Brief Report

Melatonin Does Not Reduce Anxiety More than Placebo

in the Elderly Undergoing Surgery
Maurizia Capuzzo, MD*
Barbara Zanardi, MD*
Elisa Schiffino, MD*
Cosimetta Buccoliero, MD*

Melatonin has been reported to reduce preoperative anxiety. We performed this

study to compare preoperative anxiety in elderly patients receiving melatonin (M)
or placebo (P). Anxiety was measured in patients aged 65 yr by a numerical rating
scale (range, 0 10). Each patient was randomized to receive M 10 mg or P orally:
71 patients were in group P and 67 in group M. The median (quartiles) anxiety level
was 5 (2 8) before and 3 (17) 90 min after premedication in group M and 5 (3 6)
and 3 (15) in group P, respectively. M and P reduce anxiety in elderly patients to
a similar degree.
(Anesth Analg 2006;103:1213)

Daniela Gragnaniello, MD
Stefano Bianchi, PhD
Raffaele Alvisi, MD*

atients preoperative anxiety influences postoperative anxiety (1), pain (2), analgesic requirements (2),
length of hospital stay (1), and satisfaction with perioperative care (3). Among drugs reducing preoperative
anxiety, midazolam is the most commonly used (4), even
though it is associated with adverse effects in elderly
patients (5 6). It has been suggested that melatonin may
reduce anxiety (79). The purpose of this study was to
compare anxiety in elderly patients receiving melatonin
or placebo as premedication.

METHODS
The study was prospective, double-blind, and randomized. Patients aged 65 yr, ASA physical status
IIII, consecutively undergoing elective surgery were
enrolled. The study was approved by the Ethics
Committee of the hospital and each patient gave
consent.
Considering the anxiety scores of van Vlymen et al.
(4), to detect a 30% difference between 2 groups with
0.05 and power 0.80, the required sample size
From the *Department of Surgical, Anesthetic and Radiological
Sciences. Section of Anesthesiology and Intensive Care, Department of Neurosciences, Section of Neurology, and Department of
Pharmacy, University Hospital of Ferrara, Ferrara, Italy.
Accepted for publication March 28, 2006.
Supported, in part, by a grant from the Ministero Italiano
dellUniversita` e della Ricerca (MIUR).
Address correspondence and reprint requests to Maurizia
Capuzzo, MD, Dipartimento di Scienze Chirurgiche, Anestesiologiche e Radiologiche Sezione di Anestesia e Rianimazione
Azienda Ospedaliera S. Anna Corso Giovecca 203, 44100 Ferrara,
Italy. Address e-mail to cpm@unife.it.
Copyright 2006 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000222476.62547.ed

Vol. 103, No. 1, July 2006

for each group would be 66 patients. In our study, 75

patients per group were enrolled.
The pharmacist prepared, by computer-generated
randomization, 150 sealed envelopes, each reporting a
code number and containing 2 capsules. Each indistinguishable capsule contained either 5 mg melatonin
or placebo. Each patient received either melatonin 10
mg or placebo.
At the preoperative evaluation, the Mini Mental
Status Examination (10) was administered to the patients. On the day of surgery, in a quiet room (T-basal),
the study investigator, not involved in patient care,
collected information about years of education, ASA
physical status, smoking habits, and previous surgical
experiences. Subsequently, anxiety and depression
were measured, cognitive tests administered, and the
study medication given to the patient. Ninety minutes
after study medication administration, before surgery
(T-pre), anxiety and depression were assessed. The
anesthesia (general or spinal), previously standardized, was arranged by the anesthesiologist responsible
for the patient. After surgery (T-post), the investigator
measured anxiety, depression, and pain and administered cognitive tests. Seven days after hospital discharge (T-fup), anxiety, depression, pain, and satisfaction with anesthesia (11) were assessed, and cognitive
tests were administered.
The level of anxiety was measured using a numerical rating scale ranging from 0 to 10, where 0 means no
anxiety and 10 means the maximum anxiety possible
(12). The level of depression and pain was measured
by a numerical rating scale (range, 0 10).
Executive brain functions were explored with the
Frontal Assessment Battery (13,14), with scores ranging
from 0 to 18. Episodic memory was evaluated with the
121

Table 1. General Characteristics of the Patients Studied

Group

Placebo (P)
(n 71)

Melatonin (M)
(n 67)

P value

Male (%)
Age (yr)
Education: 04 yr
57 yr
812 yr
1317 yr
Smoking habits: Previous
Actually
Sedative use: Occasionally
Regularly
Previous surgery
ASA III
MMSE (quartiles)
Length of surgery (min)
Type of surgery: Abdominal
Thoracic
Endocrinologic
Vascular
Skin

37 (52)
72.1 5.4
25
32
7
7
31
5
19
11
5
13
26.9 (26.227.9)
131 63
16
1
10
17
27

32 (48)
73.2 5.9
26
25
7
9
25
6
14
11
4
19
26.7 (25.727.7)
131 76
12
3
13
16
23

0.734
0.255

Values are n or mean

SD.

0.798
0.729
0.721
0.799
0.232
0.530
0.989

0.699

MMSE Mini Mental Status Examination

Babcock Story Recall Test, with scores ranging from 0 to

16 (15), by immediate and delayed recall (16).
Continuous variables are reported as mean 1 sd,
when indicated. Anxiety, depression, pain, and cognitive test scores are reported as median and 25th and
75th percentiles (quartiles). Statistical analysis was
performed using the software package SPSS version
11.5 (SPSS, Chicago, IL). A value of P 0.05 was
considered statistically significant. In two group comparisons, Students t-test, Mann-Whitney U-test, and
2 tests were used. In each group, Wilcoxons test was
performed to compare variables at different times.

RESULTS
Of the 150 patients enrolled, 5 in the placebo group
(P) and 7 in the melatonin (M) group did not complete

the study as the result of unplanned intensive care

unit admission (2 in each group), surgery postponed
(3 in each group), or refusal after taking study medication (2 in group M). The analysis was performed in
71 patients in group P and 67 in. group M, 52 and 51
receiving general anesthesia, respectively.
The patients characteristics are reported in Table 1.
There was no significant difference between the two
groups. The results of the assessment of anxiety,
depression, pain, and cognitive tests at the different
times are reported in Table 2. The anxiety level was 5
(2 8) at T-basal and 3 (17) at T-pre in group P and 5
(3 6) and 3 (15), respectively, in group M. The
analysis performed separately on males and females
did not show any difference. In each group, the
anxiety levels showed a significant decrease from

Table 2. Variables Measured in the Study

Group
Time of assessment
Anxiety
Depression
FAB
Similarities
Lexical fluency
Motor series
Conflicting instructions
Go - No Go
Prehension behavior
Total score
BSRT
Immediate
Delayed
Pain

Placebo (P)
T-basal
5 (28)
3 (07)
3 (23)
2 (13)
3 (23)
3 (33)
3 (33)
3 (33)
16 (1417)
5.9 (5.37.1)
6.0 (5.36.8)

T-pre

T-post

3 (17) 0 (02)
2 (06) 0 (01)
3 (23)
2 (23)
3 (33)
3 (33)
3 (23)
3 (33)
17 (1517)

Melatonin (M)
T-fup

T-basal

4 (26)
2 (05)

5 (36)
3 (05)

3 (23)
2 (23)
3 (33)
3 (33)
3 (33)
3 (33)
17 (1617)

3 (23)
2 (13)
3 (33)
3 (33)
3 (23)
3 (33)
16 (1417)

6.7 (6.18.1) 7.1 (6.38.3) 6.4 (5.37.5)

6.6 (5.98.1) 7.1 (6.38.3) 6.3 (5.37.5)
1 (13)
0 (03)

T-pre

T-post

3 (15) 0 (02)
2 (04) 0 (02)
3 (23)
2 (12)
3 (23)
3 (23)
3 (23)
3 (33)
16 (1417)

T-fup
3 (25)
2 (05)
3 (23)
2 (22)
3 (33)
3 (33)
3 (23)
3 (33)
17 (1417)

6.9 (6.18.4) 7.4 (6.68.6)

6.7 (5.58)
7.3 (6.38.6)
2 (04)*
0 (02)*

Data are reported as median (25th and 75th percentiles). T-basal in the ward, before anesthetic premedication; T-pre in the preanesthesia room (before anesthesia and surgery); T-post
in the recovery room (after surgery); T-fup at the follow-up consultation (one week after surgery). BSRT Babcock Story Recall Test; FAB frontal assessment battery
*Placebo versus melatonin at T-post (P 0.019) and at T-fup (P 0.032) P 0.05 in placebo and in melatonin group for anxiety: T-pre versus T-basal; T-post versus T-pre; T-fup versus
T-basal; P 0.05 in placebo and in melatonin group for depression: T-pre versus T-basal; T-post versus T-pre; T-fup vs T-basal; P 0.05 in placebo and in melatonin group for pain: T-fup
versus T-post; P 0.005 in placebo and in melatonin group for BSRT both immediate and delayed: T-post versus T-basal 7.

122

Brief Report

ANESTHESIA & ANALGESIA

T-basal to T-pre, to T-post. The median score of

satisfaction with anesthesia at T-follow-up was 100
(range, 76 100) in group P and 99 (range, 80 100) in
group M.

DISCUSSION
This study shows that melatonin, compared with
placebo, does not reduce anxiety and depression in
elderly patients undergoing surgery. The difference
between our results and those reported by others (79)
could be explained by differences in populations (age,
gender, and types of surgery) or methodologies.
First, the mean age of patients in other studies was
29.7 (7), 27.9 (8), and 38.7 (9) years, whereas our
patients were older than 65 years. Exogenous melatonin has been reported to reduce sleep onset latency
(17), but not to improve sleep in subjects aged 65
years (18 19). Melatonin has shown anxiolytic effects
in young adults (79) and children (20) but not in the
elderly (21). Second, other investigators (7,8) studied
only females. Males were approximately half of our
patients in both groups, and no different effect was
recorded in males and females.
Concerning methodology, we administered melatonin 10 mg by mouth, whereas it was given sublingually and in different doses by others (79). Despite
poor absolute bioavailability of melatonin (22), oral
doses of 15 mg result in serum melatonin concentrations 10 100 times larger than the nighttime peak
within one hour after ingestion (23). The level of
preoperative anxiety at 90 min was also decreased by
33% and 21% in our M and P groups, respectively,
whereas it was surprisingly increased in group P and
decreased in group M in other studies (79). Therefore, the reduction in anxiety in our group P appears
to be the key finding to explain the negative results of
our study; the placebo effect is well known (24).
One of the study limitations was the lack of measurement of melatonin plasma concentration. Also,
sedation was not objectively measured, but we were
interested in reducing patient anxiety rather than the
appearance of anxiety.
In conclusion, we showed that melatonin, in comparison with placebo, does not significantly reduce
anxiety in elderly patients undergoing elective
surgery.
REFERENCES
1. Caumo W, Schmidt AP, Schneider CN, et al. Risk factors for
postoperative anxiety in adults. Anaesthesia 2001;56:7208.

Vol. 103, No. 1, July 2006

2. Thomas V, Heath M, Rose D, Flory P. Psychological characteristics and the effectiveness of patient-controlled analgesia. Br J
Anaesth 1995;74:2716.
3. Jamison RN, Taft K, OHara JP, Ferrante M. Psychosocial and
pharmacologic predictors of satisfaction with intravenous
patient-controlled analgesia. Anesth Analg 1993;77:1215.
4. van Vlymen JM, Sa Rego MM, White PF. Benzodiazepine
premedication. Anesthesiology 1999;90:7407.
5. Weinbrown AA, Szold O, Ogorek D, Flaishon R. The
midazolam-induced paradox phenomenon is reversible by
flumazenil. Epidemiology, patient characteristics and review of
the literature. Eur J Anaesthesiol 2001;18:78997.
6. Fredman B, Lahav M, Zohar E, et al. The effect of midazolam on
mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. Anesth Analg 1999;89:11616.
7. Naguib M, Samarkandi AH. Premedication with melatonin: a
double-blind, placebo-controlled comparison with midazolam.
Br J Anaesth 1999;82:87580.
8. Naguib M, Samarkandi AH. The comparative dose-response
effects of melatonin and midazolam for premedication of adult
patients: a double-blinded, placebo-controlled study. Anesth
Analg 2000;91:4739.
9. Acil M, Basgul E, Celiker V, et al. Perioperative effects of
melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Eur J Anaesthesiol 2004;21:5537.
10. Folstein MF, Folstein SE, McHough PR. Mini Mental State:
practical method for grading the cognitive status of patients for
the clinician. J Psychiatr Res 1975;12:189-98.
11. Capuzzo M, Landi F, Bassani A, et al. Emotional and interpersonal factors are most important for patient satisfaction with
anaesthesia. Acta Anaesthesiol Scand 2005;49:73542.
12. Kindler CH, Harms C, Amsler F, et al. The Visual Analog Scale
allows effective measurement of preoperative anxiety and detection of patients anesthetic concerns. Anesth Analg 2000;90:
70612.
13. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal
assessment battery at bedside. Neurology 2000;55:16216.
14. Iavarone A, Ronga B, Pellegrino L, et al. The Frontal Assessment
Battery (FAB): normative data from an Italian sample and
performances of patients with Alzheimers disease and frontotemporal dementia. Funct Neurol 2004;19:1915.
15. Spinnler H, Tognoni G. Standardizzazione e taratura italiana di
test neuropsicologici. Ital J Neurol Sc 1987;6 (supp l8):12120.
16. Barigazzi R, Della Sala S, Laiacona M, et al. Esplorazione
testistica della memoria di prosa. Ric Psicol 1987;1:5080.
17. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev
2005;9:4150.
18. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve
sleep in older people? A randomised crossover trial. Age Aging
2003;32:16470.
19. Zhdanova IV. Melatonin as a hypnotic: Pro Sleep Med Rev
2005;9:5165.
20. Samarkandi AH, Naguib M, Riad W, et al. Melatonin vs.
midazolam premedication in children: a double-blind, placebocontrolled study. Eur J Anaesthesiol 2005; 22:18996.
21. Cardinali DP, Gvozdenovich E, Kaplan MR, et al. A double
blind-placebo controlled study on melatonin efficacy to reduce
anxiolytic benzodiazepine use in the elderly. Neuro Endocrinol
Lett 2002;23:5560.
22. De Muro RL, Nafziger AN, Blask DE, et al. The absolute
bioavailability of oral melatonin. J Clin Pharmacol 2000;40:
7814.
23. Brzezinski A. Melatonin in humans. N Engl J Med 1997;
336:186195.
24. Thompson GW. Placebos: a review of the placebo response. Am
J Gastroenterol 2000;95:163743.

2006 International Anesthesia Research Society

123