Hypnotic Effect of Perioperative Exogenous
Melatonin Supplementation in Adult Patients
Undergoing Major Surgery
By
Ashraf F. Aboushady, MD,
Tarek M. Bader, MD,
And Amr A. Keera,MD.
Department of Anaesthesiology, Benha faculty of Medicine
Benha University, Egypt
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Hypnotic Effect of Perioperative Exogenous Melatonin Supplementation in Adult Patients undergoing Major Surgery
Ashraf F. Aboushady, MD, Tarek M. Bader, MD, and Amr A. Keera, MD
Department of Anaesthesiology, Benha Faculty of Medicine,
Benha University, Egypt
Abstract
We have evaluated the hypnotic effect of perioperative sublingual melatonin administration in 50 adult patients undergoing major surgery in a prospective, randomized, double blind, placebo-controlled study. 25 patients were given sublingual melatonin and 25 patients were given saline, approximately 100 minutes before a standard anaesthetic and again at23:00 hours on the day of the operation and on the following day. Sedation and anxiety 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. Blood samples were taken for evaluation of melatonin and stress hormones “cortisol and epinephrine” concentrations. On the 3rd day postoperatively, patients were asked about satisfaction with the premedication, sleep disruption and any of the suspected side effects of melatonin. Patients who received melatonin had a significant decrease in anxiety levels and increase in levels of sedation before operation compared with controls. Melatonin was effective in decreasing perioperative levels of cortisol and epinephrine compared to placebo. Patients in the placebo group had a decreased nocturnal secretion of melatonin during the first 48 hours postoperatively while patients received melatonin had a better circadian rhythm. Patients received melatonin were more satisfied with premedication without significant differencesin the side effects as compared to placebo. It can be concluded that melatonin can be used safely and effectively for premedication and postoperatively as a hypnotic in patients undergoing major surgery.
Introduction
Melatonin is a neurohormone mainly secreted by the pineal gland. It posses a circadian secretion pattern, with low blood concentrations during the day and high concentrations at night (Nowak and Zawilska, 1998). Melatonin is said to has several functions including; regulation of circadian rhythm (Brzezinski, 1997), regulation of reproductive axis (Tamarkin, 1985), and antioxidant activity (Reiter, 1998). Several investigators found that the exogenous administration of melatonin facilitates sleep onset and improves quality of sleep (Garfinkel et al., 1995), (Shamir et al., 2000) and (Kayumov et al., 2001). It is also used effectively in relieving jet lag symptoms (Suhner et al., 1998). Also, melatonin supplementation is used for treatment and prevention of postoperative delirium (Hanania and Kitian, 2002). Benzodiazepines (BNZ) decrease duration of rapid eye movement(REM) sleep (Borbely and Achermann, 1987). It also reduces slow wave sleep, and thus negatively influencing sleep quality (Frederickson and Krueger, 1989). Postoperative opioid analgesics have been shown to decrease both REM and slow wave phases (Cornin et al., 2001). Non-steroid anti-inflammatory drugs increase awakenings and decrease sleep efficiency, possibly due to inhibition of melatonin secretion (Bourne and Mills 2004). In contrast,
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melatonin produced no suppression of REM. Furthermore, unlike BNZ, melatonin does not induce “hangover” effects (Zhdanova et al., 1995).
The unusually small amplitude of the nocturnal melatonin secretion on the first postoperative night suggests the possibility that sleep disturbance in surgical patients is a manifestation of a decreased melatonin circadian rhythm. Pharmacological replacement of melatonin restores sleep (Reid and Dawson, 1997). The relation between melatonin secretion and circadian rhythmhas not been well defined in the complicated physiological state of surgical patients. It is possible that profound sleep disturbance in postoperative patients could be prevented by melatonin replacement therapy (Cronin et al., 2000).
Variable amounts of ingested melatonin are metabolized in the liver to 6-hydroxymelatonin. After conjugation with sulfuric or, glucuronic acid, it is excreted by the kidneys. Non-metabolized melatonin is transported via the systemic circulation to various tissues in the body (Brzezinski, 1997). However, melatonin given sublingually did not undergo first pass metabolism in the liver. Drowsiness starts about 45 minutes after melatonin ingestion and lasts for more than one hour (Hartter et al., 2000).
This prospective randomized, double blind, placebo controlled study was designed to evaluate the perioperative effects of sublingual melatonin as regards; anxiolytic, sedative, its effect on stress response to surgery and postoperative hypnotic effect in adult patients undergoing major surgery.
Patients and methods
After obtaining institutional approval and informed consent, we studied 50 adult patients, physical status ASA I or II subjected to surgical operations of long duration “more than 2 hours” under general anesthesia with postoperative hospitalization for 3 days at least. No patient was pregnant or lactating, abusing centrally acting drugs, on treatment with beta blockers or corticosteroids. Also patients with history of seizure disorders were excluded from the study.
Approximately 2 hours before surgery, patients were transported to an isolated quiet room in the operating suite. Arterial blood pressure, heart rate and oxygen saturation were monitored. Patients were randomly allocated to one of two groups (n=25 in each) to receive either 5mg sublingual melatonin (colloidal melatonin, Nova Natural products, Twinlab, Kingdom of Saudi Arabia) or, sublingual saline (placebo). Both melatonin and placebo were prepared to a fixed volume of 3ml in a syringe and marked only with a coded label to maintain the double-blinded nature of the study. The content of the syringe was given sublingually approximately 100min before induction of general anesthesia 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. Patients were instructed not to swallow before 3 min. Again , 5mg melatonin or, placebo were given sublingually in a double-blind nature at 23:00 hours on the day of the operation and on the following day.
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The dose of melatonin was 5mg according to several previous reports and studies investigated melatonin for premedication (Naguib and Samarkandi, 1999) and for hypnosis (Stone et al., 2000) and (Sharkey and Eastman, 2002)
Anxiety was evaluated using a visual analogue scale (VAS) which is a 10-cm high. The extremes were marked “no anxiety” at the top end and the lower as “anxiety as bad as ever can be”. Also, sedation was assessed by using a sedation score (1=awake; 2=drowsy; 3=a sleep but arousable and 4=asleep not arousable). All were evaluated before, and 10, 30, 60 and 90 minutes after premedication and postoperatively at 15, 30, 60 and 90 minutes after admission to recovery room.
Perioperative stress response was assessed by evaluating the stress hormones cortisol and epinephrine just before premedication “baseline”, 60 min after premedication, 60 min after skin incision, 60 minutes after admission to the recovery room and after 8 hours postoperatively. Blood samples for evaluation of serum melatonin were taken before premedication “baseline” and 60 minutes after premedication, at 1:00 and9:00 hours of the first 3 postoperative days. Blood samples immediately sent to lab. and centrifuged. Serum was then stored at -20°C till analysis. Cortisol analysis was performed by radioimmunoassay (RIA), while epinephrine analysis was carried out using liquid chromatography with electrochemical detection. Plasma melatonin concentration was assessed in duplicate samples by a commercially available RIA kit (stockgrand, Guildford, UK).
Anesthesia was induced with 1ug/kg fentanyl, 2mg/kg propofol and 0.6mg/kg rocuronium. After tracheal intubation, anesthesia was maintained with sevoflurane in oxygen, supplemented with fentanyl and muscle relaxant rocuronium. End tidal carbon dioxide, hemoglobin oxygen saturation, blood pressure, continuous ECG and peripheral nerve stimulation were monitored in addition to a nasopharyngeal thermistor for temperature monitoring. At the end of surgery, residual muscle relaxation was reversed. Surgery time (skin incision to closure), and anesthesia time (induction to emergence) were recorded.Postoperative pain was treated with i.v morphine. The total dose of morphine was recorded.
On the second postoperative day, patients were questioned about their medication: “was it satisfactory or not? “and if needed, would they prefer the same or, another premedication in the future?” After the 3rd postoperative day, patients were asked about morning grogginess, daytime hangover and average sleep hours in the first 3 postoperative nights. The number of patients who asked for hypnotic and the number of patients who had interrupted sleep “awakening more than 3 times/night” were recorded. The incidence of nausea, vomiting and pruritus is also recorded.
Data are presented as means and their standard deviation (SD) or, number of patients and percentage. The data were analyzed with SPSS package (version 10.0; SPSS, Inc. Chicago, IL). Chi-square test or X2 test were used according to suitability. Non parametric analysis of variance (Friedman test) was used to compare sequential alternation in plasma melatonin, cortisol and epinephrine with their baseline values. A p-value < 0.05 was considered statistically significant.
Results
Patients in both groups were under abdominal or, orthopedic operations. They were comparable in age, weight, height, surgery and anesthesia times. Also, there were no
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significant differences between both groups as regards intraoperatively administered fentanyl or, postoperative cumulative morphine consumption (table 1).
Premedication with melatonin significantly reduces anxiety VAS as compared with placebo preoperatively (P<0.05). However, there was no significant difference between both groups postoperatively (Figure 1).
Patient who received melatonin showed increased levels of sedation at 60 and 90 minutes after premedication (P<0.05) compared to placebo. After operation, there was no difference except at 30 minutes where patients in the melatonin group showed an increased sedation level in comparison with the placebo (table 2).
There was no significant difference between both groups as regards baseline serum cortisol concentrations. But significant reduction in cortisol level was detected one hour after premedication in melatonin group compared to baseline (P<0.05). Significant increase in cortisol levels were detected intraoperatively in both groups compared with the baseline levels. Plasma cortisol values decreased in both groups during the recovery period, reaching the baseline level in melatonin group 8 hours postoperaratively but still significantly higher in placebo group at that time. Plasma cortisol levels were significantly lower in melatonin group compared to placebo in all samples except, the baseline one (table 3).
As regards serum epinephrine levels, there was no significant difference between both groups before premedication (baseline), but there was a significant higher concentrations of epinephrine in all the subsequent samples in placebo group in comparison with melatonin.In between patients of the same group, the increase of epinepherine levels was insignificant in melatonin group, while it was significantly increased in placebo group as compared with the baseline level (table 3).
Table (1). Demographic and Periopeartive Data
Data are presented as mean ±SD, no significant differences.
Data are presented as mean ± SD, no significant differences.
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0.6
0.4
0.2
0------
-0.2
*
-0.4
*
-0.6
-0.8
* *
-1.0
-1.2
-1.4
1030609015’30’60’90’
Time (min)
Preoperative Recovery Room
Figure (1). Changes in anxiety VAS “mean” relative to baseline
= statistically significant difference (P<0.05)
Table (2) Pre-and postoperative sedation in the studied groups
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Data are presented as number of patients and percentage
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Table (3): Cortisol, epinepherine and melatonin blood levels
Data are presented as mean ± SD
Table (4): Patients satisfaction and side effects of perioperative melatonin medication
Data are presented as number of patients and percentage.
As regards serum melatonin concentrations, there was no significant difference in baseline or one hour after premedication samples between both groups or, inbetween patients of the same group. Patients in placebo group had a deficiency in nocturnal secretion of melatonin during first and second postoperative nights as reflected by comparing the serum melatonin levels at 1:00 a.m. of previous nights with that at the 3rd one. There was a significant higher concentration of melatonin at 1:00 a.m. of the
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first and second postoperative nights in melatonin group in comparison with the placebo group which reflects a better circadian rhythm in patients received perioperative melatonin. However samples taken at 9:00 a.m. showed no significant difference between both groups or, in between patients of the same group at different days (table 3).
All patients in the melatonin group were satisfied with their premedication. This is to be contrasted with twelve patients (48%) in the placebo group (P<0.005). All patients in the melatonin group would prefer to have the same premedication and ten patients (40%) in the placebo group said they would prefer to have another premedication in the future (table 4). There was no any patient in melatonin group asking for hypnotics during the first three postoperative nights versus seven patients in the placebo group (P<0.05). Perioperative melatonin administration has been associated with a significant increase in sleeping hours during first three postoperative nights, there was only one patient had an average sleeping hours less than 6 hours per night in comparison with 6 patients in the placebo group. No patient in melatonin group complained of interrupted night sleep versus five patients in placebo group (P<0.05). There was no statistically significant difference between both groups as regards daytime hangover, morning grogginess and body temperature changes. Three patients in melatonin group had decreased body temperature between 0.5 to 0.8°C from baseline values versus two patients in the placebo group. This occurred mainly in the early postoperative period. Perioperative melatonin medication had not resulted in increase in the incidence of postoperative nausea & vomiting nor in postoperative pruritus (table 4).
Discussion
We have demonstrated that patients who received premedication with sublingual melatonin had a significant decrease in anxiety levels and increase in the levels of sedation preoperatively compared with those who received placebo. Postoperatively, there was no difference between both groups as regards anxiety levels. The onset and peak effect of melatonin induced sedation were noted at 60 and 90 min respectively after sublingual administration.
Naguib and Smarkandi found that melatonin is comparable to midazolam for premedication as regards alleviation of anxiety and in producing preoperative sedation. However, they reported that, sublingual midazolam had a more rapid onset in comparison with melatonin and midazolam diminished anterograde recall but melatonin had no amnestic effects (Naguib and Samarkandi, 2000).
The hypnotic and analgesic effects of iv 2-bromomelatonin were investigated on Sprague – Dawley rats by Naguib et al., (2003). They compared its effect with those of propofol. They found that 2-bromomelatonin was comparable to propofol in terms of its rapid onset and short duration of hypnosis. It was 6 - 10 times less potent than propofol. But, unlike propofol, the reduced nocifensive behavior persisted for a longer period. These property is desirable in anesthetics or anesthetic adjuvants.
Wassmer et al., (2001) used melatonin as a sleep inductor for electroencephalogram (EEG) recording in children. They concluded that melatonin can reliably be used for obtaining sleep EEG in children. Its use seems to provide a good alternative to pharmacological sedation.
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In agreement with our results, Satomura and his colleagues found that, exogenous
melatonin supplementation significantly increased total sleep time and sleep efficiency, and melatonin 6mg was observed to demonstrate hypnotic effect that was equal to those of triazolam at 0.125mg (Satomura et al., 2001).
Plasma cortisol and epinephrine concentrations decreased significantly after melatonin premedication and we found more increase in those stress hormones after skin incision in the unpremedicated patients.Our results are consistent with previous study done by Kehlet (1988), he found that plasma cortisol levels were significantly lower in patients received 3.0mg bromazepam orally, one hour before general anesthesia as compared with the unpremedicated patients.
In our study, melatonin secretion patterns in the placebo group were disrupted in the early postoperative period. Circadian melatonin secretion was restored after 48 hours postoperatively. However, patients received melatonin pre- and postoperatively had a higher level of melatonin plasma concentration at 1:00 a.m. hour which reflects a better circadian level change. In agreement with our results, Guo and his colleagues found that patients undergoing coronary artery bypass grafting had plasma melatonin concentrations below the minimum sensitivity concentration during surgery, yet small concentrations, without circadian variation were detected during the immediate postoperative period. During the second and third postoperative days, circadian secretion patterns of melatonin were started again and showed an inverse correlation with light intensity (Guo et al., 2002).
Reber et al. had investigated the effect of isoflurane and propofol, as well as darkness in gynecological patients. They reported increased melatonin concentrations that persisted in the recovery period in patients anesthetized with isoflurane, whereas melatonin concentrations decrased gradually during the recovery period in patients anesthetized with propofol. They also reported that plasma melatonin concentrations were significantly smaller in both groups, after premedication with benzodiazepine (Reber et al., 1998).
We found a good postoperative hypnotic effect of perioperative supplementation with melatonin as reflected by a more satisfied patients with the premedication and more sleep hours during postoperative nights with less frequent awakening up during night sleep, no any side effect of the used dosage incomparison with placebo. In agreement with our results Shilo and his colleagues studied the effect of melatonin on sleep quality of COPD intensive care patients. They found that melatonin administration to patients in intensive care units may be indicated as a treatment for sleep induction and resynchronization of the biologic clock (Shilo et al.,2000). Stone and his colleagues found that hypnotic activity of melatonin when given presumably in conditions with decreased endogenous melatonin is similar to 20mg temazepam (Stone et al., 2000).