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Brief Report

Melatonin Does Not Reduce Anxiety More than Placeboin the Elderly Undergoing Surgery 

Maurizia Capuzzo, MD*

Barbara Zanardi, MD*

Elisa Schiffino, MD*

Cosimetta Buccoliero, MD*

Daniela Gragnaniello, MD†

Stefano Bianchi, PhD‡

Raffaele Alvisi, MD*

Melatonin has been reported to reduce preoperative anxiety. We performed thisstudy to compare preoperative anxiety in elderly patients receiving melatonin (M)or placebo (P). Anxiety was measured in patients aged65 yr by a numerical ratingscale (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 levelwas 5 (2–8) before and 3 (1–7) 90 min after premedication in group M and 5 (3–6)and 3 (1–5) in group P, respectively. M and P reduce anxiety in elderly patients toa similar degree.(Anesth Analg 2006;103:121–3)

Patients’ preoperative anxiety influences postopera-tive anxiety (1), pain (2), analgesic requirements (2),length of hospital stay (1), and satisfaction with periop-erative care (3). Among drugs reducing preoperativeanxiety, midazolam is the most commonly used (4), eventhough it is associated with adverse effects in elderlypatients (5–6). It has been suggested that melatonin mayreduce anxiety (7–9). The purpose of this study was tocompare anxiety in elderly patients receiving melatoninor placebo as premedication.

METHODS

The study was prospective, double-blind, and ran-domized. Patients aged  65 yr, ASA physical statusI–III, consecutively undergoing elective surgery wereenrolled. The study was approved by the EthicsCommittee of the hospital and each patient gaveconsent.

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

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

The pharmacist prepared, by computer-generatedrandomization, 150 sealed envelopes, each reporting acode number and containing 2 capsules. Each indis-tinguishable capsule contained either 5 mg melatoninor placebo. Each patient received either melatonin 10mg or placebo.

At the preoperative evaluation, the Mini MentalStatus Examination (10) was administered to the pa-

tients. 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, ASAphysical status, smoking habits, and previous surgicalexperiences. Subsequently, anxiety and depressionwere measured, cognitive tests administered, and thestudy medication given to the patient. Ninety minutesafter study medication administration, before surgery(T-pre), anxiety and depression were assessed. Theanesthesia (general or spinal), previously standard-ized, was arranged by the anesthesiologist responsiblefor the patient. After surgery (T-post), the investigatormeasured anxiety, depression, and pain and adminis-tered cognitive tests. Seven days after hospital dis-charge (T-fup), anxiety, depression, pain, and satisfac-tion with anesthesia (11) were assessed, and cognitivetests were administered.

The level of anxiety was measured using a numeri-cal rating scale ranging from 0 to 10, where 0 means noanxiety 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 rangingfrom 0 to 18. Episodic memory was evaluated with the

From the *Department of Surgical, Anesthetic and RadiologicalSciences. Section of Anesthesiology and Intensive Care, †Depart-ment 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 Italianodell’Universita e della Ricerca (MIUR).

Address correspondence and reprint requests to MauriziaCapuzzo, MD, Dipartimento di Scienze Chirurgiche, Anestesio-logiche e Radiologiche Sezione di Anestesia e RianimazioneAzienda 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   121

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Babcock Story Recall Test, with scores ranging from 0 to16 (15), by immediate and delayed recall (16).

Continuous variables are reported as mean 1   sd,when indicated. Anxiety, depression, pain, and cogni-tive test scores are reported as median and 25th and75th percentiles (quartiles). Statistical analysis wasperformed using the software package SPSS version11.5 (SPSS, Chicago, IL). A value of   P     0.05 wasconsidered statistically significant. In two group com-parisons, Student’s   t-test, Mann-Whitney  U -test, and 2 tests were used. In each group, Wilcoxon’s 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 careunit admission (2 in each group), surgery postponed(3 in each group), or refusal after taking study medi-cation (2 in group M). The analysis was performed in71 patients in group P and 67 in. group M, 52 and 51receiving general anesthesia, respectively.

The patients’ characteristics are reported in Table 1.There was no significant difference between the twogroups. The results of the assessment of anxiety,depression, pain, and cognitive tests at the differenttimes are reported in Table 2. The anxiety level was 5

(2–8) at T-basal and 3 (1–7) at T-pre in group P and 5(3–6) and 3 (1–5), respectively, in group M. Theanalysis performed separately on males and femalesdid not show any difference. In each group, theanxiety levels showed a significant decrease from

 Table 1. General Characteristics of the Patients Studied

Group Placebo (P) Melatonin (M)   P  value(n 71) (n 67)

Male (%) 37 (52) 32 (48) 0.734Age (yr) 72.1 5.4 73.2 5.9 0.255Education: 0–4 yr 25 26

5–7 yr 32 258–12 yr 7 713–17 yr 7 9 0.798

Smoking habits: Previous 31 25Actually 5 6 0.729Sedative use: Occasionally 19 14

Regularly 11 11 0.721Previous surgery 5 4 0.799ASA III 13 19 0.232MMSE (quartiles) 26.9 (26.2–27.9) 26.7 (25.7–27.7) 0.530Length of surgery (min) 131 63 131 76 0.989Type of surgery: Abdominal 16 12

Thoracic 1 3Endocrinologic 10 13Vascular 17 16Skin 27 23 0.699

Values are  n  or mean SD. MMSE Mini Mental Status Examination

 Table 2. Variables Measured in the Study

Group Placebo (P) Melatonin (M)

Time of assessment T-basal T-pre T-post T-fup T-basal T-pre T-post T-fup

Anxiety 5 (2–8) 3 (1–7) 0 (0–2) 4 (2–6) 5 (3–6) 3 (1–5) 0 (0–2) 3 (2–5)Depression 3 (0–7) 2 (0–6) 0 (0–1) 2 (0–5) 3 (0–5) 2 (0–4) 0 (0–2) 2 (0–5)

FABSimilarities 3 (2–3) 3 (2–3) 3 (2–3) 3 (2–3) 3 (2–3) 3 (2–3)Lexical fluency 2 (1–3) 2 (2–3) 2 (2–3) 2 (1–3) 2 (1–2) 2 (2–2)Motor series 3 (2–3) 3 (3–3) 3 (3–3) 3 (3–3) 3 (2–3) 3 (3–3)Conflicting instructions 3 (3–3) 3 (3–3) 3 (3–3) 3 (3–3) 3 (2–3) 3 (3–3)Go - No Go 3 (3–3) 3 (2–3) 3 (3–3) 3 (2–3) 3 (2–3) 3 (2–3)Prehension behavior 3 (3–3) 3 (3–3) 3 (3–3) 3 (3–3) 3 (3–3) 3 (3–3)Total score 16 (14–17) 17 (15–17) 17 (16–17) 16 (14–17) 16 (14–17) 17 (14–17)

BSRTImmediate 5.9 (5.3–7.1) 6.7 (6.1–8.1) 7.1 (6.3–8.3) 6.4 (5.3–7.5) 6.9 (6.1–8.4) 7.4 (6.6–8.6)Delayed 6.0 (5.3–6.8) 6.6 (5.9–8.1) 7.1 (6.3–8.3) 6.3 (5.3–7.5) 6.7 (5.5–8) 7.3 (6.3–8.6)Pain 1 (1–3) 0 (0–3) 2 (0–4)* 0 (0–2)*

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-fupversus T-post;  P  0.005 in placebo and in melatonin group for BSRT both immediate and delayed: T-post versus T-basal 7.

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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) ingroup M.

DISCUSSION

This study shows that melatonin, compared withplacebo, does not reduce anxiety and depression in

elderly patients undergoing surgery. The difference between our results and those reported by others (7–9)could be explained by differences in populations (age,gender, and types of surgery) or methodologies.

First, the mean age of patients in other studies was29.7 (7), 27.9 (8), and 38.7 (9) years, whereas ourpatients were older than 65 years. Exogenous melato-nin has been reported to reduce sleep onset latency(17), but not to improve sleep in subjects aged   65years (18–19). Melatonin has shown anxiolytic effectsin young adults (7–9) and children (20) but not in theelderly (21). Second, other investigators (7,8) studied

only females. Males were approximately half of ourpatients in both groups, and no different effect wasrecorded in males and females.

Concerning methodology, we administered melato-nin 10 mg by mouth, whereas it was given sublin-gually and in different doses by others (7–9). Despitepoor absolute bioavailability of melatonin (22), oraldoses of 1–5 mg result in serum melatonin concentra-tions 10–100 times larger than the nighttime peakwithin one hour after ingestion (23). The level of preoperative anxiety at 90 min was also decreased by33% and 21% in our M and P groups, respectively,

whereas it was surprisingly increased in group P anddecreased in group M in other studies (7–9). There-fore, the reduction in anxiety in our group P appearsto 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 mea-surement of melatonin plasma concentration. Also,sedation was not objectively measured, but we wereinterested in reducing patient anxiety rather than theappearance of anxiety.

In conclusion, we showed that melatonin, in com-parison with placebo, does not significantly reduceanxiety in elderly patients undergoing electivesurgery.

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