Abstract
Melatonin has been used to relief preoperative anxiety and stress. Several investigators reported that melatonin produces preoperatively anxiolysis and sedation. Patients undergoing laparoscopic cholecystectomy and pretreated with melatonin or midazolam exhibited less anxiety and increased sedation preoperatively compared with the controls. Similarly, patients undergoing gynecological laparoscopic surgery and premedicated with 5 mg of melatonin or with 15 mg of midazolam, or placebo were sedated in contrast to the control group. Psychomotor impairment after premedication was observed only in patients treated with midazolam.
However, these effects are not reproducible by other studies. In elderly patients undergoing elective surgery 5 mg of melatonin or placebo given by mouth decreased anxiety scores to a similar degree. Melatonin premedication did not enhance the induction of anesthesia with sevoflurane as assessed by the bispectral index (BIS) monitor. Regarding the effect of sedative interventions and anesthesia on the endogenous melatonin release, acupuncture and acupressure may or may not affect melatonin levels. Also the inhalation anesthetic sevoflurane has been reported to decrease or to have no effect on endogenous melatonin.
The different results may be attributed to the great variability associated with the measurements in melatonin levels, the different anesthetic techniques and co-administration of other agents, different populations in the relevant studies and other undetermined factors. Nevertheless, the interaction of sedative and anesthetic techniques with melatonin and vice versa is challenging and provocative in understanding the underlying mechanisms of sedation and anesthesia.
Introduction
Melatonin is produced by the pineal gland from the aminoacid L-tryptophan, mainly during night as its secretion is regulated by darkness. In the pineal gland L-tryptophan is catalyzed to 5-hydroxytryptophan by tryptophan-5-hydroxylase, which is subsequently decarboxylated to serotonin by L-aromatic amino acid decarboxylase. Serotonin is metabolized to N-acetylserotonin by N-acetyltransferase, which in turn is methylated by hydroxyindole-O-methyltranferase to melatonin. As soon as melatonin is synthesized it is released into the general circulation. Its half life varies between 30 and 60 minutes. Melatonin is metabolized to 6-hydroxymelatonin of which the greater part is metabolized to 6-hydroxymelatonin sulfate and only 10% to 6-hydroxymelatonin glucuronide. There are other minor metabolites and a small percentage of melatonin is excreted unchanged in the urine (1).
Melatonin exerts its effects by binding to the MT1 and MT2 membrane receptors, which are coupled to the G-proteins. The MT1 and MT2 receptors are mapped to different chromosomes and consist of 350 and of 363 aminoacids respectively. The MT3 melatonin receptor is involved in intraocular pressure regulation (1). The hormone maintains the normal circadian rhythms, induces sleep and is a potent free radical scavenger. Its plasma levels reflect the activity of the pineal gland and are highest prior to bedtime.
Melatonin has been used to relieve preoperative anxiety and stress. Several studies have investigated the effect of melatonin in the preoperative setting and its efficacy with respect to the relief of fear and stress. These effects are significant as melatonin is not associated with respiratory depression, heavy sedation or nausea and vomiting, effects produced by premedicants such as benzodiazepines and opioids. On the other hand a potential effect of sedative and anesthetic drugs and techniques on melatonin levels may interfere positively or negatively with normal uninterrupted sleep.
The present article reviews the work investigating the role of exogenous melatonin as premedicant and/or as an adjunct in patients receiving anesthesia as well as the literature available on the effect of sedative and anesthetic techniques and drugs on endogenous melatonin release.
Effect of Melatonin on Anesthesia
Relief of Preoperative Stress – Premedication
Melatonin has been used as premedicant to relieve preoperative anxiety and stress. In a prospective randomized double-blind controlled trial patients undergoing laparoscopic cholecystectomy received either 5 mg of melatonin or 15 mg of midazolam or placebo sublingually, 90 minutes before surgery. Those patients treated with melatonin or midazolam exhibited less anxiety and increased sedation preoperatively compared with patients in the placebo group. However, postoperatively neurophysiological performance was similar in the three groups (2).
In another double-blind placebo-controlled trial also comparing melatonin to midazolam patients were premedicated with 5 mg of melatonin or 15 mg of midazolam, or placebo 100 min before the operation. The premedicants were administered sublingually. The authors reported that melatonin and midazolam treatments produced sedation in contrast to the placebo treatment. Anterograde recall was impaired only in the midazolam group (3).
In a dose response study patients were pretreated with 0.05, 0.1 and 0.2 mg/kg of sublingual midazolam or melatonin. At 90 min sedation was observed in 33.3%, 33.3% and 66.7% of midazolam group respectively, while for the same doses of sublingual melatonin 41.7%, 33.3% and 66.7% of patients were sedated. Psychomotor impairment preoperatively was observed in those patients treated with midazolam but not in patients treated with melatonin or placebo (4).
In both Naguib studies midazolam but not melatonin premedication was associated with psychomotor impairment before operation. Melatonin in contrast to midazolam did not enhance postoperative sedation and was not associated with cognitive and psychomotor dysfunction.
Nevertheless, these effects are not reproducible in all studies. Elderly patients (>65 years) undergoing elective surgery received 10 mg of melatonin or placebo by mouth. Anxiety scores were decreased to a similar degree in both the melatonin and placebo groups (5).
Another study that failed to demonstrate a beneficial effect of melatonin as sedative was conducted in children undergoing magnetic resonance imaging. Melatonin 3 or 6 mg given orally for the smaller (<12 kg) or bigger (>12 kg and < 40 kg) children respectively neither shortened the onset time nor prolonged the duration of sedation produced by chloral hydrate in the smaller or temazepam and droperidol for the bigger children respectively (6). Several reasons may account for these differences such as the route, the dose and the time of melatonin administration.
Melatonin and General Anesthesia
Melatonin has been reported to exhibit a hypnotic effect and to enhance the intravenous induction of anesthesia by thiopental and propofol.
In animal studies (rats) intravenous administration of melatonin produced loss of righting reflex in a dose dependent manner. In the same study intravenous melatonin increased the threshold of paw withdrawal after pinching the rat at the paw, effect similar to that produced by intravenous propofol. The response to tail clamping was abolished in 43% of rats injected intravenously with 257 mg/kg melatonin, in 100% of rats treated with 20 mg/kg intravenous propofol, and in 71% of rats treated with 20 mg/kg intravenous thiopental. Thus melatonin exhibits hypnotic and antinociceptive effects but the doses required are much higher than the doses of thiopental and propofol (7).
In another animal study the analogue of melatonin 2-bromomelatonin given to rats intravenously produced loss of the response to tail clamping and of the righting reflex (8). These effects were found to be dose dependent and 6-10 times less potent than the same effects produced by propofol. Also in rats melatonin given orally in a dose of 20 mg/kg enhanced the loss of righting reflex produced by ketamine and thiopental and prolonged their effect. The onset of anesthesia was assessed by the loss of righting reflex. It appears that there is a synergistic effect of melatonin with these anesthetics. However, melatonin had no effect on the anesthesia produced by ether (9).
Thiopental, propofol or melatonin injected into the internal jugular vein of rats in ED95 doses required to loose the righting reflex, i.e. 23.8 mg/kg, 14.9 mg/kg and 312 mg/kg respectively, produced EEG changes on the processed EEG. All drugs decreased the relative spectral edge 95% and the relative approximate entropy. However, melatonin was associated with a slower onset and a longer duration of these EEG parameters (10).
Not only experimental studies but studies in humans as well support the efficacy of melatonin as an adjunct to the drugs producing general anesthesia. In a double-blind randomized study 200 adults were assigned to receive by mouth either 0.2 mg/kg melatonin or placebo. Melatonin given 50 minutes before induction of anesthesia was found to decrease the thiopental and propofol ED50 doses required to abolish the eyelash reflex and the response to a verbal stimulus. After melatonin premedication the relative potency of thiopental was increased by 1.3 and that of propofol by 1.7 compared to the relative potencies recorded after placebo premedication (11).
Incremental doses of 10 mg of propofol required to obtain a BIS value of 45 were decreased when patients were premedicated with 3 or 5 mg of melatonin given orally 100 minutes before surgery. The mean doses of propofol required were 115 ± 19.5 mg, 114 ± 20.9 mg and 134 ± 25 mg in the 3 and 5 mg melatonin groups and the placebo group respectively. The dose of propofol required to bring the BIS value down to 45 was similar after melatonin 3 or 5 mg. Melatonin decreased the dose of propofol required to abolish the eyelash reflex and the responses to verbal stimuli (12).
However, all studies do not demonstrate an enhancement of anesthetics by melatonin. Melatonin premedication in patients anesthetized with inhalation induction using sevoflurane in oxygen did not enhance the induction of anesthesia as assessed by the bispectral index (BIS) monitor. BIS indicates the level of anesthesia at the cerebral cortex and BIS values were not affected in the melatonin treated group as compared to the controls. The dose of melatonin was 9 mg given sublingually, and the patients studied were outpatients and did not receive any premedication except for melatonin as determined by the study protocol (13).
Effect of Melatonin on Postoperative Outcome
In addition to its sedative effect melatonin has anti-inflammatory and analgesic actions, rendering this hormone a useful premedicant drug with an impact on the postoperative pain control (14).
In a randomized, double-blind, placebo-controlled trial, women scheduled for abdominal hysterectomy received 5 mg of melatonin orally the evening before operation and one hour before surgery. A control group was treated identically but received placebo instead. Patients treated with melatonin exhibited less postoperative pain up to 36 hours postoperatively as expressed by the VAS scores and consumed less morphine up to 48 hours postoperatively (15). These results appear to be very optimistic for melatonin administered preoperatively only. Also, since all patients had access to PCA morphine it is hard to explain why the patients in the placebo group experienced more pain since they had the choice to consume more morphine.
Melatonin 5 mg administered orally the night before operation and one hour preoperatively was found to decrease morphine requirements after abdominal hysterectomy in the highly anxious patients by 30% or more. This effect was not observed in the mildly anxious patients (16).
Tourniquet pain during intravenous regional anesthesia for hand surgery causes patient discomfort and requires rescue analgesia. Melatonin premedication 10 mg given 90 minutes before surgery produced less pain due to tourniquet, decreased the doses of opioid and of diclofenac during the first postoperative hours and prolonged the time to the first analgesic after surgery (17).
Nevertheless, there is a great variability among studies exploring the relationship between anesthesia and sedation on one hand and melatonin on the other. The oral route of administration of melatonin is one of the sources of variability. In recent years, administration of exogenous melatonin, primarily by the oral route, has been used to explore the effect of melatonin in humans. This approach was especially used to reveal melatonin’s sedative and/or hypnotic properties (18,19). However, oral melatonin administration is disadvantageous because of its poor and unpredictable bioavailability (5% – 56%) (20,21) as a result of extensive first-pass hepatic extraction and inconsistent absorption from the gastrointestinal tract (20,22-23). This may result in serum melatonin concentrations differing up to 25-fold among subjects after application of the same dose (19,24-25), giving a possible explanation for some of the inconsistencies in reported results (21). Furthermore, from a theoretical point of view, 6-sulphatoxymelatonin excretion may not reflect serum melatonin levels after its oral application, because of a variable first pass effect among subjects (21). Lane and Moss concluded from pharmacokinetic studies that 30-60% of oral melatonin is metabolized to 6-hydroxymelatonin in the liver during the first pass (23), and this portion of melatonin never enters the general circulation.
Poor formulation and/or poor quality of some orally administered melatonin products have been found to result in unpredictable melatonin release. Certain products have shown excessive friability, failure to disintegrate and dissolve, and excessive variation in hardness. In vitro release profiles of the two controlled-release products were found to be substantially different (26).
Differences in the pharmacokinetic profile of melatonin following its oral administration have been observed in obese subjects due to an apparent volume of distribution greater than the extracellular volume (20% of the total body weight) (20,27), while in patients with cirrhosis decreased elimination resulting in elevated serum melatonin levels has been found (28). Also, delayed elimination has been reported in patients with stomach ulcers resulting in higher blood levels (28).
Effect of Anesthesia and Traditional Sedative Techniques on Melatonin
General anesthetics may modulate several multisynaptic neuronal functions. Whether anesthetics affect pineal melatonin secretion and eventually serum melatonin levels has been the objective of several studies in animals and humans. In anesthetized patients possible changes in melatonin levels by anesthetics may interfere with the nocturnal rise in melatonin and normal biological rhythms.
In New Zealand white rabbits pentobarbital had no effect when administered in the late light and early dark period. In similar experiments with ketamine melatonin secretion was enhanced. In contrast, halothane anesthesia decreased melatonin levels (29).
The effect of anesthetic and sedative drugs on melatonin levels in humans has been studied by several investigators. In children undergoing ambulatory surgery under general anaesthesia thiopental 5 mg/kg or midazolam 0.4 mg/kg did not significantly change plasma melatonin levels measured in samples obtained 5, 10 and 20 minutes after drug administration (30).
Regarding inhalation anesthesia in adults, isoflurane in concentrations as high as 5% increased while 7% inspired concentration of sevoflurane decreased plasma levels of melatonin (31). The authors attributed the increase in melatonin levels found after isoflurane anesthesia to the stimulation of the sympathetic nervous system by isoflurane. Nevertheless, they provided no possible explanation for the decrease in melatonin plasma levels found after sevoflurane anesthesia. The study included a limited number of patients, nine in each group (31).
Other investigators have also reported increased melatonin levels after isoflurane anesthesia. Patients undergoing elective gynecological procedures under general anesthesia with thiopental and isoflurane exhibited elevated melatonin levels that persisted during the first 8 hours postoperatively, i.e. the period of last blood sample collection. Patients undergoing the same surgical procedure under propofol anesthesia also exhibited an increase in melatonin levels, which however declined during the 8 hours recovery period during which blood sampling was discontinued (32).
These results are in contrast to the results of a recent study in which sevoflurane was administered as the sole anesthetic agent in women undergoing dilatation and curettage of the uterus. Blood samples to measure serum melatonin levels were collected before, immediately after as well as 2, 4, 8, and 24 hours postoperatively. The variation in melatonin values did not differ with respect to time or to group effect when compared with a group of healthy volunteers (33). The authors attributed their findings to the fact that the operation was a minor one and to the high variability of measured melatonin levels. The investigators collected blood samples before and immediately after surgery, as well as 2, 4, 8 and 24 hours postoperatively; they did not measure melatonin levels in serum around or after midnight. Thus possibly lower melatonin night-time levels might have escaped detection. However, all patients reported no sleep disturbances as the quality, duration and type of sleep, continuous versus intermittent, did not differ before and after sevoflurane anesthesia.
Melatonin levels in saliva and 6-hydroxymelatonin sulphate in the urine were determined in ten patients undergoing general anesthesia and in nine patients undergoing subarachnoid anesthesia for minor knee surgery. Samples were collected at 21:00, 22:00, 23:00 and 24:00 on the day before surgery as well as on the day of surgery. Melatonin secretion in saliva was decreased during the first postoperative evening when compared to saliva melatonin levels measured the preoperative evening (34). A significant decrease was also found in the 6-hydroxymelatonin sulphate urine excretion, a melatonin metabolite. Since the authors collected successive samples during the night they demonstrated an abnormal circadian rhythm of melatonin postoperatively.
Surgical patients appear to exhibit disturbances in melatonin release and circadian rhythm. Cronin et al reported significantly lower melatonin serum levels during the first postoperative night in samples collected hourly versus the samples collected on the second and third postoperative night (35). These patients had hysterectomy or myomectomy and received general anesthesia plus an epidural catheter to control postoperative pain.
In patients operated for cancer of the colon melatonin concentrations in the gut tissue were elevated in samples collected during the day and night, the day-time levels being 10 times higher than the day-time levels in plasma (36). In contrast in minor surgical procedures melatonin levels in plasma did not change.
Perioperative fluctuations in plasma melatonin levels may be induced by several factors as type of anesthesia, though according to the data available there is no strong evidence supporting such changes. The type of surgery, major versus moderate or minor surgical procedures, may play a role along with the secretion of other hormones when the surgical stress is major. Attributing postoperative sleep disturbances to melatonin and circadian rhythm is rather simplistic, as anesthesia itself, the response to surgical trauma, food deprivation and most importantly inadequate pain relief bring about a disruption in body functions, particularly those of the central nervous system.
Possible derangements of melatonin secretion postoperatively may be associated with sleep disturbances occurring in the surgical patient. Melatonin replacement in the first postoperative days may help to improve or to restore normal sleep patterns during the postoperative period. Also, applying techniques which may increase melatonin secretion may be useful to treat anxiety and sleep disturbances.
Acupuncture and acupressure techniques reduce anxiety, relieve stress and may improve normal sleep. In an open clinical trial 18 adults suffering from insomnia received two sessions of acupuncture per week for five weeks. When the study was completed, concentrations of 6-sulphatoxymelatonin, the major metabolite of melatonin in urine, were increased during the periods midnight to 8 AM and decreased from 8 AM to 3 PM when compared to the pretreatment concentrations (37). Sleep improvement was noted during night. (37).
In another study stress decrease after application of acupressure on the extra 1 acupoint was not associated with significant changes in serum melatonin levels. In fact melatonin was decreased one hour after the intervention by 30% but this decrease was not statistically significant (38). However, in this study acupressure was applied only once, thus the melatonin response was acute. The great variability in measured values and the small number of volunteers studied, twelve altogether, may have prevented the detection of a possible statistically significant decrease in melatonin after this intervention (38).
There is no agreement between studies investigating the sedative and hypnotic effects of melatonin or the effect of anesthesia and traditional sedation techniques on plasma melatonin levels. Insufficient standardization of analytical methods for the determination of melatonin blood levels, experimental conditions (anesthetic techniques), selection of volunteers/patients for study populations, inclusion and exclusion criteria (e.g. co-administered drugs) in research protocols, have led to areas of controversy and generally difficulties for conclusions to be drawn with regard to it’s therapeutically/ clinical applications.
Apart from inconsistencies that arise from assay methods used to quantify melatonin (and its metabolite, 6-sulphatoxymelatonin) in biological fluids fluctuations in melatonin concentrations may be due to certain patient factors.
Firstly, the amount of melatonin produced is genetically determined and its secretion is regulated by a circadian rhythm (concentrations remain low during the day, begin to increase at 20:00, peak at 01:00 – 04:00 and fall to basal levels by 10:00). Therefore, melatonin levels vary as a result of differences in sample collection times (39). Also levels in plasma and saliva are affected by posture, increasing when a subject moves from a supine to a standing position and decreasing when these positions are reversed, probably as a result of the influence of gravity which causes a decrease in plasma volume on standing and an increase in plasma volume on lying down (40).
Secondly, the quantity of melatonin synthesized in the pineal gland is also influenced by age. Increased levels found in children are considered to be due to faster metabolism and greater synthesis and secretion by the pineal gland, compared with adults. Peak night-time serum concentrations decrease rapidly between the ages of 6 and 20 years remain stable between 20 – 40 years and then slowly decline. However, a study investigating the melatonin pharmacokinetics in premenopausal versus postmenopausal healthy female volunteers showed no difference between these two populations (41).
Finally, certain co-administered drugs have been found to affect plasma concentrations of melatonin by inhibiting its synthesis e.g. clonidine (42), atenolol (43), propranolol (44), dihydropyridines (nifedipine) (45), while calcium channel blockers prevent the release of melatonin from pineal gland into the circulation (46) and noradrenaline re- uptake inhibitors (desipramine, oxprotiline) increase its release. Fluvoxamine (serotonin reuptake inhibitor) (47) and caffeine (48) increase the bioavailability of melatonin by inhibiting CYP2D6, CYP1A2, while prostaglandin synthesis inhibitors decrease its secretion (42).
Conclusion
Emphasis should be made on the need to standardize analytical methods for melatonin assay, experimental conditions (anesthetic techniques), selection of volunteers/patients for study populations, inclusion and exclusion criteria in research protocols on melatonin, so as to avoid confusion and aid in the interpretation of results.
Melatonin as adjunct therapy may decrease the doses of anesthetics required to provide general anesthesia. This hormone may be also effective for pre-operative sedation and anxiolysis. More studies are required to confirm the efficacy of melatonin as a premedicant and an adjunct durg to general anesthesia. The Natural Standard Research collaboration (www.naturalstandard.com) based on scientific evidence classifies the relevant studies on the use of melatonin in anesthesia and as a premedicant drug as grade C, indicating that there is unclear scientific evidence for its use (www.mayoclinic.com, May 1, 2008).
