Review Article. A systematic review of peri-operative melatonin. Summary. Introduction. Methods

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1 Review Article doi: /anae A systematic review of peri-operative melatonin L. P. H. Andersen, 1 M. U. Werner, 2 J. Rosenberg 3 and I. G ogenur 4 1 PhD Fellow, 3 Professor, 4 Associate Professor, Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark 2 Associate Anaesthetic Professor, Multidisciplinary Pain Center 7612, Neuroscience Center, Copenhagen, Denmark Summary We systematically reviewed randomised controlled trials of peri-operative melatonin. We included 24 studies of 1794 participants that reported eight peri-operative outcomes: ; analgesia; sleep quality; oxidative stress; emergence behaviour; anaesthetic requirements; steal induction; and safety. Compared with, melatonin reduced the standardised mean difference (95% CI) pre-operative score by 0.88 ( ) and postoperative pain score by 1.06 ( ). The magnitude of effect was unreliable due to substantial statistical heterogeneity, with I 2 87% and 94%, respectively. Qualitative reviews suggested the melatonin improved sleep quality and emergence behaviour, and might be capable of reducing oxidative stress and anaesthetic requirements.... Correspondence to: L. P. H. Andersen lphandersen@gmail.com Accepted: 9 April 2014 Introduction Evidence-based, multi-modal, surgical and anaesthetic approaches have reduced morbidity and mortality following surgical procedures [1]. New peri-operative interventions may further improve recovery. Melatonin is a pineal hormone regulating circadian rhythms in mammals [2]. Melatonin has documented effects on sleep disturbances, and pain [3 7]. Melatonin also has anti-inflammatory and anti-oxidative effects [8]. Melatonin may therefore be a useful peri-operative drug, particularly as it does not have any known serious adverse effects [9]. The analgesic and anxiolytic effects of melatonin in adult surgical patients have been qualitatively reviewed by Yousaf et al. [7]. We conducted a systematic review and meta-analysis the efficacy and safety of melatonin for peri-operative patients. Methods We searched the PubMed, Embase, CENTRAL, Web of Science and LILACS databases (September 2013) for randomised controlled trials (RCTs) with the terms, melatonin AND (peri-operative period OR postoperative period OR surgery OR surgical OR operation OR surgical procedures OR operative procedures). The review was conducted in accordance to the PRISMA guidelines [10]. We also searched the reference lists of identified studies. Two authors (LPHA, IG) independently assessed RCTs for inclusion, categorising risk of bias domains and extracting participant and procedure variables, melatonin regimens and outcomes [11]. Disagreements were solved by consensus. We intended to synthesise quantitatively all outcomes, consigning qualitative review to outcomes we were unable to pool through meta-analysis. We did not 2014 The Association of Anaesthetists of Great Britain and Ireland 1163

2 Andersen et al. Systematic review of peri-operative melatonin analyse outcomes reported as side-effects. We applied a random-effects model, combining continuous outcomes as standardised mean differences (SMD) with their associated 95% confidence intervals (95% CI). We transformed median (IQR or range) to mean (SD), excluding transformed data in a sensitivity analysis [11]. We quantified heterogeneity of the studies with I 2 statistics. All analyses were performed with RevMan (version 5.2; The Nordic Cochrane Centre, Copenhagen, Denmark). Results We included 24 RCTs of 1794 participants (Fig. 1) [4 6, 12 32]. Table 1 documents the risk of bias, assessed by the Cochrane Risk of Bias assessment tool. Studies reported nine outcomes: pain; ; sleep quality; oxidative stress; emergence behaviour; anaesthetic doses; steal anaesthetic induction (in a sleeping patient); and safety (Table 2). Most studies gave 3 10 mg ( mg.kg 1 ) oral melatonin [4 6, 12 16, 20 24, 27 29, 31] or sublingual melatonin [4, 15, 17 19, 25, 30]. One study gave 3500 mg orally [32] and one study gave 50 mg intravenously [26]. Most studies gave melatonin min before surgery [4, 12, 14, 17 24, 27, 29 31]. One study gave melatonin daily for one month pre-operatively [28], whereas four studies gave melatonin the night before surgery, in addition to the immediate pre-operative dose [5, 6, 13, 15]. Three studies gave melatonin at surgical incision [25, 26] or after intubation [32]. One study gave three separate melatonin doses on the first three postoperative nights [16]. The controls were inactive [4 6, 12 20, 22, 24 30, 32], clonidine [5], dexmedetomidine [29] and midazolam [15, 17 19, 21, 22, 27, 29]. One study included a control group in which patients did not receive a [23]. Participants had various operations: abdominal [15 17, 25, PubMed (n = 1529) Embase (n = 914) The Cochrane Library (n = 75) Web of Science (n = 601) LILACS (n = 175) Records found in total search (n = 3294) Records screened (n = 2589) Number of duplicates (n = 705) Full text assessed for eligibility (n = 41) Studies included in the review (n = 24) Irrelevant records screened (n = 2548) Full-text studies excluded (n = 17) - 10 studies did not investigate surgical patients - 3 studies were protocol studies - 2 studies were not randomised - 2 studies used melatonin only in combination with other drug interventions Figure 1 PRISMA flowchart The Association of Anaesthetists of Great Britain and Ireland

3 Andersen et al. Systematic review of peri-operative melatonin Table 1 Risk of bias table, categorising nine methodological domains in each of 24 included RCTs. Bias domain Acil et al [17]??? + +? + Almenrader et al [31] Borazan et al [13] ?? Capuzzo et al [20] + + +? +? + + Caumo et al [6] ?? Caumo et al [5] ? Evagelidis et al [30] ?? + G ogenur et al [16] ? Haghjooy et al [28] ? + Ismail & Mowafi 2009 [14] ?? + + Isik et al [27]?? + +?? + + Ionescu et al [15]?? + +?? + + Kain et al [21] ?? Khezri & Merate 2013 [4] ? + + K uc ukakin et al [25] + +?? K uc ukakin et al [26] +??? Naguib & Samarkandi?? + +?? [18] Naguib & Samarkandi?? + +?? [19] Naguib et al [24] ?? + Nickkholgh et al [32] Mowafi & Ismail 2008 [12] + +? +?? + + Ozcengiz et al [29] ?? + + Samarkandi et al [22] ?? + + Turkistani et al [23]??? +?? + 1, random sequence generation; 2, allocation concealment; 3, blinding of participants and personnel; 4, blinding of outcome assessors; 5, incomplete outcome data; 6, selective reporting; 7, other bias; 8, sample size calculation; 9, defined primary outcome; +,?,, low, unclear and high risks of bias, respectively. 32]; dental [27]; gynaecological [5, 6, 18, 19, 30]; ophthalmological [4, 14]; orthopaedic [12]; thoracic [28, 29]; urological [13]; vascular [26]; and mixed [20 24, 31]. The anaesthetic techniques included: general anaesthesia [13, 15 26, 28 32]; intravenous regional anaesthesia [12]; neuraxial block [5, 6, 20, 26, 31]; sedation [27]; and topical analgesia [4, 14]. Pain was investigated by 12 RCTs (n = 821) as scores [16, 17, 20], analgesic requirements [15], or both [4 6, 12 14, 18, 19]. Pain scores were documented with a visual analogue scale (VAS) [5, 6, 13, 16 19], verbal score [4, 12, 14] or numerical rating scale (NRS) [20] (Table 3). Melatonin reduced postoperative pain (Fig. 2); the extreme heterogeneity was unaffected by exclusion of RCTs for which we had converted median (IQR or range) to mean (SD) values. In individual RCTs, melatonin either reduced analgesic doses or there was no difference to control (Table 4). Fourteen studies (n = 1146) investigated before, during and after surgery using four different scales: VAS [4, 12, 14, 17 19, 23, 24]; NRS [20]; statetrait inventory [5, 6, 15]; Yale pre-operative scale [21, 22]. Melatonin reduced pre-operative, but the meta-analysis was very heterogeneous, which was partly resolved by exclusion of RCTs for which we had converted median (IQR or range) to mean (SD) values (Fig. 3). In individual RCTs, melatonin either reduced intra-operative and postoperative or was no different to control (Table 5). Only one study in children intended to record sedation as an outcome (n = 60), and found no difference between melatonin and [27]. However, sedation has been registered as an adverse effect in several studies using multiple measuring scales [13, 15, 17 19, 25, 26]. Four RCTs (n = 311) recorded the effect of melatonin on postoperative sleep quality in adults [6, 13, 16] and children [22]. Sleep was assessed using sleep questionnaires [6, 13, 16] or accelerography [6]. Melatonin improved subjective sleep quality in the early postoperative period [13, 16] and circadian rhythm during the first postoperative week [6]. Melatonin reduced sleep disturbance for two postoperative weeks in children [22]. Three RCTs (n = 121) measured concentrations of molecules in adults associated with oxidative stress. Melatonin had no effect on malondialdehyde, ascorbic acid, dehydroascorbic acid or C-reactive protein [25, 26]. Melatonin increased intra-operative levels of nuclear factor erythroid 2-related factor 2, suggesting potentiation of the anti-oxidative response [28]. Three RCTs (n = 353) studied the effect of melatonin on behaviour in children emerging from anaesthesia compared with [22, 29], dexmedetomidine [29] and midazolam [21, 22, 29]. Behaviour was assessed using the Keegan score [21], a discomfort scale [22] and an agitation scale [29]. Melatonin improved behaviour compared with [21, 22], but was no different to dexmedetomidine or midazolam [29]. Three RCTs (n = 316) investigated the effect of melatonin on anaesthetic induction dose [23, 24, 30]. The studies used bispectral index [23, 30] or clinical 2014 The Association of Anaesthetists of Great Britain and Ireland 1165

4 Andersen et al. Systematic review of peri-operative melatonin Table 2 Details of included RCTs. Acil et al [17] Almenrader et al [31] Borazan et al [13] Capuzzo et al [20] Caumo et al [6] Caumo et al [5] Evagelidis et al [30] G ogenur et al [16] Haghjooy et al [28] Ismail & Mowafi 2009 [14] Isik et al [27] Ionescu et al [15] Kain et al [21] Khezri & Merate 2013 [4] K uc ukakin et al [25] K uc ukakin et al [26] Naguib & Samarkandi 1999 [18] Naguib & Samarkandi 2000 [19] Naguib et al [24] Nickkholgh et al [32] MowafI & Ismail 2008 [12] Ozcengiz et al [29] Samarkandi et al [22] Turkistani et al [23] n Surgery Anaesthetic Control Route Dose Timing Outcomes 66 Laparoscopic GA Midazolam, SL 5 mg 90 min < Analgesia, cholecystectomy 87 Various GA Clonidine Oral 5 mg 60 min < Steal induction 52 Open prostatectomy GA Placebo Oral 6 mg 9 2 Night < and 60 min < Analgesia, sleep 138 Various GA/Spinal Placebo Oral 10 mg 90 min < Analgesia, 33 Open Epidural Placebo Oral 5 mg 9 2 Night < and Analgesia, hysterectomy 60 min <, sleep 59 Open Epidural Clonidine, Oral 5 mg 9 2 Night < and Analgesia, hysterectomy 60 min < 71 Hysteroscopy GA Placebo SL 0.1, 0.25 or 30 min < Anaesthetic 0.5 mg.kg 1 requirement 121 Laparoscopic GA Placebo Oral 5 mg > for three Analgesia, cholecystectomy nights sleep 30 CABG GA Placebo Oral 10 mg For one Oxidative month stress daily and 60 min < 40 Ophthalmological Topical Placebo Oral 10 mg 90 min < Analgesia, 60 Dental Sedation Midazolam, Oral 3 mg or 60 min < Sedation 0.5 mg.kg 1 53 Laparoscopic GA Midazolam, SL 3 mg 9 2 Night < and Analgesia, cholecystectomy 90 min < 148 Various GA Midazolam Oral 0.05, 0.2 or 45 min < Anxiety, 0.4 mg.kg 1 emergence 60 Ophthalmological Topical Placebo SL 3 mg 60 min < Analgesia, 41 Laparoscopic GA Placebo IV then 10 mg At incision Oxidative cholecystectomy oral stress 50 Major vascular GA/ Epidural 75 Laparoscopic gynaecological 84 Laparoscopic gynaecological GA GA Placebo Midazolam, Midazolam, IV then oral 50 mg then 10 mg At incision and > for 3 nights Oxidative stress SL 5 mg 100 min < Analgesia, SL 0.05, 0.1 or 100 min < Analgesia, 0.2 mg.kg Various GA Placebo Oral 0.2 mg.kg 1 50 min < Anaesthetic requirement, 36 Hepatic GA Placebo Oral 50 mg.kg 1 After Safety intubation 40 Hand IVRA Placebo Oral 10 mg 90 min < Analgesia, 100 Oesophageal dilatation GA Dex, midazolam, 105 Various GA Midazolam, Oral 0.1 mg.kg 1 45 min < Emergence Oral 0.1, 0.25 or 60 min < Anxiety, 0.5 mg.kg 1 emergence, sleep 45 Various GA Placebo Oral 3 or 5 mg 100 min < Anaesthetic requirements, CABG, coronary artery bypass grafting; GA, general anaesthesia; IVRA, intravenous regional analgesia; Dex', dexmedetomidine; SL, sublingual; IV, intravenous; <, before surgery; >, after surgery The Association of Anaesthetists of Great Britain and Ireland

5 Andersen et al. Systematic review of peri-operative melatonin Table 3 The effect of melatonin compared with on intra-operative pain scores. Effect of melatonin on pain score Capuzzo et al [20]? Ismail & Mowafi 2009 [14] Khezri & Merate 2013 [4]? Mowafi & Ismail 2008 [12]?, no statistical difference;, statistically less pain after melatonin vs. assessment [24]. Melatonin reduced the intravenous anaesthetic dose [23, 24] but not the dose of sevoflurane [30]. Melatonin was less effective than clonidine in facilitating successful steal induction of anaesthesia in 87 children [31]. Melatonin had no effect on complication rates of 36 liver resection patients [32]. Discussion Compared with, melatonin reduced postoperative pain and pre-operative. However, we consider these effects to be unreliable due to the profound heterogeneity of the meta-analyses. We were unable to conduct meta-analyses of other outcomes owing to the variability in study design. Qualitative reviews of these outcomes suggested that melatonin improved sleep quality and emergence behaviour and might reduce oxidative stress and anaesthetic requirements. Table 4 The effect of melatonin, compared with, on intra-operative and postoperative analgesic doses reported in nine and six RCTs, respectively. Analgesic dose Intra-operative Postoperative Borazan et al [13] Caumo et al [6]? Caumo et al [5]? Ionescu et al [15] Ismail & Mowafi 2009 [14] Khezri & Merate 2013 [4]? Mowafi & Ismail 2008 [12] Naguib & Samarkandi?? 1999 [18] Naguib & Samarkandi 2000 [19]???, no statistical difference;, statistically less analgesic after melatonin vs. Most RCTs were vulnerable to bias (Table 1). Only one out of 24 RCTs reported adequate limitation of risk of bias in all methodological domains [32]. Sample size calculations were inadequately documented in 7/24 RCTs, increasing the risk of false negative findings (type-2 errors) [4, 17, 23, 24, 28, 30, 32]. A primary outcome was not documented in 14/24 RCTs [12, 14, 15, 17 20, 22 24, 27 30]. Finally, some RCTs failed to adjust when testing the significance of multiple outcomes, increasing the risk of false positive findings (type-1 errors). Melatonin Placebo Std. mean difference Std. mean difference IV, Random 95%CI Study Mean SD Total Mean SD Total Weight IV, Random, 95% CI POP all studies Borazan % [ 15.01, 9.91] Capuzzo % 0.43 [0.09, 0.77] Caumo % 1.02 [ 1.75, 0.29] Caumo % 0.88 [ 1.53, 0.22] % 0.12 [ 0.24, 0.48] Ismail % 0.00 [ 0.62, 0.62] Khezri % 0.00 [ 0.51, 0.51] Mowafi % 1.04 [ 1.70, 0.37] Subtotal (95% CI) % 1.06 [ 1.88, 0.23] Heterogeneity Tau 2 = 1.24; Chi 2 = , df = 7 (p < ); I 2 = 94% Test for overall effect: Z = 2.52 (p = 0.01) POP sensitivity analysis Borazan % [ 15.01, 9.91] Caumo % 1.02 [ 1.75, 0.29] Caumo % 0.88 [ 1.53, 0.22] Subtotal (95% CI) % 4.36 [ 7.74, 0.98] Heterogeneity Tau 2 = 8.32; Chi 2 = 75.76, df = 2 (p < ); I 2 = 97% Test for overall effect: Z = 2.53 (p = 0.01) Favours melatonin Favours /controls Figure 2 Forest plot and meta-analyses of postoperative pain scores. We used pain scores reported at, or as near to, 12 h postoperatively. We excluded three studies that inadequately reported data [17 19]. The sensitivity analysis only included RCTs that reported mean (SD) scores. POP, postoperative pain The Association of Anaesthetists of Great Britain and Ireland 1167

6 Andersen et al. Systematic review of peri-operative melatonin Melatonin Placebo Std. mean difference Std. mean difference IV, Random 95% CI Study Mean SD Total Mean SD Total Weight IV, Random, 95% CI POA all Studies Acil % 0.60 [ 1.20, 0.01] Capuzzo % 0.00 [ 0.33, 0.33] Ionescu % 0.56 [ 1.23, 0.10] Ismail % 0.59 [ 1.23, 0.04] Khezri % 0.84 [ 1.37, 0.31] Mowafi % 0.70 [ 1.34, 0.06] Naguib % 1.56 [ 2.20, 0.92] Naguib % 0.93 [ 1.61, 0.25] Naguib % 1.99 [ 2.33, 1.65] Samarkandi % 1.00 [ 1.61, 0.39] Turkistani % 0.93 [ 1.58, 0.28] Subtotal (95% CI) % 0.88 [ 1.33, 0.44] Heterogeneity Tau 2 = 0.48; Chi 2 = 74.95, df = 10 (p < ); I 2 = 87% Test for overall effect: Z = 3.90 (p < ) POA sensitivity analysis Acil % 0.60 [ 1.20, 0.01] Ionescu % 0.56 [ 1.23, 0.10] Naguib % 1.56 [ 2.20, 0.92] Naguib % 0.93 [ 1.61, 0.25] Samarkandi % 1.00 [ 1.61, 0.39] Subtotal (95% CI) % 0.93 [ 1.29, 0.58] Heterogeneity Tau 2 = 0.06; Chi 2 = 6.13, df = 4 (p = 0.19); I 2 = 35% Test for overall effect: Z = 5.15 (p < ) Favours melatonin Favours Figure 3 Forest plot and meta-analyses of pre-operative. Pre-operative was defined as the last evaluation of before the surgical procedure. We excluded one study that did not have a group [21]. The sensitivity analysis only included RCTs that reported mean (SD) scores. POA, pre-operative. Table 5 The effect of melatonin, compared with, on intra-operative and postoperative scores reported in two and eight RCTs, respectively. Anxiety score Intra-operative Postoperative Acil et al [17] Capuzzo et al [20]? Caumo et al [6] Caumo et al [5] Ionescu et al [15] Ismail & Mowafi 2009 [14] Khezri & Merate 2013 [4] Naguib & Samarkandi? 1999 [18] Naguib & Samarkandi 2000 [19]??, no statistical difference;, statistically less after melatonin vs. The analgesic effect of melatonin remains uncertain. The reduction in SMD of 1.06 equates to 20 mm in the VAS: as previously commented, the extreme heterogeneity within this analysis makes this pooled effect unreliable. Therefore, additional RCTs would be needed to establish melatonin s clinical effect. Melatonin affects nociception [33, 34]. Analgesia may be mediated through peripheral and central effects [35 37]. The central action is attributed to specific melatonin receptors (MT 1 and MT 2 ) and interaction with opioid, γ-aminobutyric acid (GABA) or N-methyl-Daspartate receptor systems [35, 36]. Peripherally, melatonin has anti-inflammatory actions [37]. Any effect of peri-operative melatonin would vary with dosage, administration route and timing. A robust doseresponse relationship for melatonin has yet to be demonstrated in humans, which might be provided in non-clinical settings [38, 39]. Peri-operative is unpleasant and may increase postoperative pain [40]. Benzodiazepines are associated with psychomotor impairment, paradoxical psychological reactions, amnesia and respiratory depression, particularly when combined with the residual effects of hypnotics and opioids. These adverse effects may impede early mobilisation and recovery of the patient [41, 42]. Melatonin is not associated with these adverse effects. Melatonin reduced pre-operative by the equivalent of 19 mm on a VAS. However, as with postoperative analgesia, the considerable heterogeneity makes this pooled effect unreliable. Surgery initially abolishes rapid eye movement (REM) sleep, followed by a REM rebound, increased duration of light sleep and reduced slow wave sleep [43]. Melatonin induces sleep and shifts the circadian phase [44]. However, there is only limited evidence for the sleep-regulating effect of melatonin in surgical patients that might be documented by the use of perioperative polysomnography The Association of Anaesthetists of Great Britain and Ireland

7 Andersen et al. Systematic review of peri-operative melatonin An excess of oxidising free radicals results in oxidative stress [25, 26]. Free radicals can damage cells and is associated with morbidity, e.g. pulmonary oedema [45, 46]. Haghjooy et al. demonstrated that prolonged melatonin treatment induces anti-oxidant enzyme activity in patients undergoing coronary artery bypass grafts [28]. In infants, anti-oxidative effects of high-dose melatonin administration (up to 10 repeated administrations of 10 mg.kg 1 bodyweight over 72 h) have been correlated to clinical outcomes [8, 47 49]. As two RCTs in this meta-analysis did not show any effect of melatonin, these results in infants should not be generalised to adults [25, 26]. These findings need to be confirmed in future series. Confusion on emergence from anaesthesia may last min [50 54] and is associated with an increased rate of peri-operative complications and increased staffing costs [52, 54, 55]. The aetiology, diagnosis and management of emergence behaviour are still uncertain, making the conclusions concerning the effect of melatonin inconclusive. The possible reduction in dose of intravenous anaesthetic induction agent by melatonin may be through GABA-A-receptors, comparable with similar properties of benzodiazepines [56 58]. Steal induction is the induction of anaesthesia in a sleeping child. The rationale is that this might reduce peri-operative stress and, including subsequent anaesthetics. Melatonin has not been compared with, but appears to be inferior to clonidine [31]. Several studies have demonstrated that melatonin is without the adverse effects associated with opioids, nonsteroidal anti-inflammatory drugs1 and benzodiazepines, in both animals and in humans [9, 59 63]. Melatonin was not associated with any serious side-effect in the RCTs included in this systematic review. In conclusion, melatonin significantly reduced postoperative pain scores and pre-operative scores. The profound heterogeneity of the meta-analyses, especially with regard to analgesic effect, limits our conclusions, which can only be regarded as preliminary. Acknowledgements We thank Janne Wendt, Librarian at Herlev Hospital for her work in relation to the literature search. We thank Tobias Wirenfeldt Klausen, Statistician at Herlev Hospital for meta-analyses. LPHA receives a salary from the University of Copenhagen. Competing interests No additional external funding and competing interests declared. References 1. Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Annals of Surgery 2008; 248: Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Medicine Reviews 2005; 9: Dawson D, Encel N. Melatonin and sleep in humans. Journal of Pineal Research 1993; 15: Khezri MB, Merate H. The effects of melatonin on and pain scores of patients, intraocular pressure, and operating conditions during cataract surgery under topical anesthesia. Indian Journal of Opthalmology 2013; 61: Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine comsumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, -controlled study. Journal of Pain 2009; 10: Caumo W, Torres F, Moreira NL, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesthesia and Analgesia 2007; 105: Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomised trials. Anesthesiology 2010; 113: Gitto E, Romeo C, Reiter RJ, et al. Melatonin reduces oxidative stress in surgical neonates. Journal of Pediatric Surgery 2004; 39: Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of pituitary hormones. Journal of Clinical Endocrinology and Metabolism 1977; 45: Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analysis of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology 2009; 62: e Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions version The Cochrane Collaboration, (accessed 01/10/2013). 12. Mowafi HA, Ismail SA. Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesthesia and Analgesia 2008; 107: Borazan H, Tuncer S, Yalcin N, Erol A, Otelcioglu S. Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial. Journal of Anesthesia 2010; 24: Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesthesia and Analgesia 2009; 108: The Association of Anaesthetists of Great Britain and Ireland 1169

8 Andersen et al. Systematic review of peri-operative melatonin 15. Ionescu D, Badescu C, Ilie A, Acalovschi I. Melatonin as premedication for laparoscopic cholecystectomy: a doubleblind, -controlled study. South African Journal of Anaesthesia and Analgesia 2008; 57: G ogenur I, K uc ukakin B, Bisgaard T, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, -controlled trial. Anesthesia and Analgesia 2009; 108: Acil M, Basgul E, Celiker V, Karag oz AH, Demir B, Aypar U. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, scores and psychomotor performance. European Journal of Anaesthesiology 2004; 21: Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, -controlled comparison with midazolam. British Journal of Anaesthesia 1999; 82: Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, -controlled study. Anesthesia and Analgesia 2000; 91: Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce more than in the elderly undergoing surgery. Anesthesia and Analgesia 2006; 103: Kain ZN, MacLaren JE, Herrmann L, et al. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology 2009; 111: Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam premedication in children: a double-blind, controlled study. European Journal of Anaesthesiology 2005; 22: Turkistani A, Abdullah KM, Al-Shaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. European Journal of Anaesthesiology 2007; 24: Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin premedication on propofol and thiopental induction dose-response curves: a prospective, randomized, doubleblind study. Anesthesia and Analgesia 2006; 103: K uc ukakin B, Klein M, Lykkesfeldt J, Reiter RJ, Rosenberg J, G ogenur I. No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomised -controlled trial. Acta Anaesthesiologica Scandinavica 2010; 54: K uc ukakin B, Wilhelmsen M, Lykkesfeldt J, Reiter RJ, Rosenberg J, G ogenur I. No effect of melatonin to modify surgicalstress response after major vascular surgery: a randomised -controlled trial. European Journal of Vascular and Endovascular Surgery 2010; 40: Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam in anxious children. Pediatric Anesthesia 2008; 18: Haghjooy Javanmard S, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxidative Medicine and Cellular Logevity 2013; 2013: Ozcengiz D, Gunes Y, Ozmete O. Oral melatonin, dexmedetomidine, and midazolam for prevention of postoperative agitation in children. Journal of Anesthesia 2011; 25: Evagelidis P, Paraskeva A, Petropoulos G, Staikou C, Fassoulaki A. Melatonin premedication does not enhance induction of anaesthesia with sevoflurane as assessed by bispectral index monitoring. Singapore Medical Journal 2009; 50: Almenrader N, Haiberger R, Passariello M. Steal induction in preschool children: is melatonin as good as clonidine? A prospective, randomised study. Pediatric Anesthesia 2013; 23: Nickkholgh A, Schneider H, Sobirey M, et al. The use of highdose melatonin in liver resection is safe: first clinical experience. Journal of Pineal Research 2011; 50: Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V. Melatonin: a hormone that modulates pain. Life Sciences 2009; 84: Srinivasan V, Pandi-Perumal SR, Spence DW, et al. Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Research Bulletin 2010; 81: Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Research Bulletin 2005; 64: Phansuwan-Pujito P, Govitrapong P, Møller M. Immunohistochemical demonstration of opioids and tachykinins in human pineal gland. Journal of the Medical Association of Thailand 2005; 88: S Esposito E, Paterniti I, Mazzon E, Bramanti P, Cuzzocrea S. Melatonin reduces hyperalgesia associated with inflammation. Journal of Pineal Research 2010; 49: Pedersen JL, Kehlet H. Hyperalgesia in a human model of acute inflammatory pain: a methodological study. Pain 1998; 74: Werner MU, Petersen KL, Rowbotham MC, Dahl JB. Healthy volunteers can be phenotyped using cutaneous sensitization pain models. PLoS ONE 2013; 8: e Caumo W, Schmidt AP, Schneider CN, et al. Risk factors for postoperative in adults. Anaesthesia 2001; 56: Richardson MG, Wu CL, Hussain A. Midazolam premedication increases sedation but does not prolong discharge times after brief outpatient general anesthesia for laparoscopic tubal sterilization. Anesthesia and Analgesia 1997; 85: Fredman B, Lahav M, Zohar E, Golod M, Paruta I, Jedeikin R. The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. Anesthesia and Analgesia 1999; 89: G ogenur I, Wildschiøtz G, Rosenberg J. Circadian distribution of sleep phases after major abdominal surgery. British Journal of Anaesthesia 2008; 100: Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Medicine Reviews 2005; 9: Cornu-Labat G, Serra M, Smith A, et al. Systemic consequences of oxidative stress following aortic surgery correlate with the degree of antioxidant defenses. Annals of Vascular Surgery 2000; 14: Hafez HM, Berwanger CS, McColl A, et al. Myocardial injury in major aortic surgery. Journal of Vascular Surgery 2000; 31: Gitto E, Karbownik M, Reiter RJ, et al. Effects of melatonin treatment in septic newborns. Pediatric Research 2001; 50: Fulia F, Gitto E, Cuzzocrea S, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. Journal of Pineal Research 2001; 31: Gitto E, Reiter RJ, Amodio A, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. Journal of Pineal Research 2004; 36: The Association of Anaesthetists of Great Britain and Ireland

9 Andersen et al. Systematic review of peri-operative melatonin 50. Scott GM, Gold JI. Emergence delirium: a re-emerging interest. Seminars in Anesthesia, Perioperative Medicine and Pain 2006; 25: Radtke FM, Franck M, Hagemann L, Seeling M, Wernecke KD, Spies CD. Risk factors for inadequate emergence after anesthesia: emergence delirium and hypoactive emergence. Minerva Anesthesiologica 2010; 76: Yu D, Chai W, Sun X, Yao L. Emergence agitation in adults: risk factors in 2,000 patients. Canadian Journal of Anesthesia 2010; 57: Bong CL, Ng AS. Evaluation of emergence delirium in Asian children using the Pediatric Anesthesia Emergence Delirium Scale. Pediatric Anesthesia 2009; 19: Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit. Anesthesia and Analgesia 2003; 96: Lepouse C, Lautner CA, Liu L, Gomis P, Leon A. Emergence delirium in adults in the post-anaesthesia care unit. British Journal of Anaesthesia 2006; 96: Kissin I, Vinik HR, Bradley EL Jr. Midazolam potentiates thiopental sodium anesthetic induction in patients. Journal of Clinical Anesthesia 1991; 3: McAdam LC, MacDonald JF, Orser BA. Isobolographic analysis of the interactions between midazolam and propofol at GABA (A) receptors in embryonic mouse neurons. Anesthesiology 1998; 89: Wang F, Li J, Wu C, Yang J, Xu F, Zhao Q. The GABA(A) receptor mediates the hypnotic activity of melatonin in rats. Pharmacology Biochemistry and Behavior 2003; 74: Kehlet H. Postoperative opioid sparing to hasten recovery: what are the issues? Anesthesiology 2005; 102: Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 2011; 123: Barthelemy O, Limbourg T, Collet JP, et al. REACH Registry Investigators. Impact of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors. International Journal of Cardiology 2013; 163: Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicological Sciences 1999; 50: Shaw KM, Stern GM, Sandler M. Melatonin and parkinsonism. Lancet 1973; 1: The Association of Anaesthetists of Great Britain and Ireland 1171