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Anesth Analg 2007; 105:1263-1271
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000282834.78456.90
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ANESTHETIC PHARMACOLOGY

The Clinical Impact of Preoperative Melatonin on Postoperative Outcomes in Patients Undergoing Abdominal Hysterectomy

Wolnei Caumo, MD, PhD*{dagger}, Fernanda Torres, MSc{ddagger}, Nívio L. Moreira, Jr, MD§, Jorge A. S. Auzani, MD§, Cristiano A. Monteiro, MD§, Gustavo Londero, MD§, Diego F. M. Ribeiro||, and Maria Paz L. Hidalgo, MD, PhD||

From the *Anesthesia Service and Perioperative Medicine at Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS); {dagger}Instituto de Ciências Bsicas da Saúde, Pharmacology Department, UFRGS; {ddagger}Multidisciplinary Group of Development of Biological Rhythms of Universidade de São Paulo; §Registrar of Anesthesia Service and Perioperative Medicine at Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS); ||Psychiatric Service of Hospital Materno Infantil Presidente Vargas, Hospital de Clínicas de Porto Alegre (HCPA); and ¶Hospital de Clínicas de Porto Alegre (HCPA), Psychiatric Department of School of Medicine, UFRGS, Brazil.

Address correspondence and reprint requests to Dr. Maria Paz Loayza Hidalgo, Castro Alves 167 sala 204, CEP 90430-131 – Porto Alegre, RS, Brazil. Address e-mail to mpaz{at}cpovo.net.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Melatonin has sedative, analgesic, antiinflammatory, antioxidative, and chronobiotic effects. We determined the impact of oral melatonin premedication on anxiolysis, analgesia, and the potency of the rest/activity circadian rhythm.

METHODS: This randomized, double-blind, placebo-controlled study included 33 patients, ASA physical status I–II, undergoing abdominal hysterectomy. Patients were randomly assigned to receive either oral melatonin 5 mg (n = 17) or placebo (n = 16) the night before and 1 h before surgery. The analysis instruments were the Visual Analog Scale, the State-Trait Anxiety Inventory, and the actigraphy.

RESULTS: The number of patients that needed to be treated to prevent one additional patient reporting high postoperative anxiety and moderate to intense pain in the first 24 postoperative hours was 2.53 (95% CI, 1.41–12.22) and 2.20 (95% CI, 1.26–8.58), respectively. The number-needed-to-treat was 3 (95% CI, 1.35–5.0) to prevent high postoperative anxiety in patients with moderate to intense pain, when compared with 7.5 (95% CI, 1.36–{infty}) in the absence of pain or mild pain. Also, the treated patients required less morphine by patient-controlled analgesia, as assessed by repeated measures ANOVA (F[1,31] = 6.05, P = 0.02). The rest/activity cycle, assessed by actigraphy, showed that the rhythmicity percentual of 24 h was higher in the intervention group in the first week after discharge ([21.16 ± 8.90] versus placebo [14.00 ± 7.10]; [t = –2.41, P = 0.02]).

CONCLUSIONS: This finding suggested that preoperative melatonin produced clinically relevant anxiolytic and analgesic effects, especially in the first 24 postoperative hours. Also, it improved the recovery of the potency of the rest/activity circadian rhythm.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Millions of patients receive sedatives to reduce anxiety before surgery, but the choice of premedication is often determined by habit and tradition, rather than by scientific evidence 1. A study recorded that more than 75% of the anesthesiologists in the United States usually administer sedative premedication to healthy patients admitted for surgery 2. Although the use of preoperative benzodiazepines is the most common practice, the potential clinical benefits of new therapeutic options in this setting remain to be investigated. The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), has several putative functions that may make it an attractive option for premedication, including the regulation of circadian rhythms, and sedative, analgesic, antiinflammatory and antioxidative effects 3.

Melatonin is a methoxyindole synthesized from tryptophan and secreted principally by the pineal gland. It has an endogenous circadian rhythm of secretion induced by the suprachiasmatic nuclei of the hypothalamus that is entrained to the light/dark cycle 4. In mammals, melatonin is present in almost all tissues, with or without the melatonin receptors, because it acts both as a hormone and an antioxidant 5. Considering the time-dependent action of melatonin, it can be better classified as a chronohypnotic 6.

Five milligrams of oral melatonin per day has been used to alleviate jet lag 7 and as a preoperative sedative 8–10. Also, melatonin has been associated with the relief of pain in patients with extensive tissue injuries 3. Considering the potential pharmacological benefits of melatonin, we designed this study to determine the impact of oral melatonin premedication on anxiolysis, analgesia, and the potency of the rest/activity circadian rhythm.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After ethics committee approval and written informed consent, 35 patients, ASA classification I–II, aged 30–55 yr scheduled total abdominal hysterectomy were enrolled into the randomized, double-blind, placebo-controlled study. Patients with contraindications to regional anesthesia, mental impairment, chronic pain, or a history of congestive heart failure, valvular heart disease, renal or hepatic disease, or who had used psychotropic drugs in the present or in the past, or had language or communication difficulties were excluded. Also, patients with a body mass index higher than 25 kg/m2, those with sleep disorders, a history of psychiatric disorder and/or those patients with positive screening for minor psychiatric disorders (scores ≥8) on the World Health Organization's Self-Reporting Questionnaire (SRQ-20) were excluded 11. The SRQ-20 measures somatic symptoms, depressive mood, depressive thoughts, and decreased energy.

Patients were allocated in a double-blind manner, using a random number table, to receive either 5 mg oral melatonin (Sigma Chemical, St. Louis, MO) or placebo the night before (10 pm) and 1 h before surgery. No other preoperative medication was given. Blinding and randomization were performed by two investigators not involved in the patients' evaluations. Other individuals involved in the patient's care were unaware of patient group assignment.

The primary outcomes were postoperative pain, as assessed by pain scores and analgesic consumption. Secondary outcomes were rest-activity cycles and anxiety.

The first evaluation was 1 wk before the hospitalization in the ambulatory Perioperative Medicine and Anesthesia Service area. Patient characteristics were collected using a structured questionnaire, and each patient underwent psychological testing. The six evaluators received 1 mo (60 h) of training with role-playing activities and discussion, focusing on difficulties that might occur during the interviews. They presented the tests in a random order to prevent order effects, and were assisted in 15% of the interviews by the principal investigator. To ensure blinding, postoperative assessment was performed by a different physician from the one who had performed the preoperative evaluation. The staff who provided instructions on patient-controlled analgesia (PCA) use and program changes was unaware of group assignment. The principal investigator attached the actigraph on the dominant wrist and explained its use 12. The second evaluation was the day before the surgery, after admission to the hospital. On the night before surgery, all patients were evaluated by the same anesthesiologist, who provided them with information on the perioperative course and instructed them on how to use the PCA pump. Moreover, each patient underwent anxiety assessment and instruction on the use of the Visual Analog Scale (VAS) pain scoring system.

A 100 mm VAS was used to assess pain, sleepiness, nausea, and vomiting. Scores ranged from 0 (absence of symptom) to 100 (maximum symptom) 13. Furthermore, satisfaction with pain management was assessed by the same method and scores ranged from 0 (very dissatisfied) to 100 (very satisfied). After surgery, the assessment was recorded at the following times: nausea and vomiting was recorded at 24, 48, and 72 h; pain and sleepiness at 6, 12, 18, 24, 36, 48, and 72 h; state anxiety at 6, 24, 36, 48, and 72 h; and satisfaction with pain management was performed 72 h after the surgery. Sleepiness, nausea, and vomiting were defined as the global average of ratings obtained at each time point.

All of the psychological tests used in this study were validated for the Brazilian population. To measure anxiety, the State-Trait Anxiety Inventory (STAI) 14 was used. The Montgomery-Äsberg Depression Rating Scale was used to measure depressive symptoms 15. The SRQ-20 was used to screen for minor psychiatric disorders (sensitivity = 86%; specificity = 77%) 12. Exposure to alcohol was evaluated by the CAGE Questionnaire (sensitivity and specificity of 88% and 83%, respectively) 16.

Sleep quality before hospitalization was assessed through the Pittsburgh Sleep Quality Index (PSQI), which is a self-rated questionnaire with previously established reliability and validity 17 that assesses sleep quality and disturbances over a 1-mo time interval. The global PSQI score ranges from 0 to 21; higher scores indicate worse sleep quality 18. The global PSQI score more than 5 has yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% in distinguishing good and poor sleepers 18.

The rest–activity cycle was assessed by actigraphy 12. The actigraph model used in this work was an Actiwatch-L® (Mini Mitter Company), which measures activity and ambient light exposure. Actiwatch is an activity monitor designed for long-term monitoring of gross motor activity in humans. It contains an accelerometer that is capable of sensing any motion with a minimal resultant force of 0.01 g. All communication with the actigraph is accomplished using an Actiwatch reader® (Mini Mitter Company) that is connected to a computer via an RS-232 Serial Port. The epoch length was 1 min. The software used was the Actiware Sleep-Circadian Rhythm Analysis® (Mini Mitter Company). The data were converted into a .txt format that could be processed by the Cosana Program 19. The patients wore wrist actigraphs with a light sensor for 18 days (7 days before surgery, during the hospital stay, and 7 days after discharge at home).

On arrival in the anesthesia room, all patients underwent standard monitoring. Before the epidural anesthesia, physiologic solutions 0.9% 10 mL/kg and IV fentanyl (100 µg) were administered. Then, all patients had an extradural catheter inserted at the lumbar segments L2/L3 or L3/L4. Ropivacaine (10 mg/mL) 16–20 mL was administered epidurally. If there were signs of inadequate analgesia, an additional 5 mL doses were used. Continuous propofol (0.08–0.1 mg · kg–1 · min–1) was administered to maintain conscious sedation during the surgery. Intraoperative variables, including ropivacaine and ephedrine doses, length of surgery, blood loss, and anesthetic and surgical complications, were noted. At the end of the surgery, the sedation was stopped and the extradural catheter was removed.

After being transferred to the postanesthesia care unit, the patients were connected to a morphine PCA pump, with a delivery of 2.5 mg morphine, a 10 min lockout and a maximum dose of 30 mg per 4 h. If their pain was unrelieved, the PCA dose was increased by 0.8 mg until pain control was achieved. The PCA was maintained during the first 72 h after the procedure. The analgesic consumption was measured by recording the amount of morphine used via PCA and adjusted by patient weight. No other pain medication was allowed. The analgesia in all patients at 72 h after surgery was maintained with 30 mg codeine plus 500 mg acetaminophen every 6 h and 75 mg sodium diclofenac three times per day. If pain was not relieved, 1000 mg of dipyrone was given every 6 h. If required, 10 mg metoclopramide was administered for nausea. If this was ineffective, 4 mg ondansetron was given. For analytical purposes, the number of antiemetic doses used in the first 72 h after surgery was considered, including both antiemetics (metoclopramide and ondansetron).

A checklist was used to monitor respiratory, urinary, cardiovascular, and neurological complications. This checklist covered points related to the surgery, anesthesia, surgical wound, electrolytic disturbance, and bleeding. The presence of infection was defined by clinical and laboratory investigation. The diagnosis was established by a gynecologist unaware of the treatment group. Patients who did not present with complications were discharged on the third day after surgery on any day of the week. The gynecologist in charge of discharge was blinded to the aim of the study and all other measures. The length of hospital stay was defined as the number of complete days spent in the hospital.

After discharge, the analgesic schedule at home was maintained with 75 mg sodium diclofenac three times daily and 30 mg codeine plus 500 mg acetaminophen every 6 h, if patients experienced pain. One week after discharge, the patients were evaluated in the ambulatory Perioperative Medicine and Anesthesia Service. They responded to Montgomery-Äsberg Depression Rating Scale, the State Anxiety Inventory of STAI, and the VAS of pain. Also, in this assessment, the data obtained by the actigraphy at home were downloaded.

A previous external pilot study, with 10 patients in each group, followed the same inclusion criteria described in the present study. Therefore, these patients were not included in the overall analysis of the data 20. On the basis of the data obtained by the pilot study, sample size calculations were performed after primary end-point measurements: postoperative pain measured by VAS and morphine consumption. To calculate the sample size, the average postoperative pain rating on the VAS scale and morphine consumption in different time periods during the first 72 h after surgery were incorporated into a cumulative mean. Twenty-eight patients (14 per group) were required to detect a 35% difference between groups on primary end-point measurements with a power of 90% and set at 0.05 21.

The differences between groups for continuing data were examined by the t-test for independent samples, and categorical data were examined by {chi}2 or Fisher's exact tests. After first checking assumptions of normality for the outcomes measures by skewness and Kurtosis tests, the experimental groups (melatonin and placebo) were compared for differences in pain, anxiety, and morphine consumption by repeated measures analysis of variance (ANOVA), with the treatment group as a factor and time as the repeated measure. One-way ANOVA with post hoc multiple comparisons by Bonferroni test was used to identify differences between groups at each time point.

The magnitude of the effect of melatonin throughout the first 24 postoperative hours was demonstrated by the number of patients that needed to be treated (NNT). The cutoff point used to classify the anxiety level in the STAI was based on the {delta} score (mean of postoperative state-anxiety assessed 6 and 24 postoperative hours minus preoperative state-anxiety): mildly anxious (scores ≤0) and highly anxious (scores >0) 22. To analyze the effect of melatonin on pain, the patients were classified into two groups according to the mean pain VAS score at 6, 12, 18, and 24 h after surgery: absence of pain or mild pain (mean scores ≤3 cm); and moderate, intense, or worst possible pain (>3 cm) 14. For a nonsignificant result, the 95% CI around the NNT expands from a positive value to a negative value, and thus the 95% CI for the NNT will include infinity ({infty}) 23.

The variation in rest–activity was fitted to a sinusoidal curve by the cosinor method, a linear method of least squares 17 (Cosana Program, version 3.1) 19. The cycle duration (period of a completed cycle) was fixed in a 24 h period, because the normal rest/activity cycle for adult humans has a circadian pattern. The rhythmicity percentual of 24 h (proportion of oscillation into the circadian pattern present in a temporal data sequence) was analyzed to characterize the strength of the circadian rhythm 13. Also, the mean rhythmicity percentual from each period was compared between groups (melatonin and placebo) by the unpaired t-test. For all analyses, statistical significance was set at P < 0.05, two-tailed. Data were analyzed using SPSS version 9.0 (SPSS, Chicago, IL) and SigmaPlot software version 10.0.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Thirty-five patients were randomized to one of two groups. Two patients, however, were excluded for major protocol violations. Patients' characteristics and perioperative variables are summarized in Tables 1–3. The mean melatonin dose used orally in the 12 h before surgery was 0.15 ± 0.03 mg/kg.


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  		Table 1. Characteristics of the Study Sample

 


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  		Table 2. Psychological Characteristics, Satisfaction with Pain Treatment and Sleepiness Levels

 


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  		Table 3. Clinical Variables Measured During Intraoperative and Postoperative Periods.

 
There was an effect on anxiolysis in the treatment group (F[1,31] = 6.27, P = 0.018). However, there was no effect on time (F[1,31] = 0.061, P = 0.81) or an interaction between factors (F[1,31] = 0.31, P = 0.58) (Fig. 1). In the intervention group, the NNT to prevent one additional patient from reporting high state postoperative anxiety in the immediate 24 h postoperative period was 2.53 (95% CI, 1.41–12.22).


Figure 117
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  		Figure 1. Anxiety scores reported on State-Trait Anxiety Inventory (STAI) measured on the night before surgery, 6, 24, 36, 48, and 72 h after surgery and 1 wk after discharge. Data are presented as mean ± sem. Asterisks (*) positioned above the symbols indicate significant difference (P < 0.05) at time points between the intervention and control groups compared by one-way ANOVA, followed by the Bonferroni test for post hoc comparisons.

 

There was an effect in the treatment group on postoperative pain over time (F[1,31] = 46.94, P < 0.001) and as reported by the VAS (F[1,31] = 4.64, P = 0.04). However, there was no interaction between factors (F[1,31] = 0.95, P = 0.34) (Fig. 2). In the intervention group, the NNT to prevent one additional patient from reporting moderate to intense postoperative pain on VAS during the first 24 postoperative hours was 2.20 (95% CI, 1.26–8.58).


Figure 217
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  		Figure 2. Pain scores reported on Visual Analog Scale (VAS) measured on the night before surgery, 6, 12, 18, 24, 36, 48, and 72 h after surgery and 1 wk after discharge. Data are presented as mean ± sem. Asterisks (*) positioned above the symbols indicate significant difference (P < 0.05) at time points between the intervention and control groups compared by a one-way ANOVA, followed by the Bonferroni test for post hoc comparisons.

 

In the presence of moderate to intense postoperative pain during the first 24 postoperative hours, 30% of patients in the melatonin group presented with high state anxiety 24 h after surgery when compared with 76.90% in the placebo group. In contrast, in the absence of pain or mild pain, 20% of the melatonin group presented with high state anxiety, when compared with 33.30% in the placebo group. The NNT was 3 (95% CI, 1.35–5.0) to prevent high postoperative anxiety in patients with moderate to intense pain when compared with 7.5 (95% CI, 1.36–{infty}) in the absence of pain or mild pain.

Analysis of morphine consumption showed an effect on the treatment group (F[1,31] = 6.05, P = 0.02) and there was a significant reduction in morphine consumption across time, independent of the treatment group (F[1,31] = 68.10, P < 0.001). Morphine consumption was not affected by the interaction between time and treatment (F[1,31] = 1.61, P = 0.21) (Fig. 3).


Figure 317
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  		Figure 3. Morphine consumption inpatient-controlled analgesia (PCA). Data are presented as mean ± sem of cumulative morphine consumption by PCA, which express the total dose used in each 6-h period from the moment the patient was connected to the PCA until 72 h after surgery. Asterisks (*) positioned above the symbols indicates significant difference (P < 0.05) at time points between intervention and control groups compared by one-way ANOVA, followed by the Bonferroni test for post hoc comparisons.

 

The melatonin group showed a better recovery on the rhythmicity percentual in the first week after discharge ([t = –2.41, P = 0.02]) (Fig. 4).


Figure 417
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  		Figure 4. The perceptual of rhythmicity of groups in the preoperative period (7 days before surgery); during hospitalization period and during the first 7 days after discharge. Data are presented as mean ± sem. Asterisks (*) positioned above the symbols indicate significant difference (P < 0.05) at time points between the intervention and control groups compared using the t-test for independent samples.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Patients treated with melatonin preoperatively had a significant decrease in pain and anxiety at all time points assessed during the first 36 h after surgery. Furthermore, they required less morphine in the postoperative period and had better recovery of the rhythmicity percentual in the first postoperative week after discharge. We also demonstrated by NNT, which defines the treatment-specific effects of an intervention, that melatonin had a significant clinical effect on pain and anxiety during the first 24 h after surgery.

The anxiolytic properties during the postoperative period are presented in Figure 1. The benefit observed in the present study is clinically relevant with respect to anxiolysis, especially in patients with moderate to intense pain that presented an incidence of high anxiety more than twice the placebo group (30.00% vs 76.90%). This anxiolytic effect is supported by previous studies in animals and humans. In animals, Guardiola-Lemaitre et al. 24 tested the combined actions of melatonin and diazepam in two test models of anxiolytics in mice, and reported that the pineal hormone enhanced the antianxiety activity of benzodiazepine. Likewise, Golombek et al. 25 reported a significant anxiolytic activity in rats that was abolished by the benzodiazepine receptor antagonist. In humans, it was also demonstrated that 5 mg of melatonin administered preoperatively had a clinical effect on anxiolysis expressed by a NNT of similar magnitude to that of the present study 9,10.

Also, the magnitude of the melatonin effect on pain was clinically relevant, because the NNT relative to placebo for one additional patient to report moderate to intense pain was 2.2. This effect on pain response was also evidenced by a reduction in the morphine consumption in the intervention group. To the best of our knowledge, this is the first investigation that builds on published data to provide additional evidence about the analgesic effect of melatonin in the clinical setting. Although the potential clinical analgesic effects of melatonin have not been widely explored, and the exact mechanism and site of action of melatonin to induce antinociception are not clear 26,27, the magnitude of its clinical effect is important. Because no significant difference was observed between groups in the perioperative period, it is unlikely that factors other than the use of melatonin can account for these results in the intervention group.

The potential analgesic effect of melatonin that we observed is supported by previous studies in animals in which systemically administered melatonin produced dose-dependent antinociception and enhanced morphine analgesia 26–28. Possibly, this antinociceptive effect of melatonin involves the activation of supraspinal sites 26,29,30 and the inhibition of "spinal windup" 29. This effect may be mediated by membrane receptors linked to G proteins, and possibly through nuclear receptors 31. Also, experimental evidence suggests that its analgesic effect is mediated by the opioid system, because it augments {gamma}-aminobutyric acid (GABA)-ergic systems and morphine antinociception 32, enhancing {gamma}-aminobutyric acid-induced currents and inhibiting glycine effects 32–34. Moreover, it produces marked antiinflammatory effects on peripheral sites by inhibiting the release of proinflammatory cytokines 27,35,36 and the rolling and adhesion of neutrophils to the endothelial layer 37. This effect on cell defense occurs even in concentrations compatible with nocturnal secretion 37. However, further studies are needed to examine why preoperative melatonin has these effects on postoperative pain and to determine the mechanisms by which exogenous melatonin modulates nociceptive circuits.

The rhythmicity percentual of 24 h of the rest/activity cycle, which is a circadian marker 36, was higher in the melatonin group during the first week after discharge. This effect was observed only after discharge, and suggests that, in the immediate postoperative period, there are many other rhythm "signals," including environmental factors, such as noise, nursing procedures, discomfort, positioning 36, and clinical factors related to tissue injury, drugs, pain and increased stress, which can be blunted via the melatonin effect on rhythmicity percentual. One additional explanation for this result is the suppression of nocturnal melatonin production in the immediate postoperative period 38 and during inflammation, when the levels of tumor necrosis factor are high 39–41. This hypothesis suggests there is an immune-pineal axis in which proinflammatory cytokines disconnect the organism from environmental stimuli that synchronize biological rhythms 39. Thus, the chronobiotic effect of exogenous melatonin may explain the accelerated recovery of the rhythmicity percentual of 24 h in patients of the intervention group. Although its clinical importance and mechanism implicated in this response are unclear, the accelerated synchronization of biological rhythm can be a marker of health 42, which suggests a better recovery in those patients receiving melatonin.

Several methodological issues related to the design of this study must be addressed. First, attending physicians, nurses, and evaluators did not know which treatment had been prescribed until the data collection was complete. Therefore, bias was unlikely. Second, mechanisms that underlie the effects of preoperative melatonin on postoperative outcomes are unclear, but experimental studies have demonstrated long-term effects on spinal cord nociceptive transmission after one systemic melatonin dose, suggesting that its long-term effect could be explained by genomic changes 42. Third, the present results do not allow us to establish whether melatonin modulates pain behavior by a direct mechanism on the central nervous system or by an indirect mechanism through its neuroendocrine activity. Fourth, we emphasize that the results of this study are relevant only to the investigated patient population. Specifically, we excluded patients with a history of an affective disorder, chronic pain, and past or present use of psychotropics. Moreover, we excluded patients with ASA status higher than II, and obese or overweight (body mass index ≥25) individuals because of the high lipid solubility of melatonin and the influence of obesity/overweight on circadian variables.

Although the homogenous population of this study is methodologically advantageous, the issue of external validity arises. That is, hysterectomy may be associated with a specific psychological and behavioral state that is not common in other surgical populations, because the level of preoperative anxiety is related to gender, age, and surgery type 43–45; thus, it may be that the anxiety level of our sample would be higher if compared with that of patients undergoing minor inpatient surgery or outpatient surgery. Alternatively, it is possible that the anxiety level of our sample may be linked with young age and gender. This hypothesis is supported by previous reports that indicate that women and young people are more susceptible to pain and preoperative anxiety 45,46. This is important because it is possible that the pharmacological response to sedatives is related to the anxiety level 47. Another point to consider is that a different dosage, administration schedule, or timing in relation to surgery will result in different findings, because the anxiolytic effect of preoperative melatonin observed in this study and other previous studies that used 5 mg oral melatonin in female patients contrasts with the results reported by Capuzzo et al. 48, who used 10 mg sublingual melatonin once, immediately before the surgery. Furthermore, there are several other methodological differences between the present study and the study reported by Capuzzo et al. 48, such as age, gender, type of surgery, anesthesia technique, and the instruments used to assess anxiety level.

Although these differences do not permit comparison of the results, they suggest that future clinical trials with similar methodologies will be required to compare the results. Also, it is important to consider that the patients included in this investigation had their first evaluation 1 wk before the hospitalization. Because it is well established that the preoperative anxiety responses develop days or weeks before the surgery, it is possible that the attention that the patient received had some influence in the clinical course; thus, this factor has implications for the practical applicability of these results, but it cannot explain the differences in the postoperative outcomes observed in our study, because the management was the same in the placebo and melatonin groups. It is also important to emphasize that, although the melatonin was effective in attenuating the anxiety and improving the postoperative pain response among patients undergoing epidural anesthesia associated with conscious sedation, these findings cannot be generalized to patients undergoing general anesthesia or another type of sedation. At present, we do not know why the melatonin has postoperative effects; thus, we need new studies to measure whether the melatonin response observed in this study would be applicable to patients undergoing other types of surgery and with other clinical characteristics. Finally, we used actigraphy, a valid, reliable and objective tool used to measure rest/activity rhythms. This miniaturized motion detection system collected motion activity quantitatively and enabled us to assess the chronobiotic effects of melatonin, as evidenced by accelerated postoperative resynchronization of circadian rhythms in the melatonin group.

In conclusion, clinically relevant anxiolytic and analgesic effects of melatonin were observed, at least at the dosage used in this study. Furthermore, this finding indicates that the administration of melatonin before surgery may accelerate the resynchronization of circadian rhythms in the postoperative period, suggesting better recovery quality, which could be a consequence of melatonin's effects on pain and anxiety, which usually enhance rhythmicity disruption in stressful situations such as surgeries.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Nara Rejane Niderauer, who gave all the anesthetics.


   Footnotes
 
Accepted for publication July 16, 2007.

Supported by the Graduate Research Group (GPPG) at Hospital de Clínicas de Porto Alegre, Brazil.

There was no financial relationship between any of the authors and any commercial interest in the outcome of this study.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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