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[Anesthetic Pharmacology: Research Report] <Previous Article Table of Contents Next Article >

Anesthesia & Analgesia

Issue: Volume 103(6), December 2006, pp 1448-1452Copyright: © 2006 International Anesthesia Research Society

Publication Type: [Anesthetic Pharmacology: Research Report]

DOI: 10.1213/01.ane.0000244534.24216.3a

ISSN: 0003-2999

Accession: 00000539-200612000-00024

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The E ects of Melatonin Premedication on Propofol and Thiopental

Induction Dose–Response Curves: A Prospective, Randomized,

Double-Blind StudyNaguib, Mohamed MB, BCh, MSc, FFARCSI, MD*; Samarkandi, Abdulhamid H. MB, BS, KSUF, FFARCSI†; Moniem,

Mohamed A. MD†; Mansour, Emad El-Din MD†; Alshaer, Ahmad A. MD†; Al-Ayyaf, Hasan A. MB, BCh†; Fadin, Awatif MB,

BCh†; Alharby, Saleh W. MB, BS, FRCS (Glas)‡

Section Editor(s): Bovill, James G.

Author InformationFrom the *Department of Anesthesiology and Pain Medicine, The University of Texas M. D. Anderson Cancer

Center, Houston, Texas; and Departments of †Anesthesia and ‡Surgery, King Saud University, Riyadh, Saudi

Arabia.

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.

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

[email protected]

.

Abstract

BACKGROUND: The e ect of melatonin on the intraoperative requirements for IV anesthetics has not been

documented. We studied the e ect 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 reex 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 reex from 3.4 mg/kg (95%condence 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 signicantly decreased the doses of both propofol and thiopental

required to induce anesthesia.

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 e ects 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).

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OutlineAbstract

METHODS

RESULTS

DISCUSSION

REFERENCES

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Premedicants decrease the intraoperative requirements for IV anesthetics (9–11). Although we previously

demonstrated that melatonin is an e ective premedicant in both adult and pediatric surgical patients (12–14),

the e ect 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 e ect

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 reex.

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METHODS

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 xed 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

rst 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. Theattending 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 owing IV infusion. The disappearance of the patients’ ability to

respond to the command, “open your eyes,” and the disappearance of the eyelash reex 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–isourane 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

modied 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 signicant, 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 reex in 50% (ED50)

and 90% (ED90) of patients at 60 s were determined by tting 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 speci ed,

the results are expressed as mean ±sd and were considered signicant when P <0.05.

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RESULTS

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 modied Aldrete scale score of 8 ( Table 1).

Table 1


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There were no di erences 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 di erence 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 signicantly enhanced the e ects of both

propofol and thiopental, resulting in signicantly lower ED50 andED90 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 di ered

signicantly between the placebo and melatonin groups ( Table 2).

Table 2

Figure 1 Figure 2

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DISCUSSION

The results of the present study conrm our earlier ndings that melatonin is an e ective premedicant (12–14).

Here, oral premedication with 0.2 mg/kg melatonin approximately 50 min before induction of anesthesia

signicantly reduced preoperative anxiety and increased sedation without impairing orientation, and

signicantly decreased the dose requirements for propofol and thiopental at end points commonly used for

induction of anesthesia. At the ED50 values reecting loss of responses to verbal command and eyelash reex,

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 e ects of thiopental and propofol

(9,11,23–25). For example, in one study, premedication with 0.02 mg/kg midazolam decreased the ED 50 for

thiopental from 2.4 to 1.6 mg/kg. (24) This enhancement has been attributed to the e ect 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 e ect 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 theanesthetic e ects 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 signicantly reduces the doses of both propofol

and thiopental required for loss of responses to verbal commands and eyelash stimulation.

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Table 1

Table 2

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