 0.9 mg/kg (0.8–0.96 mg/kg) and 0.9 mg/kg (0.8–0.95 mg/kg), respectively (P < 0.05).

CONCLUSIONS: Melatonin premedication significantly decreased the doses of both propofol and thiopental required to induce anesthesia.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The pineal hormone melatonin (N-acetyl-5-methoxytryptamine) regulates a variety of physiological processes, including circadian, cardiovascular, reproductive, and neuroendocrine functions, and enhances immune responses (1–3). However, it is the hypnotic effects of melatonin that are considered an integral component of its physiological role (4,5). Administration of melatonin facilitates sleep onset and improves the quality of sleep (6–8).

Premedicants decrease the intraoperative requirements for IV anesthetics (9–11). Although we previously demonstrated that melatonin is an effective premedicant in both adult and pediatric surgical patients (12–14), the effect of melatonin on the requirements of IV anesthetics to induce anesthesia has not been documented. To that end, we designed and performed a prospective, randomized, double-blind study to evaluate the effect of melatonin premedication on the dose–response curves of propofol and thiopental calculated for the two commonly used end-points: abolition of response to verbal commands and loss of eyelash reflex.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After obtaining IRB approval from King Khalid University Hospital (Riyadh, Saudi Arabia) and written informed patient consent, we enrolled 200 adult patients of both sexes who met the criteria for ASA physical status I. Patients who had taken benzodiazepines, opioid drugs, or other sedative drugs within 1 mo of the planned date of surgery were excluded.

Patients were randomly assigned to four groups (n = 50 patients per group) (according to a computer-generated list) based on whether they would receive 0.2 mg/kg melatonin premedication or placebo (saline) and the type of induction drug used (propofol or thiopental). The randomization list was maintained by the pharmacy. Before surgery, patients were transported to an isolated, quiet room in the operating suite. A pulse oximeter probe was placed on each patient, and blood oxygen saturation, arterial blood pressure, and heart rate were recorded continuously. The melatonin (Sigma Chemical, St Louis, MO) and placebo (saline) solutions were prepared by a pharmacist to a fixed volume of 3 mL in a syringe from which the needle had been removed and marked only with a coded label to maintain the double-blind nature of the study.

The contents of the syringe were given sublingually approximately 50 min before the induction of general anesthesia by a resident not involved in the management of the patient or in data collection. The patient was first asked to touch the tip of the tongue to the back of the upper teeth. The drug was then placed under the tongue, and the patient was asked to close his or her mouth without swallowing. After 180 s, the patient was permitted to swallow the medication.

A visual analog scale (VAS) was used to evaluate the patients’ anxiety. The scale was a 50-cm long and 10-cm high card that was divided diagonally into a white triangle and a bright red triangle. A centimeter scale was marked on the back of the card (15,16). The white end was marked "no anxiety," and the red end was marked "anxiety as bad as ever can be." One investigator blinded to group assignment performed all test scoring in the perioperative period. The same investigator evaluated anxiety VAS score, orientation score (0 = none; 1 = orientation in either time or place; 2 = orientation in both), and sedation score (1 = awake; 2 = drowsy; 3 = asleep, but arousable; 4 = asleep and not arousable) before the administration of premedication and approximately 50 min later (on arrival of the patient in the operating room).

In the operating room, the following predetermined doses of drugs were administered to subgroups of 10 patients each: propofol at 0.5, 1.0, 1.5, 2.0, or 2.4 mg/kg; or thiopental at 2.0, 3.0, 4.0, 5.0, or 6.0 mg/kg. The attending anesthesiologist was unaware of the premedication or induction medication used. Because propofol in aqueous emulsion is a milky substance that can be easily distinguished from thiopental, all syringes were taped to prevent the observer from seeing their contents. Standard intraoperative monitoring was used.

All drugs were injected over 15 s into a rapidly flowing IV infusion. The disappearance of the patients’ ability to respond to the command, "open your eyes," and the disappearance of the eyelash reflex were assessed by one investigator blinded to premedication and induction medication used 60 s after the end of the injection of propofol or thiopental. These outcomes were used as end points for induction of anesthesia. Thereafter, additional doses of propofol or thiopental were administered to ensure an adequate depth of anesthesia, and anesthesia was maintained with oxygen–nitrous oxide–isoflurane and fentanyl titrated to maintain a bispectral index value in the range of 40. The times from premedication to induction of anesthesia (start of injection of propofol or thiopental) and the duration of anesthesia were noted. Recovery times to a score of 8 on the modified Aldrete scale (17) were noted.

Demographic data were analyzed with analysis of variance, {chi}2 test, or Mann–Whitney test as appropriate. If analyses of variance results were significant, the Duncan post hoc test was used to compare the study groups. Statistical analyses were performed using the BMDP statistical software package (release 7.01; University of CA Press, Berkeley, CA) and StatXact for Windows (version 6.2.0; CYTEL Software Corporation, Cambridge, MA). The doses of propofol or thiopental that were required to abolish verbal response and eyelash reflex in 50% (ED50) and 90% (ED90) of patients at 60 s were determined by fitting to a probit model the number of patients unable to respond to the command at each dose using Winnonlin version 5.0.1 software (Pharsight Corporation, Mountain View, CA). Regression lines were compared using analysis of covariance. Unless otherwise specified, the results are expressed as mean ± sd and were considered significant when P < 0.05.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
This study included 200 patients aged 18–50 yr (mean ± sd, 33.2 ± 9.2 yr) and weighing 51–95 kg (73.9 ± 10.9 kg). Patients in the four treatment groups were comparable with respect to age, sex distribution, weight, height, premedication-induction time, duration of anesthesia, and time to modified Aldrete scale score of 8 (Table 1).


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  		Table 1. Patient and Anesthesia Characteristics

 

There were no differences between the melatonin and placebo groups in baseline anxiety VAS scores (median 29 [range 10–48] vs 30, [5–47] respectively), sedation scores (1 [1–1] for both groups), or orientation scores (2 [2–2] for both groups). On arrival in the operating room, patients who received melatonin premedication were more sedated (sedation score, 2 [1–3]) and less anxious (VAS, 10 [6–27]) than those who received placebo (1 [1–2] and 27, [3–46] respectively; P < 0.0001 for both comparisons). There was no difference in orientation scores between the two groups, although eight patients (8%) in the melatonin group were not orientated in either time or place.

The calculated ED50 and ED90 doses are shown in Table 2. Melatonin premedication significantly enhanced the effects of both propofol and thiopental, resulting in significantly lower ED50 and ED90 values. In addition, melatonin premedication shifted all dose– response curves to the left (Figs. 1 and 2), and the slopes of the dose–response curves of propofol and thiopental differed significantly between the placebo and melatonin groups (Table 2).


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  		Table 2. ED50 and ED90 Values and 95% Confidence Limits for Propofol and Thiopental

 

Figure 124
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  		Figure 1. Propofol quantal dose– response curves for abolition of response to verbal command (A) and eyelash stimulation (B), with and without melatonin premedication. Each point represents a group of 10 patients. Horizontal lines at ED50 and ED90 indicate 95% confidence limits.

 


Figure 224
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  		Figure 2. Thiopental quantal dose– response curves for abolition of response to verbal command (A) and eyelash stimulation (B), with and without melatonin premedication. Each point represents a group of 10 patients. Horizontal lines at ED50 and ED90 indicate 95% confidence limits.

 

   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study confirm our earlier findings that melatonin is an effective premedicant (12–14). Here, oral premedication with 0.2 mg/kg melatonin approximately 50 min before induction of anesthesia significantly reduced preoperative anxiety and increased sedation without impairing orientation, and significantly decreased the dose requirements for propofol and thiopental at end points commonly used for induction of anesthesia. At the ED50 values reflecting loss of responses to verbal command and eyelash reflex, the relative potency of propofol after melatonin premedication was 1.7–1.8 times greater than that of propofol after the administration of placebo. Similarly, the relative potency of thiopental was 1.3–1.4 times greater after premedication with melatonin than that of thiopental after placebo. The ED50 values of thiopental alone and propofol alone for loss of response to verbal command in this study were comparable to the previously reported values of 2–3 mg/kg for thiopental (18–21) and 1.1–1.34 mg/kg for propofol (9,19,21–23).

Premedication with IV midazolam has been shown to enhance the effects of thiopental and propofol (9,11,23–25). For example, in one study, premedication with 0.02 mg/kg midazolam decreased the ED50 for thiopental from 2.4 to 1.6 mg/kg. (24) This enhancement has been attributed to the effect of the interaction between midazolam and thiopental or propofol on {gamma}-aminobutyric acid type A (GABAA) receptors. There is also evidence that the propofol–midazolam interaction depends on the concentration of GABA at the receptor (26). GABAA receptors are inhibitory ligand-gated pentameric chloride ion channels in the central nervous system. Propofol, thiopental, and midazolam enhance the effect of GABA-evoked chloride currents at the GABAA receptors (27–29). Midazolam binds to a benzodiazepine recognition site on the receptor, altering the functional response of the receptor.

In accordance with our results, orally administered melatonin in rats has been shown to enhance the anesthetic effects of thiopental and ketamine (30). In mammals, melatonin activates two G-protein-coupled melatonin membrane receptors, MT1 and MT2 (31,32). There is evidence that the hypnotic activity of melatonin is also linked to the GABAA receptor (33,34). Several studies have shown that melatonin increases in vivo GABA accumulation in the rat brain (35), binds to GABAA receptors (36), enhances GABAA receptor-mediated current (37), and enhances [3H]GABA binding to GABAA receptors (38).

In humans, normal melatonin production is about 28.8 µg/day (39), and its half-life is relatively short (approximately 20 min) (40). Oral administration of 80 mg melatonin results in peak serum melatonin concentrations 350–10,000 times more than those occurring physiologically at nighttime within 60–150 min after ingestion with an elimination half-life of 48 min (41). Oral administration of smaller doses of 1–5 mg of melatonin result in lower serum melatonin concentrations, but still 10–100 times more than that observed at nighttime (42).

The present study demonstrated that melatonin premedication significantly reduces the doses of both propofol and thiopental required for loss of responses to verbal commands and eyelash stimulation.


   Footnotes
 
Accepted for publication August 17, 2006.

Supported by institutional and/or departmental sources.

The results of this study were presented at the ASA Annual Meeting, Chicago, Illinois, October 14–18, 2006.


   REFERENCES
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 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press