British Journal of Anaesthesia 82 (6): 87580 (1999)

Premedication with melatonin: a double-blind, placebo-controlled

comparison with midazolam
M. Naguib* and A. H. Samarkandi
Department of Anaesthesiology, King Saud University, College of Medicine at King Khalid University
Hospital, PO Box 7805, Riyadh 11472, Saudi Arabia
*Corresponding author
We have evaluated the perioperative effects of melatonin with those of midazolam in 75
women in a prospective, randomized, double-blind, placebo-controlled study. Patients were
given sublingual midazolam 15 mg, melatonin 5 mg or placebo, approximately 100 min before
a standard anaesthetic. Sedation, anxiety and orientation were quantified before, and 10, 30,
60 and 90 min after premedication, and 15, 30, 60 and 90 min after admission to the recovery
room. Psychomotor performance was evaluated at these times also, using the digitsymbol
substitution test (DSST) and the Trieger dot test (TDT). Patients who received premedication
with either midazolam or melatonin had a significant decrease in anxiety levels and increase in
levels of sedation before operation compared with controls. Midazolam produced the highest
scores for sedation at 30 and 60 min after administration and significant psychomotor
impairment in the preoperative period compared with melatonin or placebo. After operation,
patients who received midazolam or melatonin premedication had increased levels of sedation
at 30 min and impairment in performance on the DSST at 15, 30 and 90 min compared with
controls. There were no significant differences between the three groups for anxiety levels or
TDT performance after operation. Amnesia was notable only in the midazolam group for one
preoperative event (entry into the operating room). Patient satisfaction was noted in the
midazolam and melatonin groups only. We have demonstrated that melatonin can be used
effectively for premedication of adult patients.
Br J Anaesth 1999; 82: 87580
Keywords: premedication, midazolam; premedication, melatonin; memory; psychological
responses, postoperative
Accepted for publication: November 23, 1998

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

Oral melatonin 5 mg daily has been used to alleviate jet

lag and tiredness after long flights11 and for treatment of
sleep disorders in blind subjects12 13 and in patients with
delayed phase sleep syndrome.12 13 Therefore, we selected
a 5-mg dose of melatonin for this study.
To our knowledge, the use of melatonin in anaesthesia
has never been evaluated previously. This prospective,
randomized, double-blind, placebo-controlled study was
designed to compare the effect of sublingual melatonin
with that of sublingual midazolam as premedication. The
sedative, anxiolytic and amnesic effects of both drugs in
addition to the residual effects in the immediate postoperative period were evaluated.

Patients and methods

After obtaining institutional approval and informed
consent, we studied 75 ASA I women, aged 1944 (mean
29.7) yr, weighing 4187 (mean 67.2 (SD 11)) kg, under-

British Journal of Anaesthesia

Naguib and Samarkandi

going gynaecological laparoscopic procedures. No patient

was pregnant or lactating, abusing centrally acting drugs,
consuming monoamine oxidase inhibitors or allergic to the
drugs under study. The day before surgery, a psychologist
explained to the patient the study plan and the different
scales used in the assessment.
Approximately 2 h before surgery, patients were transported to an isolated quiet room in the operating suite. A
pulse oximeter probe was placed on all patients and SpO2,
arterial pressure and heart rate were recorded continuously.
Resuscitative equipment was available at the bedside.
Patients were allocated randomly to one of three groups
(n525 in each). The midazolam group received sublingual
midazolam 15 mg using a 0.5% ampoule solution originally
intended for i.v. use (Dormicum, Roche). The melatonin
group received sublingual melatonin 5 mg (colloidal melatonin, Innovative Natural Products, Escondido, CA 92025,
USA). The control group received sublingual placebo
(saline). Study drugs and placebo were prepared in 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 content
of the syringe was given sublingually approximately 100 min
before induction of general anaesthesia by a resident not
involved in the management of the patient or in data
collection. The patient was first asked to place the tip of
the tongue to the back of the upper teeth. The drug was
then placed under the tongue, the patient was asked to close
their mouth, and was instructed Dont swallow!; at 180 s,
the patient was permitted to swallow the medication. We
did not add any flavour to midazolam as it has been reported
that addition of candy flavour did not improve acceptance of
or compliance with sublingual midazolam administration.14
A visual analogue scale (VAS) was used to evaluate
anxiety. The scale is a 50-cm long and 10-cm high card,
divided diagonally into white and bright red triangles. The
centimetre scale was on the rear side of the card.15 16 The
extremes were marked no anxiety at the white end and
anxiety as bad as ever can be at the red end. The same
psychologist blinded to group assignment performed all test
scoring and calculations. The psychologist evaluated anxiety
VAS, orientation score (05none; 15orientation in either
time or place; 25orientation in both) and sedation score
(15awake; 25drowsy; 35asleep, but arousable; 45asleep,
but not arousable) before, and 10, 30, 60 and 90 min after
administration of premedication, and after operation at 15,
30, 60 and 90 min after admission to the recovery room.
In addition, patients were asked to perform the digitsymbol
substitution test (DSST)17 18 and Trieger dot test (TDT)19
at these times. The DSST forms part of the performance
scale of the Wechsler adult intelligence test. These tests
were used to quantitatively assess psychomotor activity.
All patients were positioned with 30 head elevation and
used the same writing implement (ballpoint pen, medium
point, black) for all tests. The DSST score represented the
number of correct symbol substitutions made in 60 s and

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

Melatonin for premedication

Fig 1 Mean change in anxiety VAS (mean (SD)) relative to baseline

(B) before and after operation (see text for explanation of anxiety VAS).
*P,0.05 compared with the two other groups. RR5Recovery room.
Table 1 Patient data (mean (SD or range)) for the three groups. No significant
differences

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)

Wallis test for multiple comparisons and chi-square test.

For multiple comparisons in the former test, the null
hypothesis was rejected if ZSTAT was larger than the
critical value ZC, where
1PHI(ZC)5ALPHA/(K(K1))
where PHI5cumulative standard normal distribution
function, ALPHA5desired overall significance level and
K5number of groups compared. All analyses were carried
out using the BMDP statistical package (release 7.01,
University of California Press, Berkeley, CA, USA 1994)
on a Compaq computer (Pentium II processor) operated by
Microsoft Windows 98. Unless otherwise specified, results
are expressed as mean (SD), and were considered significant
when P,0.05.

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-

operative anxiety VAS. However, there were no differences

in anxiety VAS between the groups after operation. At
30 min after premedication, sedation was evident only in
the midazolam group (Table 2). Patients who received
midazolam and melatonin showed increased levels of
sedation at 60 and 90 min (P,0.001) after premedication
compared with the placebo group (Table 2). Furthermore,
patients in the midazolam group showed significantly
(P,0.05) higher levels of sedation compared with the
melatonin group at 30 and 60 min after premedication
(KruskalWallis test). After operation, there was no difference in the level of sedation between groups except at
30 min where patients in the midazolam and melatonin
groups showed an increased level of sedation (P50.016)
compared with the placebo group (Table 2).
The mean dose of fentanyl administered in the intraoperative period was similar between groups (105 (41), 106
(39) and 105 (30) g for the midazolam, melatonin and
placebo groups, respectively). Neither postoperative pain
scores nor morphine consumption were different between
the groups at any time during their stay in the recovery
room. The number of patients requiring one or more
injections of morphine in the recovery room was eight,
seven and five in the midazolam, melatonin and placebo
groups, respectively. Cumulative morphine consumption
during recovery room stay was 53, 46.5 and 42 mg for the
midazolam, melatonin and placebo groups, respectively.
Orientation scores were similar, except at 30 min after
premedication. At that time, only 18 (72%) patients in the
midazolam group were orientated in both time and place
compared with 24 (96%) and 22 (88%) patients in the
melatonin and placebo groups, respectively (P50.012).
There were no differences between the midazolam, melatonin and placebo groups in baseline NDSST score (10 (3),
9 (2) and 9 (2), respectively), TDT score for missed dots
(12 (7), 14 (7) and 11 (8), respectively), TDT deviation
(4 (3), 4 (3) and 5 (5) mm, respectively) or TDT time
(13 (6), 14 (6) and 13 (4) s, respectively). Ten minutes after
administration of premedication, patients in the midazolam
group had significantly poorer performance on both tests
compared with the melatonin and placebo groups (Figs 2,
3). There was no difference in the time needed to perform
the TDT test between groups. In the recovery room, the
placebo group performed the DSST significantly better at
15, 30 and 90 min than the other two groups (Fig. 2).
However, there was no difference in TDT score, deviation
or time between the three groups in the recovery room.
Patients who were deeply sedated (asleep, but not arousable;
Table 2) were unable to perform the DSST and TDT and
were not included in the statistical analysis.
In the melatonin group, at 24 h one patient did not recall
the two simple line diagrams and a second patient recalled
only one diagram. All other patients in the three groups
recalled the two diagrams (Fig. 4). Patients who received
midazolam had a higher incidence of amnesia for one
preoperative event only (entry into the operating room)

877

Naguib and Samarkandi

Table 2 Pre- and postoperative sedation in the three groups

30 min after premedication

Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
60 min after premedication
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
90 min after premedication
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
15 min after operation
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
30 min after operation
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
60 min after operation
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable
90 min after operation
Awake
Drowsy
Asleep, but arousable
Asleep, but not arousable

Midazolam (No. (%))

Melatonin (No. (%))

Placebo (No. (%))

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%)

17 patients (68%) (P50.055) were satisfied with their

premedication. All patients in the midazolam and melatonin
groups stated they would prefer to have the same premedication and 14 patients (56%) in the placebo group said they
would prefer another premedicant in future. One patient in
the melatonin group who had midazolam premedication for
a previous surgery several months earlier (and was not
included in the midazolam group in this study) indicated
that she would prefer to have melatonin (rather than
midazolam) premedication in future. No side effects were
noted.

Discussion

Fig 2 Mean changes in normalized digitsymbol substitution test (NDSST)

scores (mean (SD)) relative to baseline (B) before and after operation.
*P,0.05 compared with the two other groups; P,0.05 compared with
placebo. RR5Recovery room.

(Fig. 4). Twenty-three patients (92%) in the midazolam

group and 22 patients (88%) in the melatonin group were
satisfied with their premedication. In the placebo group,

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

Melatonin for premedication

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.

Fig 4 Incidence of amnesia for the diagrams shown before premedication,

for insertion of the i.v. catheter in the operating room and for entry into
the operating room (OR). **P,0.01 compared with the two other groups.

differences between the three groups for anxiety levels or

TDT performance in the postoperative period. Amnesia was
notable only in the midazolam group for one preoperative
event.
Before operation, DSST and TDT scores, and TDT
deviation improved in the melatonin and control groups
10 min after administration of melatonin and saline, respectively. This reflects learning behaviour in these groups. In
contrast, significant impairment in performance on the
DSST and TDT relative to baseline was noted in the
midazolam group. These findings are consistent with other
studies of psychomotor effects produced by midazolam
premedication.20 21 The decreased number of errors on the
DSST and TDT tasks noted after administration of melatonin
is somewhat surprising as one might expect errors to
increase after administration of a substance with sedativelike properties. However, it has been shown that administration of large doses of melatonin (240 mg divided into three
doses) to volunteers did not impair either fine motor
performance or tests of memory and visual sensitivity.22
The onset and peak effect of midazolam-induced sedation
were noted at 30 and 60 min, respectively, after sublingual
administration. Other investigators have reported similar
observations.23 Although seven patients (28%) were asleep
30 min after administration of melatonin, the onset of
significant levels of sedation and the peak effect were
delayed in this group (60 and 90 min, respectively). Furthermore, patients in the midazolam group showed significantly
(P,0.05) higher levels of sedation compared with the
melatonin group at 30 and 60 min after premedication. It
should be noted, however, that despite substantial impairment of performance on the DSST and TDT, and substantial
sedation after midazolam premedication before operation,
there were no significant differences between the midazolam
and melatonin groups after operation. This finding could
not be accounted for by differences in duration of surgery,
duration of anaesthesia or total number of cumulative doses
of morphine administered in the recovery room. Other
investigators noted that premedication with midazolam
was associated with preoperative anxiolysis, sedation and
impairment of psychomotor skills without affecting the
quality of recovery or discharge time after ambulatory
surgery.20 24
Although we did not observe any difference between the
three groups in TDT performance after operation, the
placebo group performed the DSST significantly better at
15, 30 and 90 min compared with the two other groups.
Similarly, others20 25 observed that the DSST was more
sensitive than the TDT for detection of psychomotor/
cognitive impairment. Tsai and colleagues25 noted that
several of their patients (after recovery from isoflurane
anaesthesia) stated that they perceived distortion of the
symbols and numbers of the DSST even after they had
managed to pass the TDT. It appears that the DSST is a
more sensitive test than the TDT for detection of residual

879

Naguib and Samarkandi

cortical depression and can be used as an indicator of the

progress of recovery.
The amnesic properties of the benzodiazepines have been
well studied in adults. Benzodiazepines impair acquisition
of new information with no effect on retention or retrieval
of previously stored information.26 In this study, midazolam
diminished anterograde recall for one preoperative event
compared with the melatonin and placebo groups. Our
results indicate that melatonin had no amnesic effects.

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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