Melatonin- Works like a dream!

16 September 2011 No. 32

Melatonin- Works like a dream!

J Kanjee Commentator: L van Zyl Moderator: K de Vasconcellos

Department of Anaesthetics

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CONTENTS

INTRODUCTION .................................................................................................... 3 MELATONIN BIOSYNTHESIS ............................................................................... 4 LIGHT REGULATES MELATONIN SYNTHESIS .................................................. 5

MELATONIN CATABOLISM ................................................................................. 9 MELATONIN RECEPTORS ................................................................................... 9

MELATONIN AND ANAESTHESIA ..................................................................... 12 MELATONIN AND SLEEP IN ICU ....................................................................... 23

OTHER USES OF MELATONIN .......................................................................... 27 1. Sleep disorders ........................................................................................... 27 2. Cancer .......................................................................................................... 28 3. Aging ............................................................................................................ 29 4. Immune Protection ...................................................................................... 29 5. Melatonin as an Anti-Oxidant ..................................................................... 29

6. Melatonin and Apoptosis ........................................................................... 30

CONCLUSION ..................................................................................................... 32 REFERENCES ..................................................................................................... 33

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MELATONIN – WORKS LIKE A DREAM! INTRODUCTION Melatonin was originally discovered fifty years ago by the American dermatologist Aaron Lerner and his co-workers as an amphibian and fish skin-lightening factor. This was only of interest to some specialists, as skin colouring was not applicable to mammals, whose melanocytes do not contain physiologically controlled, mobile melanosomes. Lerner subsequently named the molecule melatonin because it induces contraction of stellate amphibian melanophores. Subsequently melatonin was reported to be present in a wide spectrum of organisms including bacteria, fungi, plants, protozoa, invertebrates and vertebrates including man. The hormone thereafter received more attention when it was found to reset and regulate the circadian rhythms. Melatonin, also known chemically as N-acetyl-5-methoxytryptamine, is produced predominantly by the pineal gland pinealocytes. Extra- pineal gland sites of production include the retina (photoreceptor cells), GIT, bone marrow, platelets, and skin. Except the retina, their physiological significance is still a matter of debate. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Melatonin is a nocturnal hormone, stimulated by darkness and inhibited by light. Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA. Melatonin has several important physiological functions, including regulation of the circadian rhythms, regulation of the reproductive axis, antioxidant, oncostatic, anti-inflammatory and anticonvulsant effects1. Melatonin has numerous uses: treatment of sleep disorders and jet lag, reduction of oxidative stress in neonates in the perioperative period, protection of the skin from ultraviolet damage and treatment of psychosis in the ICU (Table 1). Most importantly, its hypnotic effects may be exploited for its use as a preoperative sedative. Pineal Gland and Melatonin

It is believed that Galen (130-210 AD), a Greek physician and philosopher was the first to provide anatomical and functional descriptions of the pineal gland. In the 17th century the French philosopher Rene Descartes thought that the pineal gland was involved in sensation, memory and body movements, and he viewed it as the ‘centre of the spirit or the seat of the soul’ in his writings. The pineal gland is a small endocrine gland in the vertebrate brain. Its shape resembles a tiny pine cone (hence its name), and is located near the centre of the brain, between the two hemispheres, tucked in a groove where the two rounded thalamic bodies join. It lies outside the blood-brain barrier. The pineal gland is 5mm long, 1-4 mm thick, and weighs about 100g. It contains two major cells types: neuroglial cells and the predominant pinealocytes that produce

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melatonin.The pineal gland is a central structure in the circadian system that is innervated by a neural multi-synaptic pathway originating in the suprachiasmatic nucleus (SCN) located in the anterior hypothalamus. The pineal gland produces melatonin in a marked circadian fashion reflecting signals originating in the SCN. The retinohypothalamic tract carries information from the retina to the SCN, which generates the signal to the pineal gland to regulate melatonin production accordingly2, 3. MELATONIN BIOSYNTHESIS Melatonin is synthesized from a dietary amino acid precursor L-tryptophan, which is converted to serotonin (5-HT) by tryptophan hydroxylase. Serotonin is metabolized by the rate-limiting enzyme arylalkamine N-acetyltransferase (AANAT) to N-acetyl-serotonin (NAS), and in turn by hyroxyindole-O-methylytransferase to melatonin (Figure 1). The role of melatonin in regulating the circadian rhythm lies in the observation that the O-methylation of N-acetyl-serotonin is light dependent, and that light-dependent effects are mediated by sympathetic input arising in the superior cervical ganglia. It has also been demonstrated that some nutritional factors such as the availability of tryptophan, folate, and vitamin B6 could also influence the production of melatonin.

Figure 1. Synthesis of melatonin in the pinealocyte

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LIGHT REGULATES MELATONIN SYNTHESIS The classical photoreceptor cells, i.e. the rods and cones, do not seem to be involved in light perception that modulates pineal melatonin production. Rather, there are specialized photoreceptive retinal ganglion cells containing melanopsin as a photopigment that respond to light. This information is transduced into a neural message which is transferred to the anterior hypothalamus via axons of retinal ganglion cells in the optic nerve; this is part of the so-called retino-hypothalamic tract. In the hypothalamus, the axons from the retina terminate in the suprachiasmatic nuclei (SCN), a type of nucleus whose neurons exhibit inherent circadian electrical rhythms; these nuclei constitute the biological clock or the central circadian pacemaker. Between the SCN and the pineal gland, the neural pathways, at least centrally, are somewhat less defined but are believed to be as follows: SCN, paraventricular nuclei, intermediolateral cell columns of the upper thoracic cord (preganglionic sympathetic neurons), superior cervical ganglia (postganglionic sympathetic neurons), and pineal gland. This circuitous pathway conveys information about the light: dark environment to the pineal gland and thereby determines the melatonin synthesis cycle4. The primary neurotransmitter released from the postganglionic sympathetic terminals that terminate in the pineal gland is norepinephrine (NE); during darkness at night, NE is discharged onto the pinealocytes, the endocrine cells of the gland, where it couples especially to beta-adrenergic receptors. This leads to a marked rise in intracellular cAMP levels, to de novo protein synthesis and eventually to the stimulation of the rate-limiting enzyme in melatonin production, AANAT (figure 2). The dramatic rise in AANAT drives melatonin synthesis and, consequently, the melatonin content of the pineal increases substantially at night. The most striking feature about the melatonin-generating system is its daily variation and sensitivity to light, which suppresses AANAT activity. Melatonin secretion is stimulated by darkness which is independent of sleep, and is inhibited by exposure to natural light. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles. Light at night prevents the SCN from signalling the pineal gland to activate the molecular machinery to produce melatonin. For example, while the light: dark cycle at the equinoxes is 12:12 (in hours), the actual duration of darkness humans witness is usually significantly less. As a result, the use of artificial light (sometimes referred to as the misuse of light) truncates the period of melatonin synthesis to an interval shorter than it would normally be, thereby limiting the total amount of melatonin produced. In this case, light acts a ‘drug’ to reduce melatonin levels. Light exposure has two basic functions on the melatonin synthesis cycle: acute light exposure at night (even of very short durations) inhibits melatonin production while alternating periods of light (and darkness) serve to synchronize the

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melatonin rhythm to 24 hours. When these regularly alternating periods of light: dark are disturbed, so too is the rhythm of the biological clock, i.e. the SCN, and the melatonin synthesis cycle5. The degree of inhibition of melatonin synthesis by mistimed light depends on its wavelength, intensity and the circadian phase at which the exposure occurs. It is principally blue light, around 460 to 480nm that suppresses melatonin, increasingly with increased light intensity and length of exposure.

Figure 2. Neural pathway involved in stimulating melatonin synthesis Endogenous melatonin starts to rise in dim light, the so called dim light melatonin onset (DLMO), normally between 19:30 and 21:30. This DLMO is characteristic for each individual’s circadian rhythm. Maximum plasma levels occur around 03:00–04:00, and declines over the rest of the night (Figure 3, 4).

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Figure 3. Circadian peaks of melatonin secretion

Figure 4. Differences in plasma concentrations of melatonin in the young and elderly and males and females

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Maternal melatonin which crosses the placenta is one of the maternal rhythmic signals capable of synchronizing the foetal biological clock. The pronounced daily melatonin rhythm in the milk could take over in the new-born. After maturation, rhythmic melatonin production reaches the highest levels at the age of 3–6 years. Then the nocturnal peak drops progressively by 80% until adult levels are reached. This alteration is temporally linked with the appearance of sexual maturity and is not simply the consequence of both increasing body size and constant melatonin production due to lack of pineal growth during childhood. With aging, the melatonin rhythm progressively dampens, and can be completely abolished in advanced age (Figure 5). This is probably related to calcification of the pineal gland6. The age related decline in melatonin formed the rationale for treatment of elderly insomniacs with this hormone.

Figure 5. Age related changes in melatonin production

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MELATONIN CATABOLISM The pineal gland does not store melatonin, after synthesis it diffuses out of the pinealocyte into the rich capillary bed within the gland and directly into the cerebrospinal fluid. Therefore plasma levels correlate well with pineal gland activity. More than 90% of circulating melatonin is deactivated by the liver. Melatonin is first hyroxylated at the 6-position by hepatic cytochrome p450 system. 6-hydroxymelatonin is then conjugated with sulphate and to a lesser extent glucoronic acid, and the conjugates are excreted in the urine. Urinary melatonin closely reflects plasma melatonin levels and is frequently used in evaluation of melatonin rhythm. In addition to hepatic metabolism, oxidative pyrrole-ring cleavage appears to be the major metabolic pathway in other tissues, including the CNS. Metabolism of exogenously administered melatonin is rapid, the half-life ranging between 10 and 60min. MELATONIN RECEPTORS Melatonin has a variety of means by which it influences the physiology of the organism; some of these actions are receptor-mediated while others are receptor-independent. 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. Two mammalian receptors have been identified, MT1 and MT2. They are G-protein coupled receptors, and their activation modulates a wide range of intracellular messengers (e.g. cAMP, cGMP, or calcium concentrations). Those mammalian tissues in which melatonin receptors are most consistently found include the SCN and the pars tuberalis of the adenohypophysis but, in reality, as data continue to accumulate, it seems that few tissues are devoid of membrane receptors, for melatonin4. Given melatonin’s high lipophilicity and the ease with which it enters cells, investigations into potential intracellular binding sites have also been initiated. MT1 and MT2 receptors have been identified in nervous system structures involved in nociceptive transmission. Autoradiographic studies indicate that melatonin receptors are expressed in the thalamus, hypothalamus, anterior pituitary, the dorsal horn of the spinal cord, spinal trigeminal tract and trigeminal nucleus. Specifically melatonin receptors are distributed in lamina I-V and X of the spinal cord which are crucial regions in pain control. These anatomical locations support the role of melatonin in nociceptive transmission.

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Table 1. Uses of Melatonin

Regulation of:

Circadian rhythms

Neuroendocrine functions

Reproductive functions

Sedative, analgesic effects

Anti-inflammatory

Anti-oxidant

Vasomotor control

Anti-oncotic

Prevention of apoptosis

Reduction of intra-ocular pressure

Treatment of:

Jetlag

Insomnia

Alzheimer’s disease

Epilepsy

Sepsis

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Figure 6. Pleiotropic effects of melatonin

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MELATONIN AND ANAESTHESIA 1. Anxiolytic and Analgesic effects of Melatonin premedication The commonly used analgesic and sedative drugs have drawbacks and limitations, such as respiratory depression, disorientation, excessive sedation, or excitation. Also, a premedicant that reduces analgesic requirements would be of value. Benzodiazepines are commonly used to alleviate perioperative anxiety but may impair psychomotor skills and negatively affect sleep. Recently accumulated experimental evidence supports an important role of melatonin in anxiolysis and analgesia. Pre-medication with melatonin, 0.05, 0.1, or 0.2 mg/kg sublingually or orally has been shown to:1) be an effective anxiolytic, 2)reduce intra-operative and post-operative opioid requirements,3) improve quality of recovery without affecting psychomotor skills,4) and improve postoperative sleep quality. Oral administration of 1- 5mg of melatonin results in plasma levels of 10-100 times more than the observed endogenous night-time levels. In a study by Ismail et al9, melatonin was compared to placebo in patients undergoing cataract surgery under topical anaesthesia. 40 ASA physical status I–III adult patients older than 60 years were included in the study. Patients were randomly allocated into two groups (20 patients each) to receive either melatonin 10 mg tablet (melatonin group) or a placebo tablet (control group) orally 90 min before surgery. On arrival in the operating room (OR), anxiety was assessed using the Verbal Anxiety Score (VAS). An ophthalmologist who was blinded to the group allocation applied the topical anaesthesia, and measured intra-ocular pressure (IOP) in the non-operated eye. IOP was recorded before premedication and on arrival to the OR and at the end of surgery. Pain was assessed, using the Verbal Pain Score (VPS), at 10-min intervals during surgery and if the patient complained of pain. The maximal pain score during the interval was recorded at 10, 20, 30 min after the start of surgery, at the end of surgery, and postoperatively before discharge from the recovery room. Supplemental 0.5ug/kg IV fentanyl was given if VPS >4 and was repeated after 5 min if necessary. The total intraoperative fentanyl consumption was recorded. Results: Anxiety scores decreased significantly after premedication in the melatonin group (P< 0.05). There were significant differences between the two groups in anxiety scores after premedication (P=0.04) and intraoperatively (P= 0.005). Pain scores were significantly lower in the melatonin group than in the control group. Fifteen patients in the control group and seven patients in the melatonin group needed fentanyl boluses (P= 0.025) resulting in a lower fentanyl requirement (median, interquartile range) during surgery in the melatonin group compared with the control group, 0, 0–32.5 vs 47.5, 30–65 ug, respectively, P= 0.007.There was no significant difference in the baseline IOP between both

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groups, however, after premedication IOP decreased significantly in the melatonin group and this reduction was maintained to end of surgery (P< 0.001). The main findings in this study was that melatonin premedication provided anxiolytic effects, improved perioperative analgesia and decreased IOP with better operating conditions during cataract surgery under topical anaesthesia. Caumo et al10 investigated the postoperative outcomes of patients undergoing total abdominal hysterectomy that were given melatonin preoperatively. In their study, 35 patients, ASA classification I–II, aged 30–55 years were enrolled into the randomized, double-blind, placebo-controlled study. Patients were allocated to receive either 5 mg oral melatonin or placebo the night before (10 pm) and 1 hour before surgery. The primary outcomes were postoperative pain, as assessed by pain scores and analgesic consumption. Secondary outcomes were rest-activity cycles and anxiety. A visual analogue scale (VAS) was used to assess pain, sleepiness, nausea, and vomiting. 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. To measure anxiety, the State-Trait Anxiety Inventory (STAI) was used. The rest–activity cycle was assessed by actigraphy, which measures activity and ambient light exposure. 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). In theatre, ropivacaine was administered epidurally and propofol was administered to maintain conscious sedation during the surgery. Postoperative pain control was via morphine PCA for 72 hours. The analgesic consumption was measured by recording the amount of morphine used via PCA and adjusted by patient weight. The results showed that there was an effect on anxiolysis in the treatment group (P= 0.018). In the intervention group, the NNT to prevent one additional patient from reporting high state postoperative anxiety in the immediate 24 hours postoperative period was 2.53 (95% CI, 1.41–12.22). There was an effect in the treatment group on postoperative pain over time (P<0.001) and as reported by the VAS (P=0.04). 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). 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 hours 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

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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-infnty) in the absence of pain or mild pain. Analysis of morphine consumption showed an effect on the treatment group (P=0.02) and there was a significant reduction in morphine consumption across time, independent of the treatment group (P=0.001). Morphine consumption was not affected by the interaction between time and treatment (P=0.21). The melatonin group showed a better recovery on the rhythmicity percentual in the first week after discharge (P=0.02]). The findings of this study showed that 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. They also demonstrated by NNT, that melatonin had a significant clinical effect on pain and anxiety during the first 24 hours after surgery. The benefit observed in this study was 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%). 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. Furthermore, this study has shown that the administration of melatonin before surgery may accelerate the resynchronization of circadian rhythms in the postoperative period, suggesting better quality of recovery. Caumo et al11, also investigated the preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy.63 patients, ASA classification I to II, ages 19 to 60 years, were enrolled into the randomized, double-blind, placebo-controlled study. The treatment allocation method used was advanced simple randomization without blocking or stratification. Before the recruitment phase of the study, the envelopes containing all protocol materials were prepared and numbered sequentially, which were grouped so that each envelope had an independent 50% probability of being included in either group. A sheet indicating the allocated treatment was then placed in the envelope and the envelopes were sealed. A random number was used to assign each consecutively numbered envelope to receive 5 mg oral melatonin, oral clonidine 100 g, or placebo the night before (10 PM) and 1 hour before surgery. Thirty-six hours after the surgery, the melatonin and the placebo groups received placebo, whereas the clonidine group received oral clonidine (100 g). Throughout the course of the study, the sealed envelopes were removed and opened sequentially by a pharmacy technician who delivered the tablets of melatonin (5 mg), clonidine (100 g), or placebo only after prospective patients had been screened and had consented to participation. During the entire protocol timeline, blinding, and

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randomization were undertaken by 2 investigators who were not involved in the patient’s evaluation. The primary outcomes were postoperative pain, as assessed by pain scores using VAS and analgesic consumption(morphine consumption from PCA). The secondary outcomes were postoperative state-anxiety assessed by the State-Trait Anxiety Inventory (STAI). The anxiety was recorded at 6, 24, 48, and 72 hours after surgery and the pain at 6, 12, 18, 24, 48, and 72 hours postoperatively. In theatre, ropivacaine was given epidurally, and propofol used for conscious sedation. Post op pain relief was via morphine PCA for 72hours and consumption was reordered. Results: There was an effect in the treatment groups on postoperative anxiolysis (P=0.03). The anxiety levels, assessed on the STAI, showed a significant decrease in the melatonin and clonidine group from 6, 24, and 48 hours. There was an effect in the treatment groups on postoperative pain over time (P=0.00) and as reported by the VAS (P=0.00). A statistically significant difference was observed between the treatment groups (melatonin and clonidine) and placebo groups on the levels of postoperative pain, measured by VAS during the first 48 hours after surgery. In the subgroup with high state anxiety 6 hours after surgery, the incidence of postoperative moderate to intense pain was 33.2% and 40% in the melatonin and clonidine groups, respectively, compared with 92.3% in the placebo group. In these patients with higher anxiety, the NNT to prevent moderate to intense pain during the first 24 hours postoperatively was 1.52 (95% CI, 1.14 to 6.02) and 1.64 (95% CI, 1.29 to 5.93) in the melatonin and clonidine groups, respectively, compared with the placebo. Analysis of morphine consumption showed an effect in the treatment group (P=0.00), and there was a significant reduction in morphine consumption over time, independent of the treatment group (P=0.00). Patients treated with melatonin and clonidine preoperatively presented a greater reduction in pain and required lower morphine consumption in the postoperative period. The benefits of these interventions were statistically and clinically significant to produce postoperative anxiolysis, which led to lower postoperative pain, as well as lower morphine consumption throughout the first 24 hours after surgery. This study concluded that the preoperative anxiolysis with melatonin or clonidine reduced postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy. The effects these 2 drugs were equivalent and greater than with placebo. Ionescu et al12 did a study to compare the effects of melatonin and midazolam used as premedication on sedation and anxiety scores, the quality of preoperative sleep, and amnesia after recovery from anaesthesia for laparoscopic cholecystectomy. 53 patients (ASA I, II) aged 25 to 73 years, who were about to undergo laparoscopic cholecystectomy, were included in the study. The evening before the operation, the patients were randomly allocated into three study groups: group 1 (n = 18) received 3 mg melatonin, group 2 (n = 17) received 3.75

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mg midazolam and group 3 (n = 18) received placebo tablets. The trial drugs and placebo were prepared in a volume of 3 ml. To maintain the double-blind nature of the study, the syringes were unmarked. The content of the syringe was given sublingually the night before surgery and 90 minutes before operation. Anxiety was evaluated by using STAI-S. Anxiety scores, the quality of preoperative sleep and sedation scores were evaluated before the operation, at patient arrival in the operating theatre and at 15 and 60 minutes and 6 and 24 hours postoperatively. In addition, in order to evaluate preoperative amnesia, the patients were asked to recall as many as possible of five pictures shown to them before premedication. The number of remembered pictures was recorded as a score and the mean score was calculated at every time interval. The severity of postoperative pain was also recorded as a VAS score. Results: There was no significant difference between preoperative anxiety scores in the melatonin and midazolam groups. Intra-operatively there were no significant differences in fentanyl requirements between the melatonin and midazolam groups while there were significant differences when compared with the placebo group. Postoperatively, the anxiety scores in the melatonin group at every time interval were significantly lower than those in the placebo group. Compared with midazolam, anxiety scores were also lower in the melatonin group. The number of remembered pictures was higher in the melatonin group than in the midazolam group at every time interval; the greatest differences were recorded at 15 min after the operation and at 24 hours. Melatonin has no amnesic effects, although this effect is desirable in some situations to render patients amnesic to certain perioperative experiences, amnesia is considered undesirable in some categories of patients; such are day-case patients, where instructions for the postoperative period, or at discharge, must be remembered. They conclude that 3 mg melatonin might be an adequate dose for premedication for laparoscopic cholecystectomy. At this dose, melatonin produces anxiolysis with minimal sedation, and a hastened recovery with no amnesic effects. This premedication may be a good choice for ambulatory surgery patients and in those situations where the impairment of cognitive functions and amnesia would be detrimental to the patients. Mowafi et al23, studied 40 ASA physical status I–II patients scheduled for hand surgery under Bier’s block in a double-blind study. Patients were randomly allocated into two equal groups (20 patients each) to receive melatonin 10 mg or placebo (control group), orally 90min before surgery. On arrival in the operating room, anxiety level was assessed using the VAS. When an adequate surgical block was achieved, the operative tourniquet (i.e., distal cuff) was inflated to 250 mm Hg and then the proximal cuff was released. Assessments of tourniquet-related pain were performed using verbal pain score (VPS) immediately after tourniquet inflation, at 10, 20, 30, 40, and 50 min thereafter. When the tourniquet pain score was reported to be >4, the patient was given IV 0.5 ug/kg bolus of fentanyl, which was repeated after 5 min if pain was not improved. The total

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intraoperative fentanyl consumption was calculated. Patients were given diclofenac, 75 mg IM. PRN every 8 h when the VAS >4 and the total diclofenac dosage at 24 h was recorded. All the evaluations were performed by a blinded observer. Results: Anxiety scores were similar in both groups (median, Interquartile range 5, 3.5–6 and 5, 4–6 in the control and melatonin groups respectively). These were reduced after administration of melatonin (P=0.023). VPS scores for tourniquet pain were significantly less in the melatonin group at 30, 40, and 50 min after tourniquet inflation. These lower pain scores were also reflected in the smaller supplemental fentanyl requirements during surgery in the melatonin group (P=0.002). The time to first postoperative analgesic request was prolonged in the melatonin group when compared with the control group (P= 0.001). Postoperative diclofenac consumption was significantly reduced in the melatonin group (P=0.007). The main findings in this study were that melatonin premedication reduced anxiety, decreased tourniquet related pain, and enhanced intraoperative and postoperative analgesia without producing clinically significant side effects. In contrast to the above studies, a study done by Capuzzo et al13 failed to show a significant reduction in anxiety levels in elderly patients undergoing surgery. The study was prospective, double-blinded, and randomized. Patients aged > 65 years, ASA physical status I–III, consecutively undergoing elective surgery were enrolled. Considering the anxiety scores of van Vlymen et al, to detect a 30% difference between 2 groups with α=0.05 and power= 0.80, the required sample size for each group would be 66 patients. In this 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. Anxiety and depression were assessed before any drug administration (T-basal) and 90min after administration of study drug (T-pre). 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 anaesthesia 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. The level of depression and pain was measured by a numerical rating scale (range, 0–10). Results: The analysis was performed in 71 patients in group P and 67 in group M, 52 and 51 receiving general anaesthesia, respectively. 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

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satisfaction with anaesthesia at T-follow-up was 100 (range, 76–100) in group P and 99 (range, 80–100) in group M. This study showed that melatonin, compared with placebo, did not reduce anxiety and depression in elderly patients undergoing surgery. The difference between their results and those reported by others could be explained by differences in populations (age, gender, and types of surgery) or methodologies First, the mean age of patients in other studies was 29.7, 27.9, and 38.7 years, whereas their patients were older than 65 years. Exogenous melatonin has been reported to reduce sleep onset latency, but not to improve sleep in subjects aged >65 years. Melatonin has shown anxiolytic effects in young adults and children but not in the elderly. Second, other investigators studied only females. Males were approximately half of their patients in both groups, and no different effect was recorded in males and females. Concerning methodology, they administered melatonin 10 mg by mouth, whereas it was given sublingually and in different doses by others. The level of preoperative anxiety at 90 min was also decreased by 33% and 21% in their M and P groups, respectively, whereas it was surprisingly increased in group P and decreased in group M in other studies. . This may be due to the elderly being resistant to the hypnotic and anxiolytic effects of melatonin. The reduction in anxiety in their group P appears to be the key finding to explain the negative results of their study; the “placebo effect” is well known. Possibly, this antinociceptive effect of melatonin involves the activation of supraspinal sites and the inhibition of “spinal windup”. This effect may be mediated by membrane receptors linked to G proteins, and possibly through nuclear receptors. Also, experimental evidence suggests that its analgesic effect is mediated by the opioid system, because it augments gamma-amino butyric acid (GABA)-ergic systems and morphine antinociception, enhancing GABA -induced currents and inhibiting glycine effects. Moreover, it produces marked anti-inflammatory effects on peripheral sites by inhibiting the release of proinflammatory cytokines and the rolling and adhesion of neutrophils to the endothelial layer. This effect on cell defence occurs even in concentrations compatible with nocturnal secretion11.Other mechanisms might be mediated via an interaction with the adrenergic (α2-adrenoceptors), dopaminergic (D2-receptors), serotonergic (5-HT2a receptors), and opioid systems, in addition to the l-arginine-nitric oxide pathway. All these sites could be reached considering the high lipid-solubility of melatonin. 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.

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Table 2. Summary of the included trials

Table 3. Anxiety scores in the Melatonin vs. Placebo groups in the perioperative period.

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Table 4. Effect of melatonin on anxiety

2. Melatonin and Paediatric anaesthesia

The incidence of anxiety in children has been reported to be about 65%, especially in the holding area and during induction of anaesthesia. Midazolam is widely used as premedication in the paediatric population. Similar studies done in adults comparing it to melatonin were done in children. In a randomized, double blinded, placebo controlled study by Samarkandi et al, the use of melatonin versus midazolam as a premedicant in children was studied involving seven groups of 15 children who received one of the following premedicants: midazolam (0.1, 0.25, or 0.5mg/kg), melatonin (0.1, 0.25, or 0.5mg/kg), or placebo. They found that premedication with melatonin or midazolam was equally effective in alleviating anxiety although the use of melatonin was associated with a lower incidence of excitement at 10 min postoperatively, and a lower incidence of sleep disturbance at week 2 postoperatively than that observed with midazolam25. In another study Zeev et al looked at preoperative melatonin and its effects on induction and emergence in children. They reported that melatonin was more effective in reducing post operative emergence delirium than midazolam. But they also found that midazolam (0.5mg/kg) was more effective than melatonin (0.05–0.4mg/kg) in reducing anxiety in children26.

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3. Effects of melatonin on induction of anaesthesia The effects of melatonin on anxiety and analgesia have been discussed, but what about the effect on the induction of anaesthesia? Naguib et al14 studied the effects of melatonin premedication on propofol and thiopental induction dose–response curves in a prospective, randomized, double-blind study. 200 ASA 1 patients were randomly assigned to four groups (n=50 patients per group) based on whether they would receive 0.2 mg/kg melatonin premedication or placebo (saline) and the type of induction drug used (propofol or thiopental). The pre-med was given sublingually approximately 50 min before the induction of general anaesthesia. A visual analogue scale (VAS) was used to evaluate the patients’ anxiety. In the operating room, the following predetermined doses of drugs were administered to subgroups of 10 patients each: propofol at 0.5, 1.0, 1.5, 2.0, or 2.4 mg/kg; or thiopental at 2.0, 3.0, 4.0, 5.0, or 6.0 mg/kg. The disappearance of the patients’ ability to respond to commands, and the disappearance of the eyelash reflex were assessed 60 seconds after the end of the injection of propofol or thiopental. These outcomes were used as end points for induction of anaesthesia. Their results showed that melatonin premedication significantly enhanced the effects of both propofol and thiopental, resulting in significantly lower ED-50 and ED-90 values. At the ED-50 values reflecting loss of responses to verbal commands and eyelash reflex, the relative potency of propofol after melatonin premedication was 1.7–1.8 times greater than that of propofol after the administration of placebo. Similarly, the relative potency of thiopental was 1.3–1.4 times greater after premedication with melatonin than that of thiopental after placebo (Table 5). Table 5. Naguib et al, ED50 and ED90 Values and 95% Confidence Limits for Propofol and Thiopental.

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In contrast to the above study, Evagelidis et al15 found that melatonin premedication did not enhance the induction of anaesthesia with sevoflurane as assessed by Bispectral index monitoring (BIS). 71 patients scheduled for a hysteroscopy on a day case basis, were enrolled. Patients were randomly assigned to receive melatonin 9mg sublingually (n = 37) or placebo (n = 34) 30minutes before the inhalation induction of anaesthesia. BIS values were recorded every 30 seconds for the first 300 seconds. The results showed that the BIS values did not differ between the two groups at any time during the recording period (P=0.725). Inspired and expired sevoflurane concentrations, heart rate and SpO2 also did not differ at any time point during the first 300 seconds of anaesthesia. The varied results of studies assessing the effect of melatonin on preoperative anxiety may be due to differences in age, gender, dosage or route of administration. Patients might benefit from melatonin premedication as melatonin has no effect on respiration and is not expected to interfere with spontaneous breathing and volatile anaesthetic uptake. 4. Effect of surgery and Anaesthesia on the Circadian Rhythm

Anaesthesia and surgery reportedly alter the normal circadian pattern of melatonin production, but evidence of this in the literature is inconsistent and conflicting. . In a study by Karkela et al16, 20 patients undergoing minor knee procedures were randomly assigned to receive either general or spinal anaesthesia. Melatonin secretion was measured in urine and saliva samples taken from the day before and after surgery. Sleep quality on the night before and after surgery was evaluated using a VAS. They showed that sleep quality was worse the on the night of surgery and that the level of postoperative nocturnal melatonin secretion was significantly lower than that of the preoperative evening (P<0.01 at 23:00, P<0.001 at 24:00 and P<0.001 at 08:00). The differences between the general and spinal anaesthesia groups were not significant. In an earlier study by Nishimura et al, they concluded that melatonin rhythmicity varied individually after surgery, and were unable to demonstrate a significant change in melatonin secretion. There are lots of variables that would need to be taken into consideration before it becomes clear that there is a disruption of melatonin homeostasis. Factors such as age, general versus regional anaesthesia, type and duration of surgery, time of surgery, emergency versus elective, drug interactions and effects on melatonin production, lighting conditions, premedication, pain control, sampling type: saliva, urine or plasma, and time of sampling all need to be considered Further studies are thus needed to better understand the short and long term effects of surgery on melatonin circadian rhythm.

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MELATONIN AND SLEEP IN ICU Melatonin’s role in regulating the sleep/wake cycle is all well and good for the healthy, what about the patients in ICU? Recently at some of the FMM there has been much talk surrounding the use of sedatives in the ICU, but is sedation the same as sleep? Sleep and sedation share similar neurobiological and phenotypical properties, including a reversible decrease in vigilance, a reduced metabolic rate, and muscle hypotonia. However, they are different in many characteristics: in contrast to sedation, sleep is a spontaneous behaviour that can be reversed by external stimuli. Sleep is organized in cycles of different depths, starts and stops in response to endogenous mechanisms, and is regulated by complex homeostatic and circadian factors. The biological need for sleep and the therapeutic need for sedation almost universally coexist in the critically ill patients17. Is sleep that important? The consequences of inadequate sleep are catabolism induction and impaired cellular and humeral immunity which may lead to delayed wound healing. Sleep disruption can cause respiratory muscle failure due to muscle fatigue and a decreased response to hypercapnia, which leads to prolonged ventilator support. They could also worsen comorbidities or be the result of underlying disease. They also have a role in the alteration of catecholamines and hormone secretion, alterations in nitrogen balance, and in determining insulin resistance18. More recently sleep disruptions are increasingly being recognized as a cause of post-traumatic stress disorder after discharge from ICU. Types of sleep disturbances include long sleep-onset, sleep fragmentation poor sleep efficiency, frequent arousals, a predominance of stage 1 and 2 NREM sleep, and decreased or absent REM sleep19. The causes of sleep disturbances in the ICU are multifactorial (Table 6.). Environmental factors such as excessive noise and lighting, the patient’s acute illness itself, pain, patient care activities including nocturnal check-ups, daytime sleep, and mechanical ventilation negatively impact on the quality of sleep in the ICU. Noise is often regarded as the most disruptive. The sleep of mechanically ventilated patients may be worsened by dysynchronous breathing, the ventilation setting, discomfort from the endotracheal tube, and stress related to the difficulty in communicating.

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Table 6. Factors involved in sleep disruption ICU environment: Noise Continuous nursing care Continuous light exposure Loss of physical activity Severity of illness Factors interfering with melatonin transmission: Sepsis Light exposure Mechanical ventilation Drugs: benzodiazepines, adrenergic agonists, beta blockers ,opioids, sodium valproate Mechanical ventilation Sedation Not only is sleep disturbed, but also the circadian rhythm and the release of melatonin. Several studies found melatonin levels in critically ill patients to be severely depressed, either in terms of nocturnal peaks or basal daytime serum levels. In a study by Frisk et al20 showed that mechanically ventilated patients have a decreased basal melatonin secretion and higher cortisol levels. Circadian rhythm disturbances can be demonstrated indirectly by the oscillations in core body temperature, or directly by melatonin and melatonin metabolite assays. Factors affecting the circadian rhythms and melatonin Melatonin’s influence on sleep processes has been widely investigated and the relationships seem to be highly complex. There is a common misconception that pineal melatonin synthesis at night requires sleep; this is not the case. The only requirement for increased melatonin production is darkness at night. Conversely, the night-time rises in circulating levels of melatonin seem to promote sleep onset and maintain restful sleep in some individuals. The most commonly proposed mechanisms for melatonin to induce sleepiness relate to its effects on the circadian clock, i.e. it ‘opens the sleep gate’ and also it slightly reduces body temperature which promotes sleep20. Melatonin has these effects over a wide range of doses from physiological (250 ug) to pharmacological (1–10 mg) levels. Nocturnal secretion of melatonin synchronises the sleep/wake cycles, and disruption of this homeostasis is associated with reduced sleep. Melatonin secretion is influenced by age, mechanical ventilation, light exposure, sepsis, and drugs such as benzodiazepines, corticosteroids, clonidine, or beta blockers that decrease melatonin secretion or opiates and adrenergic compounds which stimulate melatonin secretion. Melatonin acts by promoting sleep without inducing significant sedation, it could also be useful in patients in whom sedation and

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reduced respiratory effort is undesirable. Unlike benzodiazepines, melatonin maintains the normal sleep architecture21. Few studies have been done to examine the influence of melatonin in improving sleep quality in the critically ill patients. Bourne et al22 conducted a randomized double blinded placebo controlled trial on the use of melatonin to improve sleep in critically ill patients. 24 Patients were randomly assigned to receive either melatonin10mg or placebo. Their findings showed that nocturnal sleep time was 2.5 hours in the placebo group (mean sleep efficiency index=0.26, 95% CI 0.17 to 0.36) and was 1 hour longer in the melatonin group (sleep efficiency index=0.12, 95% CI -0.02 to 0.27; P=0.09) which did not reach statistical significance. In another double-blind, randomized, placebo-controlled pilot study by Ibrahim et al23, thirty-two ICU patients with tracheostomies were administered either oral melatonin (3mg) or placebo. Primary outcome measure was number of hours of observed sleep at night, assessed by the bedside nurse. Their results showed that observed nocturnal sleep was similar in the two groups: 240 minutes (range, 75-331.3) for melatonin v 243.4 minutes (range, 0-344.1) for placebo (P=0.98). Observed diurnal sleep was also similar: 138.7 minutes (range, 50-230) with melatonin v 104 minutes (range, 0-485) for placebo (P=0.42).Melatonin therefore failed to increase observed nocturnal sleep. Evidence shows that melatonin secretion in the critically ill is reduced which may lead to sleep disruptions and impairment of the circadian rhythms, the use of exogenous melatonin requires further investigation to prove any sort of physiological benefit. Melatonin and Sepsis During sepsis, a pathogen-induced sequence of intracellular events occurring in the immune cells, epithelium, endothelium, and neuro-endocrine system leads to the development septic shock. These effects are associated with the production and release of numerous proinflammatory biochemical mediators like cytokines, nitric oxide (NO), radical oxygen species (ROS), together with the development of massive apoptosis. Melatonin has been shown to be effective in reversing the symptoms of septic shock due to its significant antiapoptotic and anti-inflammatory properties, and by suppressing inducible NO synthase (iNOS) gene expression27. Several studies employed the use of rats in determining the effects of melatonin on sepsis. Sewerynek et al28, reported a reduction in lipopolysacharide (LPS)-induced oxidative insult after melatonin administration, as evidenced by decreased hepatic malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA). Melatonin prevents lipopolysacharide-induced endotoxaemia presumably through decreasing TNF-α levels, superoxide production, and iNOS in the in the liver. In septic shock, the activation of mitochondrial NOS could be a crucial trigger for the chain of event s seen. The mitochondria express constitutive and inducible forms of NOS, the latter causing mitochondrial respiratory inhibition and failure.

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Melatonin administration (60 mg/kg, Intra-peritoneally) effectively counteracted LPS-induced inhibition of complexes I and IV of the electron transport chain and decreased mitochondrial NOS activity and NO production, thereby preventing LPS toxicity . The survival rate of LPS-injected mice improved from 0% in controls to 48% and 86% after melatonin administration (2 mg/kg) 3 and 6h later, respectively 29. In another study by Carillo-Vico et al melatonin’s role as an antiapoptotic was attributed to stimulatory effects on the anti-inflammatory cytokine interleukine (IL)-1030. In sepsis induced ileus, melatonin was shown to reduce the gastric motility dysfunction in mice treated with LPS31. Melatonin also normalized the altered lipid peroxidation, p38 mitogen-activated protein kinase activation, nuclear factor–κB activation, iNOS transcription and expression, and nitrite production in intestinal tissue from septic mice31.In another study, by Shang et al32, melatonin was show to offer lung protection in LPS-induced pulmonary inflammation. Melatonin decreased pulmonary oedema, the elevated lung myeloperoxidase (MPO) activity, and lipid peroxidation after LPS. Melatonin prevented the increase of TNF-α, and increased IL-10 levels. From these experimental data, melatonin seems to exert its effect at the earliest step in the activation of the oxidative and proinflammatory cascade in preventing systemic inflammation. Melatonin modifies the inflammatory process and therefore has the potential to be a new class of anti-inflammatory agents with specificity for cyclooxygenase-2 and iNOS enzymes. Melatonin treatment also reduced myeloperoxidase activity and MDA levels. In human studies on septic patients, it was found that disruption of the circadian rhythm of melatonin secretion negatively affects the sleep/wake cycle and outcomes. Mundigler et al studied 17 septic ICU patients, 7 non-septic ICU patients, and 21 controls. 6-Sulfatoxymelatonin was determined in urine samples taken at 4-hour intervals over a total period of 24 hours. Urinary 6-sulfatoxymelatonin exhibited significant circadian periodicity in only 1 of 17 septic patients’ vs 6 of 7 in non-septic patients and 18 of 23 in normal controls. The phase amplitude (an index of the maximal levels attained at peak concentrations) was significantly lower in septic patients. In sepsis survivors, 6- sulfatoxymelatonin excretion profiles tended to normalize, but still lacked a significant circadian rhythm at ICU discharge33. More extensive work has been done on septic neonates. In two studies done by Gitto et al34, have shown that melatonin reduces oxidative stress in newborns with sepsis, distress or other conditions where there is excessive ROS production. In one study, the MDA and the nitrite/nitrate levels were measured in 20 asphyxiated newborns before and after treatment with melatonin given within the first 6 hours of life. Ten asphyxiated newborns received a total of 80 mg of melatonin (8 doses of 10 mg each separated by 2-hour intervals) orally. One blood sample was collected before melatonin administration, and 2 additional blood samples (at 12 and 24 hours) were collected after giving melatonin. Serum MDA and nitrite/nitrate concentrations in newborns with

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asphyxia before treatment were significantly higher than those in infants without asphyxia. In the asphyxiated newborns given melatonin, there were significant reductions in MDA and nitrite/nitrate levels. Three of the 10 asphyxiated children not given melatonin died within 72 hours after birth; none of the 10 asphyxiated newborns given melatonin died. In the other study, 10 septic newborns were given 2 doses of 10mg melatonin 1 hour apart, within the first 12 hours of being diagnosed with sepsis. The clinical status and the serum levels of MDA and 4-HAD were recorded. Ten other septic newborns in a comparable state were used as “septic” controls, whereas 10 healthy newborns served as normal controls. Serum MDA + 4-HDA concentrations in newborns with sepsis were significantly higher than those in healthy infants without sepsis, and they were significantly reduced by melatonin. Melatonin also improved the clinical outcome of the septic newborns as judged by measurement of sepsis-related serum parameters after 24 and 48 hours. OTHER USES OF MELATONIN 1. Sleep disorders

1.1 Jet Lag

Jet lag is a considerable problem in the modern world with widespread air travel. When the internal body clock (or circadian rhythm) is not synchronized with the external ‘local’ time (light-dark) cycle, jet lag is experienced. The symptoms, which may vary between individuals, include tiredness, inability to sleep at new bedtime, inability to concentrate, disturbed sleep for several days after a long flight, headache and gastrointestinal disturbances. Symptoms are, more marked in older travellers, when more time zones are crossed, and when travelling in an easterly direction2. Symptoms are usually transient and should resolve as the travellers circadian clock re-establishes a normal phase relationship with the local time. Westward travel generally causes less disruption than eastward travel, which can be explained by the fact that the free-running period of humans is slightly longer than 24hours, making it easier to delay rather than advance the circadian rhythms. A combination of approaches to accelerate circadian alignment, including timed light exposure and melatonin and/or behavioural strategies, has been used to improve sleep and day time function. Melatonin 0.5-5mg taken at bedtime for four days has been shown to alleviate the symptoms of jet lag. 1.2 Shift work sleep disorder

Sleep disturbances are common complaints among shift workers. The ability to cope with shift work varies from individual to individual and is influenced by multiple factors, such as age, domestic responsibility, and commute times, type of

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work schedule, diurnal preference and family responsibilities. Shift work disorder (SWD) typically presents with complaints of un-refreshing sleep excessive sleepiness and insomnia that vary depending on the work schedule. SWD results when individuals are required to work and sleep at times that are in opposition to the circadian propensity for sleep and alertness, leading to symptoms of insomnia and excessive sleepiness. Patients may complain of problems initiating and maintaining sleep as they are attempting to at a time of low circadian sleep propensity. Symptoms of insomnia and excessive sleepiness may persist for several days after the last night shift or on days off, even after sleep has been resorted to conventional times. In these individuals, the nocturnal light not only perturbs the circadian system, but additionally causes a transient melatonin deficiency, which is not compensated during later sleep phases for reasons of temporal position of the circadian clock7. Treatment for SWD involves attempting to re-align the circadian propensity for sleep and wakefulness with the work schedule (light and melatonin) and improving sleep and alertness (behavioural and pharmacological). 2. Cancer Decreased melatonin levels have been correlated with increased cancer risk, leading to suggestions of its potential as an antitumor or cancer preventative agent. The oncostatic effect of melatonin is especially pronounced in reproductive-hormone-dependent tumours (breast and ovary), possibly by antagonizing oestrogen-mediated mitogenesis7. In the case of experimental hepatomas and human breast cancer xenografts, melatonin acts on specific membrane receptors to limit the transport of linoleic acid (LA), a growth factor, into tumour cells, preventing tumour cell proliferation8. In oestrogen-receptor-positive human breast cancer cells, melatonin is thought to modulate oestrogen receptor expression and transactivation3. Physiological levels of melatonin normally restrain tumour growth. The age-associated reduction in melatonin production may be contributory to the increased frequency of cancer in the elderly. Interestingly, melatonin administration, when combined with standard chemotherapy often improves the quality of life. This probably relates to melatonin’s ability to reduce the toxicity of chemotherapeutic agents. The findings in humans are made more remarkable by the fact that melatonin was used as a cancer treatment only after all other therapies were found to be essentially ineffective. Besides inhibiting established tumours, melatonin may also decrease their initiation. As an antioxidant, melatonin has been found to be particularly effective in reducing free-radical-mediated damage to DNA. Damaged DNA, if it goes unrepaired, may mutate and initiate a tumour. As a significant portion of the cancer humans acquire is believed initially to involve DNA damage as a consequence of toxic oxygen and nitrogen by-products, antioxidants that protect

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DNA from such mutilation would be expected to reduce cancer incidence; the evidence is strong that melatonin protects DNA from such damage more effectively than other classic antioxidants.

3. Aging

Because melatonin levels decline with age in humans, as does the antioxidant status, it has been assumed that the hormone may play a part in the aging process. Experimental evidence has shown an increase in the life span of rodents treated with melatonin, but a number of shortcomings have been associated with this data. In any case, the aging of humans is far from thoroughly understood yet, and with the absence of experimental data, the conclusion of melatonin treatment cannot be drawn. 4. Immune Protection

Melatonin has been proven to have immune enhancing effects. In humans, daily oral melatonin administration increases natural killer (NK) cell activity. Additionally, melatonin reportedly regulates gene expression of several immunomodulatory cytokines including tumour necrosis factor-α (TNFα), transforming growth factor beta (TGFβ) and stem cell factor by peritoneal macrophages as well as the levels of interleukin-1β (IL-1β), interferon gamma (INFγ), TNFα and stem cell factor by splenocytes. 5. Melatonin as an Anti-Oxidant Slightly over a decade ago, melatonin was found to be a highly effective scavenger of free radicals and general antioxidant2. Melatonin directly neutralizes a number of toxic oxygen- and nitrogen-based reactants, including the hydroxyl radical (lOH), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen (lO2) and the peroxynitrite anion (ONOO-) or peroxynitrous acid (OHOOH). Furthermore, melatonin has indirect anti-oxidative actions, including stimulating the synthesis of another important intracellular anti-oxidant, i.e. glutathione (GSH), as well as promoting its enzymatic recycling in cells to ensure it remains primarily in its reduced form. Finally, melatonin preserves the functional integrity of other anti-oxidative enzymes, including the superoxide dismutase and catalase. Melatonin may also reduce free radical generation in mitochondria by improving oxidative phosphorylation, thereby lowering electron leakage, and increasing ATP generation. Neurodegenerative diseases are a group of chronic and progressive diseases that are characterized by selective and often symmetric loss of neurons in motor, sensory and cognitive systems. Clinically relevant examples of these disorders are Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s chorea and amyotrophic lateral sclerosis.

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Examples of situations in which melatonin has been found to lower induced oxidative damage include ischaemia/reperfusion injury (in the brain, heart, gut, liver, lung, urinary bladder), toxic drug exposure, bacterial toxin exposure, schistosomias, heavy metal toxicity, amyloid b (Ab) protein exposure (as a model of Alzheimer’s disease), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure (as a model of Parkinsonism), etc. The finding that melatonin reduces Ab damage to neurons prompted its use in Alzheimer’s patients where it improved the status of these individuals. Melatonin has also been successfully used as an adjuvant treatment in neonates with sepsis (a high free radical condition) and with transient ischaemia/reperfusion. Other conditions in humans where melatonin has been shown to be beneficial include the following: skin erythema due to exposure to ultraviolet radiation, iron and erythropoietin administration and tardive dyskinesia. Each of these is believed to involve, as part of the destructive processes, free radical damage to essential macromolecules. 6. Melatonin and Apoptosis Studies, by Yon JH et al, and Jevtovic-Todorovic et al have shown that exogenously administered melatonin protects against anaesthetic- induced apoptotic neurodegeneration in the developing rat brain, suggesting that melatonin serves a neuroprotective function. This protective effect is likely mediated via inhibition of the mitochondrial apoptotic cascade. Melatonin administration is associated with upregulation of the anti-apoptotic protein bcl-Xl,reduction in anaesthesia induced cytochrome c release into the cytoplasm, and decrease in anaesthesia induced activation of capase-3. These potential benefits have not yet been fully explored1. Availability of Melatonin Because melatonin occurs naturally in food, no one can patent it and gain sole rights to sell it the way a company can patent a synthetic drug it develops. Bananas and rice both contain melatonin, albeit in tiny amounts. You can buy melatonin in health food and drug stores, even in supermarkets -- at least for now. In the U.S. melatonin is currently classified as a dietary supplement and not subject to FDA approval. In Europe, melatonin is classified as a neurohormone and cannot be sold over the counter. Over-the-counter sales have been banned in Canada, England, and France. In South Africa, as in the United Kingdom, The Medicines Control Council, (MCC) have issued a directive prohibiting the sale of melatonin over the counter pending registration of the product. The MCC's stance is that there are unproven claims on melatonin and melatonin is a hormone. All hormones have to be registered by the MCC as medicines. Side effects of Melatonin

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Currently, melatonin and Ramelteon (an agonist for melatonin receptors) are approved by the US Food and Drug Administration (FDA) only for the treatment of insomnia characterized by difficulty with sleep onset. Despite the fact, it has been released for public use by the FDA and is available over the counter nationwide, information on the toxicology of melatonin seems to be insufficient. Attention should be paid to the possible side effects of melatonin (Table 7.), such as nightmares, hypotension, sleep disorders, and abdominal pain. Ramelteon may induce headache, dizziness, somnolence, and nausea. However, the vast majority of studies document the very low toxicity of melatonin and its derivatives over a wide range of doses. Table 7. Side Effects of Melatonin

Headaches Dizziness Somnolence Nausea Hypotension Nightmares Sleep disorders Abdominal pain

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CONCLUSION Although melatonin was discovered more than 40 years ago, research into its physiological role in maintaining or improving homeostasis via its interaction with just about every system in the body, it may yet prove to be the universal endogenous synchronizer. In comparison with other signalling molecules, the numerous actions that have been attributed to melatonin are exceptional. This should be taken as an expression of its overall importance as a modulator at various levels of hierarchy. Data presented above proves that melatonin has a role in anaesthesia and analgesia and its effects on sleep may be used to improve the quality and quantity of sleep in ICU. Some of the data seem to contradict each other leaving open the opportunity for further research in exploiting the possible effects that this molecule may have in improving patient care and preventing morbidity and mortality. I feel that with its limited side effect profile and its pleiotropic effects on human (and rat) physiology, melatonin may become an important therapeutic adjunct to a multitude of pathologies.

The future of Melatonin: 1. Explore the efficacy of endogenous and exogenous melatonin in pathology

that disrupts circadian rhythms and compromises immune and antioxidative defences.

2. Additional randomized controlled trials comparing melatonin premedication to other drugs.

3. Investigate its effect on more varied surgical populations. 4. Evaluation of the side effects of chronic melatonin therapy. 5. Development of melatonin antagonists to help explain its physiological role in

humans. 6. The role of excessive light at night and its impact on human health.

Key messages: Melatonin 1. Is an effective anxiolytic premedication that retains psychomotor function. 2. Role in analgesia and anaesthetic sparing require further investigation. 3. Sleep and circadian rhythm disruptions is common in ICU. 4. 1-5mg results in plasma levels 10 -100 times more than nocturnal

endogenous levels. 5. Decreases the mean latency of sleep onset time, increases sleep efficiency

and sleep time 6. Is a highly effective antioxidant. 7. Generally considered as a non-toxic molecule.

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