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Premedication With Melatonin: A Double-Blind, Placebo-Controlled Comparison With Midazolam
Premedication With Melatonin: A Double-Blind, Placebo-Controlled Comparison With Midazolam
Premedication With Melatonin: A Double-Blind, Placebo-Controlled Comparison With Midazolam
The pineal hormone melatonin (N-acetyl-5-methoxytryptamine) has several putative functions, including regulation
of circadian rhythms,1 regulation of the reproductive axis2
and antioxidant activity.3 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 humans.4
Exogenous administration of melatonin has been found
by several investigators to facilitate sleep onset and improve
quality of sleep.5 6 Available data suggest that the sleepinducing properties of melatonin may differ from those
of benzodiazepines. Benzodiazepines decrease duration of
REM sleep after single administration of a high dose7 or
long-term administration of a low dose.8 Benzodiazepines
also reduce slow-wave sleep,9 thus negatively influencing
sleep quality. In contrast, a single low dose of melatonin
produced no suppression of REM sleep.10 Furthermore,
unlike benzodiazepines, melatonin does not induce hangover effects.10
the score was normalized according to a table (the normalized DSST or NDSST score). The TDT score represented
the total number of missed dots (out of 42) connected. TDT
deviation represented the cumulative shortest distance (in
mm) between the drawn line and missed dots. The time to
perform the TDT was measured in seconds using a
stopwatch. To account for inter-patient differences in testtaking ability, anxiety VAS, NDSST and TDT scores, TDT
deviations and time to perform TDT test were normalized
to baseline scores, deviation and time for each patient.
Changes in scores of different tests and TDT deviation and
TDT time relative to baseline values were compared.
Amnesia was assessed by showing patients two simple
line diagrams before premedication. Patients were queried
24 h later as to recall of the diagrams, entry into the operating
room and i.v. catheter insertion in the operating room.
In the operating room, an infusion of lactated Ringers
solution was commenced. Anaesthesia was induced with
fentanyl 1 g kg1, propofol 2 mg kg1 and mivacurium
0.2 mg kg1. After tracheal intubation, anaesthesia was
maintained with isoflurane and 70% nitrous oxide in oxygen,
supplemented with fentanyl. End-tidal concentrations of
oxygen, nitrous oxide and carbon dioxide were measured
continuously by a multiple-gas analyser (Capnomac, Datex
Instrumentarium Corporation, Helsinki, Finland). Ventilation was adjusted to maintain normocapnia (end-tidal carbon
dioxide partial pressure 4.75.3 kPa). Haemoglobin oxygen
saturation was monitored by pulse oximetry. Temperature
was monitored by a nasopharyngeal thermistor and was
maintained at 36.560.5C. Neuromuscular function was
monitored by a peripheral nerve stimulator. Surgery time
(incision to surgery end) and anaesthesia time (induction to
emergence) were recorded. In the recovery room, postoperative pain was quantitated using a 100-mm VAS, and was
assessed at 15, 30, 60 and 90 min after arrival in the recovery
room. Postoperative pain was treated with incremental doses
of morphine i.v. and the total dose administered was
noted. Postoperative nausea and vomiting were treated with
ondansetron 4 mg i.v. On the second day, patients were
questioned about their premedication: Was the premedication satisfactory or not and If needed would they prefer
the same or another premedication in future.
Statistical analysis
With a sample size in each of the three groups of 21, a
0.05 level chi-square test has 90% power to detect a
difference in proportions characterized by a variance of
proportions (V5(I0)2/G) of 0.047 and an average
proportion of 0.347. This was based on the assumption that
placebo would have an effect in 4% of patients whereas
both midazolam and melatonin would have an effect in at
least 50% of patients. However, if the assumption was made
that the study drugs would have an effect in a greater
proportion of patients (.50%), the sample size would have
been smaller.
Statistical analysis was performed using the Kruskal
876
n
Age (yr)
Weight (kg)
Height (cm)
Surgery time (min)
Anaesthesia time (min)
Midazolam
Melatonin
Placebo
25
29.5
67.7
158.4
46.7
64.4
25
29.6
65.3
155.2
45.7
63.7
25
30.1
68.5
154.4
43.5
60.6
(1944)
(9.5)
(7.2)
(25.6)
(26.8)
(2243)
(12.4)
(7.7)
(23.2)
(25.5)
(2240)
(11.6)
(8.3)
(19.6)
(22)
Results
Patients in the three groups were comparable in age, weight,
height, surgery time and anaesthesia time (Table 1). Figure 1
shows a significantly (P,0.05) greater effect of both
midazolam and melatonin compared with placebo for pre-
877
5
6
10
4
(20%)
(24%)
(40%)
(16%)
18 (72%)
0
7 (28%)
0
22 (88%)
0
3 (12%)
0
2
6
15
2
(8%)
(24%)
(60%)
(8%)
13 (52%)
1 (4%)
11 (44%)
0
23 (92%)
0
2 (8%)
0
9
2
12
2
(36%)
(8%)
(48%)
(8%)
12 (48%)
0
13 (52%)
0
24 (96%)
0
1 (4%)
0
9 (36%)
11 (44%)
3 (12%)
2 (8%)
14
8
1
1
17
6
1
1
13 (52%)
2 (8%)
10 (40%)
0
14 (56%)
0
10 (40%)
1 (4%)
20 (80%)
4 (16%)
1 (4%)
0
16 (64%)
4 (16%)
5 (20%)
0
17 (68%)
0
7 (28%)
1 (4%)
19 (76%)
2 (8%)
4 (16%)
0
20 (80%)
2 (8%)
3 (12%)
0
18
1
5
1
23 (92%)
2 (8%)
0
0
P
,0.0001
,0.0001
0.0002
0.42
(56%)
(32%)
(4%)
(4%)
(68%)
(24%)
(4%)
(4%)
0.016
0.30
0.25
(72%)
(4%)
(20%)
(4%)
Discussion
We have demonstrated that patients who received premedication with either sublingual midazolam 15 mg or sublingual
melatonin 5 mg had a significant decrease in anxiety levels
and increase in levels of sedation before operation compared
with patients who received placebo. However, in the preoperative period, only patients in the midazolam group experienced significant impairment of psychomotor skills. After
operation, patients who received midazolam or melatonin
premedication had increased levels of sedation at 30 min and
impairment of performance on the DSST at 15, 30 and 90 min
compared with controls. However, there were no significant
878
Fig 3 Mean changes in Trieger dot test (TDT) scores for missed dots,
deviation and time to perform the test (mean (SD)) relative to baseline (B).
*P,0.05 compared with the two other groups; P,0.05 compared with
placebo; P,0.05 compared with the melatonin group. RR5Recovery
room.
879
10
11
12
13
14
Acknowledgements
We thank Fatma Khalid Al-Rifai, BSc, MCP, Department of Psychiatry,
King Khalid University Hospital for invaluable contribution to this
study. We also thank our colleagues in the Obstetrics and Gynaecology
Department and nursing staff at the recovery room for their co-operation.
This study was supported by grant number 97378 from the College of
Medicine Research Centre, King Saud University.
15
16
17
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