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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.
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{at}unife.it.
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Abstract |
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Introduction |
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METHODS |
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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, 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 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, 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.
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RESULTS |
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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 (1–7) at T-pre in group P and 5 (3–6) and 3 (1–5), 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 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.
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DISCUSSION |
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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 (7–9) 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 (7–9). Despite poor absolute bioavailability of melatonin (22), oral doses of 1–5 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 (7–9). 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.
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Footnotes |
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Supported, in part, by a grant from the Ministero Italiano dell'Università e della Ricerca (MIUR).
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