REVIEW ARTICLE Anesthesiology 2010; 113: Copyright 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins

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1 REVIEW ARTICLE Anestesiology 2010; 113: Copyrigt 2010, te American Society of Anestesiologists, Inc. Lippincott Williams & Wilkins David S. Warner, M.D., Editor Efficacy and Safety of Melatonin as an Anxiolytic and Analgesic in te Perioperative Period A Qualitative Systematic Review of Randomized Trials Farana Yousaf, M.B.B.S.,* Edwin Seet, M.B.B.S., M.Med., Lasmi Venkatragavan, F.R.C.P.C., Amir Abrisami, M.D.,* Frances Cung, F.R.C.P.C. ABSTRACT Melatonin possesses sedative, ypnotic, analgesic, antiinflammatory, antioxidative, and cronobiotic properties tat distinguis it as an attractive alternative premedicant. A qualitative systematic review of te literature concerning te perioperative use of melatonin as an anxiolytic or analgesic in adult patients was carried out using te recommended guidelines provided by te Cocrane Handbook for Systematic Reviews of Interventions. Nine of te 10 studies sowed statistically significant reduction of preoperative anxiety wit melatonin premedication compared wit placebo. An opioid-sparing effect or reduced pain scores were evident in five studies wereas tree studies were contradictory. Tus, melatonin premedication is effective in ameliorating preoperative anxiety in adults, but its analgesic effects remain controversial in te perioperative period. Additional well designed randomized controlled trials are necessary to compare melatonin premedication wit oter parmacological interventions, investigate its effect on more varied surgical populations, and to delineate its optimal dosing regimen. THE existing literature suggests tat many surgical patients experience some anxiety and pain during te perioperative period. 1 3 Preoperative anxiety is described as an unpleasant state of uneasiness or tension tat is secondary to a patient being concerned about a disease, ospitalization, anestesia and surgery, or te unknown. 4 Preoperative anxiety may also serve a * Researc Fellow, Clinical Fellow, Assistant Professor, Department of Anestesia, University Healt Network, University of Toronto, Toronto, Ontario, Canada. Received from te Department of Anestesia, University Healt Network, University of Toronto, Toronto, Ontario, Canada. Submitted for publication December 22,. Accepted for publication May 5, Support was provided solely from institutional and/or departmental sources. Address correspondence to Dr. Cung: Department of Anestesia, Toronto Western Hospital, 399 Baturst Street, McL 2-405, Toronto, Ontario, M5T 2S8 Canada. frances.cung@un.on.ca. Tis article may be accessed for personal use at no carge troug te Journal Web site, critical role in te cain of events tat control te postoperative pain response. 5,6 Te relationsip between perioperative anxiety and pain is particularly important to te perioperative pysician because preoperative anxiety can be reduced wit certain parmacological interventions. 5 Benzodiazepines are commonly used to alleviate anxiety but may impair psycomotor performance and suppress te duration of rapid eye movement sleep. 7 9 Te incidence of moderate pain after day surgery remains as ig as 25%, wereas 25 50% of surgical inpatients experience moderate to severe pain, indicating tat te standards of care for postoperative pain by te Audit Commission (1997) are not being met Opioids are potent analgesics widely utilized to provide perioperative analgesia, but teir use is sometimes limited because of adverse effects suc as sedation and respiratory depression. Moreover, postoperative opioid use can lead to an increase in ospital morbidity and cost. 14,15 Terefore, te searc for a substance tat may reduce te severity of postoperative pain is desirable. Recently accumulated experimental evidence supports an important role of melatonin (N-acetyl-5-metoxytryptae) in anxiolysis and analgesia Melatonin is a naturally occurring ormone in te uman body tat is secreted by te pineal gland in te dark and inibited by exposure to ligt. Te manufacturing and general use of exogenous melatonin remain unregulated because melatonin is not a Food and Drug Adistration-approved drug. Oral adistration of 1 5 mg of melatonin results in plasma levels of times more tan te observed endogenous nigttime levels. 19 It as an excellent safety profile, and te or adverse effects tat may be associated wit its use are drowsiness, eadace, gastrointestinal disturbances, ras, and insomnia. 20 In contrast to benzodiazepines, melatonin produces no residual effects or suppression of rapid eye movement sleep. 21 Te anxiolytic and analgesic properties of melatonin distinguis it as a compelling alternative as a premedicant. However, te clinical evidence regarding te anxiolytic and analgesic effects of melatonin in te perioperative period as 968 Anestesiology, V 113 No 4 October 2010

2 Melatonin as an Analgesic and Anxiolytic not been reviewed previously. Te objective of our systematic review is to evaluate te efficacy and safety of melatonin as a preoperative anxiolytic and analgesic in randomized controlled trials. Materials and Metods A systematic review of te literature concerning te perioperative use of melatonin as an anxiolytic or analgesic in adult patients was carried out using te recommended guidelines provided by te Cocrane Handbook for Systematic Reviews of Interventions.# Searc Metods for Identification of Studies We performed a literature searc during November using MEDLINE (1950 week 2 November ), EMBASE (1980 week 47), International Parmaceutical Abstracts (1970 November ), and Cocrane Databases of Systematic Reviews (Issue 4, ). Keywords including anxiety, pain, analgesic, surgery, perioperative, antianxiety agents, and premedication were combined wit melatonin. Te searc was restricted to te Englis language and an adult study population. We sougt additional literature troug te scanning of te bibliograpies of relevant articles. In addition, we contacted te autor of te included trials for information not reported sufficiently in te identified publications. We specifically inquired about te criteria of metodological quality and weter tabular data could be provided were suc information was missing or unclear. Study Selection Criteria Two reviewers (FY and ES) independently assessed titles, abstracts, and/or te full text paper of te records retrieved from te electronic database and te and searces for possible inclusion according to te predefined selection criteria, i.e., any randomized controlled trial evaluating te efficacy and safety of melatonin as an anxiolytic and/or analgesic in te perioperative setting and in adult patients (age older tan 18 yr) in wic validated measurement tools were used for evaluation. Studies publised in te non-englis language or studies witout preoperative assessment of anxiety were excluded. Disagreements between te autors were resolved by te senior autor (FC). # Higgins JPT, Green S (editors). Cocrane Handbook for Systematic Reviews of Interventions Version (updated September ). Te Cocrane Collaboration,. Available at: Assessment of Metodology Quality Two autors (FY and ES) assessed te metodological quality of eac trial using individual aspects of metodological quality proposed by Sculz et al. 22 Tese criteria specify four items of assessment: double-blinding, allocation concealment, follow-up completeness, and metods used to acieve randomization. In eac study, te above-mentioned components were graded as adequate, unclear, or inadequate. We resolved any conflicts in te assessment of metodological quality of eligible studies troug discussion, and if necessary, troug evaluation by te senior autor (FC). Data Extraction and Analysis Te data were extracted by FY and ES individually and validated by FC, by double data entry. Details of study population, interventions, and outcomes were extracted using a standardized data extraction form, wic included general information, trial caracteristics, study population caracteristic, interventions, and outcomes. Te primary outcomes of te review included: perioperative anxiety, assessed wit te Visual Analog Scale (VAS) or State-Trait Anxiety Inventory or any oter validated assessment tool; perioperative pain, assessed wit te VAS or Verbal Numerical Scale or any oter validated assessment tool; intraoperative opioid use; and postoperative analgesic consumption. We also listed melatoninrelated adverse effects reported in terms of psycomotor impairment, sedation, and orientation in time or place among te studies. Comparisons were made between melatonin and placebo, melatonin and anoter anxiolytic or analgesic, and different dose(s) of melatonin. Tis study is a qualitative systematic review witout meta-analysis. We summarize and present te results in several tables. To identify te significant findings in eac paper, we considered a P value 0.05 as a level of statistical significance. Tere were several reasons tat made us decide not to carry out meta-analysis in tis review. First, tere were obvious clinical inconsistencies among te papers in terms of te study population, time of assessment of outcomes, and te dosing of melatonin. Second, te data were presented in a format of median and range in te papers; owever, only mean and SD could be used for meta-analysis. Also, presenting te results in median and range by te papers could indicate tat te respective data were not normally distributed, and terefore te normality assumption could not be acieved to do a valid meta-analysis. Finally, in many papers te data were only presented in a figure or grap, and tabular data were not available. We contacted te autors to get te tabular data; owever, te autors of only two papers provided us wit te required information. 23,24 We did not carry out meta-analysis on tese two papers because tey were only a portion of te literature on te topic, and te final results could not represent te current available evidence. Results Description of Selected Studies Our searc strategy for te topic of melatonin and anxiety yielded 249 results and for te topic of melatonin and pain yielded 534 results (fig. 1). Ten and eigt studies met our inclusion criteria for te role of melatonin in anxiety and pain, respectively. Tere were eigt studies in wic bot outcomes ave been reported, so a total number of 10 studies (n 788 patients) were included in tis review (table 1) Te average sample size was 75 patients wit a range Yousaf et al. Anestesiology, V 113 No 4 October

3 EDUCATION Risk of Bias in Included Studies Sculz s quality criteria were adequately met for te specific items of metodological quality in two trials. 23,25 Te metod of randomization in tese two trials was eiter computer-generated or advanced simple randomization witout blocking or stratification. In tese trials, te allocation concealment was acieved wit te use of sealed envelopes. Te remaining eigt trials were subject to potential moderate risk of bias because one or more elements of metodological quality, tat is, randomization, allocation concealment, blinding, or follow up, were considered unclear (table 2) In tree studies, te randomization lists were kept by te person (for example, a parmacist) wo was responsible for preparing te medication (or placebo). 23,25,32 Tis person was not involved in adistering te medication to te patients, te patient s care, or data collection. Te safety assessor(s), responsible for te subjective safety assessments, were blinded to te treatment assignment in all studies. Four studies clearly reported te number and reasons for patient witdrawals. 23,25 27 Fig. 1. Flow cart of te literature searc, screening, and inclusion of te studies. Total number of te included studies is 10 because tere are 8 papers studying te effect of melatonin on bot pain and anxiety. of patients. Te main caracteristics of te included studies are sown in table 1. Clinical Evidence of Anxiolytic Effects of Melatonin in te Perioperative Period Ten studies reported preoperative anxiety as outcome measures (table 3). VAS, verbal rating scores, and te original or modified State-Anxiety Trait Inventory were used in te assessment of anxiety. Te basic caracteristics of tese trials are sown in table 1. Te sample size ranged from 33 to 200 patients wit a mean age of yr and average weigt of kg. Te surgical populations included gynecological, laparoscopic colecystectomy, and, cataract, and mixed surgeries. Te anestetic tecnique included general anestesia, regional anestesia (epidural, spinal, Bier block), and local anestesia wit or witout sedation. Te exogenous melatonin dose ranged from 3 to 15 mg and was adistered preoperatively via an oral 23 25,27 29,32 or sublingual route. 26,30,31 Tree studies followed a dual regime of melatonin adistration in wic an additional dose of melatonin was adistered on te nigt before surgery. 24,25,27 Nine of te 10 studies sowed statistically significant reduction of preoperative anxiety wit melatonin premedication compared wit placebo. Only one study refuted its anxiolytic effects. 23 Te tig of anxiety assessment varied among te trials, but a significant statistical difference in anxiety scores was evident at different points of time in te melatonin group (table 3). Te preoperative anxiety assessment time varied among te studies from 10 to 90 after adistration of melatonin (all P values 0.05). Two studies at 10, tree studies at 30 and 60, and five studies at 90 after premedication sowed tat anxiety was less in te melatonin groups compared wit te placebo groups (all P values 0.05). 26,28 31 In anoter study by Naguib et al., te anxiety score was statistically lower in te melatonin group versus te placebo group at 50 (P value 0.05). 32 Ismail et al. also demonstrated reduced anxiety scores intraoperatively during cataract surgery in te melatonin group versus placebo. 28 During te postoperative period, melatonin was sown to be associated wit less anxiety compared wit placebo. Te assessment times were 15, 30, 60, and 90 after surgery in 970 Anestesiology, V 113 No 4 October 2010 Yousaf et al.

4 Melatonin as an Analgesic and Anxiolytic Table 1. Basic Caracteristics of te Included Clinical Trials Sample Caracteristics Study ID Sample Size M:F Age Weigt (kg) Anestesia Surgery Intervention vs. Control Melatonin Dosage Ismail : Topical Cataract Melatonin, Placebo PO 10 mg, Singledose Caumo : Epidural and Abdoal Melatonin, Clonidine, PO 5 mg, Dual-dose sedation ysterectomy Placebo Ionescu 24 53? GA Lap. cole. Melatonin, Midazolam, PO 3 mg Dual-dose Placebo Mowafi : Bier block Hand Melatonin, Placebo PO 10 mg, Singledose Caumo : Epidural and Abdoal Melatonin, Placebo PO 5 mg, Dual-dose 2007 sedation ysterectomy Capuzzo : ? GA & spinal Mixed Melatonin, Placebo PO 10 mg, Singledose Naguib : GA Mixed Melatonin, Placebo PO 0.2 mg/kg Singledose Acil ? GA Lap. cole. Melatonin, Midazolam, SL 5 mg, Single-dose Placebo Naguib : GA Lap. gynecol. Melatonin, Midazolam, Placebo SL 0.05 or 0.1 or 0.2 mg/kg Single-dose Naguib :75 30? GA Lap. gynecol. Melatonin, Midazolam, Placebo SL 5 mg, Single-dose Capuzzo 23 and Naguib 32 : studies wit anxiety outcome only; te rest were studies wit bot anxiety and pain outcomes. Age and weigt are expressed as mean SD. GA general anestesia; Lap. cole. laparoscopic colecystectomy; Lap. gynecol. laparoscopic gynecological; PO per oral; SL sublingual;? missing data. one study and 6, 24, and 48 after surgery in two studies, all sowing a significant decrease in te anxiety scores of te melatonin groups versus te placebo groups (all P values 0.05) On te contrary, Capuzzo et al. demonstrated a lack of statistically significant anxiolytic effects after melatonin premedication in te elderly surgical patients at 90 preoperatively, after surgery in te recovery room, and 7 days after ospital discarge. 23 In four studies, te anxiolytic effects of melatonin were also compared wit midazolam, a sort-acting benzodiazepine commonly used as a premedication. 24,26,30,31 Tere was no statistically significant (P 0.05) difference in te anxiety scores between melatonin and midazolam groups during preoperative anxiety assessments, but bot groups sowed a statistically significant reduction in anxiety levels compared wit te placebo group. 24,26,30,31 Postoperatively, a statistical difference between melatonin and midazolam groups in anxiety scores was exibited at 15, 30, 60, and 90 in one study, and melatonin was also sown to ave a Table 2. Metodological Quality of te Included Studies Study ID/Year Ismail 28 Caumo 25 Ionescu 24 Mowafi 29 Caumo Capuzzo Naguib Acil Naguib Naguib Criteria Adequately Met R, B R, C, B, F C, B, F R, B R, B, F R, C, B, F C, B B, F B B B blinding; C concealment; F follow-up; R randomization. superior anxiolytic effect compared wit midazolam at 60 and 24 in anoter study. 24,26 However, Naguib and colleagues reported equivalent anxiety scores in melatonin, midazolam, and placebo groups postoperatively. 30,31 Te anxiolytic effect of melatonin was also compared wit clonidine, a central -adrenergic agonist, illustrating equivalent anxiolysis wit bot interventions tat were statistically superior to te placebo. 25 Te tabular data for melatonin premedication was available in only four studies (table 4) and oter studies publised only grapical data. 23,28,29,32 Te baseline anxiety in te control and melatonin groups was similar. However, a statistically significant reduction in anxiety scores was acieved after melatonin adistration in four studies. Because te data were reported in different formats among te studies (mean vs. median), statistical integration of data (meta-analysis) was not feasible, and overall efficacy of te medication was not calculated. However, a statistically significant anxiolytic effect of melatonin is evident in 9 of 10 studies. Clinical Evidence of Analgesic Effects of Melatonin in te Perioperative Period Eigt studies tat reported pain as te outcome measures were included in our review (table 1). VAS and verbal rating scores were used to assess pain at different time points. Intraoperative opioid use or postoperative analgesic consumption was recorded in seven studies. 24,25,27 31 Te sample size ranged from 33 to 84 patients wit a mean age of yr and average weigt of kg. Te surgical populations studied in tese trials included gynecological, laparoscopic colecystectomy, cataract, and and surgeries under general anestesia, epidural wit sedation, Bier block, or topical an- Yousaf et al. Anestesiology, V 113 No 4 October

5 EDUCATION Table 3. Anxiety Scores in te Melatonin vs. Placebo groups in Perioperative Period Preoperative Postoperative Study ID Tool Before Premed Ismail 28 Caumo 25 Ionescu 24 Mowafi 29 Caumo Capuzzo Naguib Acil Naguib Naguib VAS 2 STAI STAI (mod.) VAS 2 STAI VNS VAS 2 VAS VAS VAS (2) statistically significant decrease in te melatonin vs. placebo group (P 0.05); ( ) no statistically significant difference between te melatonin and te placebo groups. STAI State-Trait Anxiety Inventory; VAS Verbal Analogue Scale; VNS Verbal Numerical Scale. estesia. Te exogenous melatonin dose ranged from 3 to 15 mg and was adistered preoperatively via an oral 24,25,27 29 or sublingual route. 26,30,31 In tree studies wit dual-dosing regimen, melatonin was adistered te nigt before and before surgery. 24,25,27 Five studies demonstrated an opioid-sparing effect or reduced pain scores 24,25,27 29 wereas tree studies were contradictory. 26,30,31 Pain scores were assessed perioperatively in seven of eigt studies in wic four studies 25,27 29 sowed statistically significant (P 0.05) improvement in te pain scores in te melatonin group compared wit placebo (table 5). Intraoperative pain assessment was performed in only two studies were eiter topical or regional anestesia was adistered. 28,29 In patients undergoing cataract surgery, pain scores were significantly reduced at 10, 20, and 30 intraoperatively as well as during te postanestesia care unit stay in te melatonin versus te placebo group. 28 Hand surgery patients in te melatonin group versus placebo also reported reduced pain scores at 30, 40, and 50 after tourniquet inflation. 29 Postoperative pain scores were assessed in five studies. In te two studies conducted by Naguib et al., tere was no significant difference in pain scores in te melatonin group at 15, 30, 60, and 90 postoperatively. 30,31 Furtermore, Acil et al. did not observe any significant difference in pain scores in melatonin versus placebo groups during te stay in te postanestesia care unit. 26 In contrast, te two studies by Caumo et al. sowed a statistically significant reduction in pain scores in te melatonin group at 6, 12, 18, 24, 36, and 48 postoperatively. 25,27 It is important to note tat melatonin was adistered as a single dose in te two studies by Naguib et al. and one by Acil et al. tat sowed a lack of Table 4. Effect of Melatonin as a Premedication for Preoperative Anxiety Study ID/Year Before Premedication After Premedication Melatonin Placebo Melatonin Placebo Assessment Time () Ismail ( ) 4 ( ) 3.0 ( ) 4.0 ( ) 90 Mowafi ( ) 5 ( ) 4.0 ( ) 5.0 ( ) 90 Capuzzo ( )* 5.0 ( )* 3.0 ( )* 3.0 ( )* 90 Naguib ( ) 3.0 ( ) 1.0 ( ) 2.7 ( ) 50 Four out of te 10 included studies presented tabular data results for anxiety scores in te melatonin vs. placebo groups. Values are all Visual Analogue Scale of anxiety. N sample size. Values wit statistically significant difference (P 0.05) are in bold font. Data are expressed in median and range. * Number scale of anxiety. 972 Anestesiology, V 113 No 4 October 2010 Yousaf et al.

6 Melatonin as an Analgesic and Anxiolytic Table 5. Effect of Melatonin as a Premedication for Perioperative Pain Control Intraoperatively Postoperatively Study ID PACU Ismail 28 Caumo 25 Mowafi 29 Caumo Acil Naguib Naguib (2) statistically significant (P 0.05) decrease in pain score in te melatonin vs. placebo group. ( ) no statistically significant (P 0.05) difference in pain scores in te melatonin vs. placebo group. PACU postanestesia care unit. analgesic effects of melatonin. However, te two studies by Caumo et al. in wic te analgesic properties of melatonin were evident utilized a dual-dosing regime of melatonin adistration. It is possible tat te difference in te dosing regime of melatonin adistration among tese trials may ave contributed to te inconsistency observed regarding te analgesic effects of melatonin. Intraoperative opioid use was recorded in five studies 24,28 31 in wic tree studies reported a significantly reduced intraoperative opioid requirement in te melatonin group (P 0.05). 24,28,29 Ionescu et al. reported comparable intraoperative fentanyl use in te melatonin and midazolam groups wic was statistically lower tan te placebo group. 24 Te two studies by Ismail and Mowafi et al. also demonstrated reduced intraoperative opioid requirement. 28,29 In addition, postoperative analgesic consumption was calculated in five studies 25,27,29 31 in wic tree studies reported positive results (P 0.05). 25,27,29 Te analgesic consumption was reduced in te melatonin group compared wit placebo at 6, 12, 18, 24, 42, 48, and 54 postoperatively in two studies by Caumo and colleagues. 25,27 Te total analgesic consumption during te postoperative 24 was also reduced in a study by Mowafi et al. 29 In contrast, tere was no significant difference in te intraoperative opioid use or total doses of analgesics consumed in te melatonin, midazolam, or placebo groups during te 90- postanestesia care unit stay in te two studies by Naguib et al. 30,31 Tabular data regarding intraoperative opioid (fentanyl) usage and postoperative analgesic consumption in te control and melatonin groups was available in five studies for comparison (table 6). 24,29 31 Statistical significance between control and melatonin groups was reaced in tree studies regarding a reduced intraoperative opioid requirement and postoperative analgesic consumption. Statistical integration Table 6. Effect of Melatonin as a Premedication on Perioperative Analgesic Consumption Study ID/Year N Type of Surgery Dosage Intraoperative Fentanyl ( g) Postoperative Analgesic Diclofenac / Morpine (mg) Melatonin Midazolam Melatonin Midazolam Placebo Melatonin Midazolam Placebo Ismail 28 Ionescu 24 Mowafi 29 Naguib Naguib Cataract 10 mg 0 (0 33) 48 (30 65) 53 Lap. 3 mg 3.75 mg cole. 40 Hand 10 mg * * 84 Lap. gynecol. 75 Lap. gynecol mg/kg mg/kg ? 43? 36? 5mg 15mg ? 53? 42? Values are mean SD or median (interquartile range). Values wit statistically significant difference vs. placebo (P 0.05) are in bold font. * Postoperative (24 ) diclofenac consumption (mg). Postoperative (90 ) morpine consumption (mg). Lap. cole. laparoscopic colecystectomy; Lap. gynecol. laparoscopic gynecology; N sample size. Yousaf et al. Anestesiology, V 113 No 4 October

7 EDUCATION of te data (meta-analysis) was not carried out because of significant difference in te dose of fentanyl used in te different studies (i.e., clinical eterogeneity). In view of te opioid-sparing effect or reduced pain scores tat were evident in five studies wile tree studies were contradictory, te analgesic effects of melatonin remain controversial. Safety of Melatonin Premedication Melatonin seems to be associated wit no significant side effects. No significant adverse events after melatonin adistration were reported among te included trials. However, it sould be noted tat te included trials were not statistically powered to detect te incidence of adverse events of melatonin. Adverse events were evaluated in terms of psycomotor impairment, sedation, disorientation, and amnesia. Tree studies included in tis review ave evaluated psycomotor performance using te Digit Symbol Substitution Test, Trieger Dot Test, Trail Making A and B test, or Verbal Fluency Test. 26,30,31 In one study, Naguib et al. discovered impaired performance on te Digit Symbol Substitution Test at 30 after premedication and in anoter study at 10 after premedication in te midazolam group versus melatonin and placebo groups. 30,31 However, Trieger Dot Test scores were not significantly different among te midazolam, melatonin, and placebo groups after premedication in te preoperative period. 30,31 Tere were also no statistically significant differences in Digit Symbol Substitution Test or Trieger Dot Test performance in te midazolam, melatonin, or placebo groups after surgery up to 90. In te study by Acil et al., bot melatonin and midazolam groups exibited statistically significant impaired performance on te Trail Making Tests versus placebo at 30, 60, and 90 after premedication (P 0.05), wereas tere were no statistical differences among te groups in te 90- postoperative period. 26 Verbal Fluency Test performance was only significantly impaired in te midazolam group (P 0.001) compared wit placebo at 10, 30, 60, and 90 after premedication, wereas tere was no statistical difference in te melatonin and placebo groups at tese time points. 26 At 15, 30, and 60 postoperatively, verbal fluency scores were significantly poor in te melatonin and midazolam groups versus placebo (P 0.001). 26 Five studies included in tis review investigated te effect of melatonin on anterograde memory. 23,24,26,30,31 Te lack of amnesic effects of melatonin at 24 postoperatively were evident in tree studies tat assessed memory by asking te patients to recall pictures sown before premedication, entering te operating room, or insertion of te intravenous cateter in te operating room. 26,30,31 Memory recall scores remained unaffected at 15, 60, 6, and 24 postoperatively in te melatonin and placebo groups in te study by Ionescu et al. wic evaluated memory by asking te patients recall five pictures sown before premedication. 24 Amnesia was statistically significant only in te midazolam group versus placebo group in te four studies tat compared melatonin, midazolam, and placebo groups. 24,26,30,31 Capuzzo et al. assessed immediate and delayed recall memory using Babcock Story Recall Test before premedication, 90 after premedication, in te recovery room, and 1 week after surgery and found no statistically significant difference between melatonin and placebo groups. 23 Five studies included in tis review compared sedation levels after premedication wit melatonin, midazolam, or placebo. 24,26,30 32 Te melatonin group exibited increased levels of sedation only at 90 after premedication versus placebo (P 0.05). 26 However, significantly decreased sedation levels were evident in te melatonin versus midazolam group at 10, 30, and 60 after premedication (P 0.001). 26 Tere was no statistical difference in te sedation levels among te groups after surgery. 26 Increased levels of sedation in te melatonin and midazolam groups versus placebo were also evident at 60 and 90 after premedication in te two studies by Naguib et al. 30,31 Te midazolam group sowed significantly iger levels of sedation tan te melatonin group at 30 and 60 after premedication. 30 Postoperatively, a statistically significant increase in sedation levels was observed only at 30 in bot melatonin and midazolam groups in one study and at 90 only in patients receiving 0.2 mg/kg midazolam compared wit 0.05 and 0.1 mg/kg melatonin in te oter study. 30,31 Naguib et al. also reported increased sedation scores on arrival in te operating room in te melatonin versus placebo group. 32 Significantly lower sedation scores in te melatonin versus midazolam group were also reported at 15 and 60 after surgery (P 0.05). 24 Four studies included in tis review assessed orientation scores wit respect to time and place at multiple times during te study period among te intervention and placebo groups. 26,30 32 In two studies, te orientation scores were similar in te melatonin, midazolam, and placebo groups except at 30 after premedication wen te midazolam group exibited significant disorientation (P 0.05). 26,30 In anoter study, all patients remained oriented in time and place at all times except at 15 after surgery wen bot intervention groups illustrated significant disorientation compared wit te placebo group. 31 However, no statistically significant difference was observed in te orientation score between te melatonin and placebo groups in anoter study by Naguib et al. 32 Discussion Our review provides, for te first time, an up-to-date qualitative systematic analysis of te existing clinical trials on te anxiolytic and analgesic properties of melatonin in te perioperative setting. Te results of our systematic analysis of te eligible clinical trials suggest tat melatonin possesses a significant anxiolytic effect and tus may be useful in igly anxious patients undergoing painful surgeries. Compared wit midazolam, melatonin as similar anxiolytic efficacy but less psycomotor impairment and fewer side effects. 974 Anestesiology, V 113 No 4 October 2010 Yousaf et al.

8 Melatonin as an Analgesic and Anxiolytic Te evidence regarding its potential analgesic effects in te perioperative setting is inconsistent and limited. Tere are very few or no adverse effects wit sort-term melatonin use. 33 On te oter and, midazolam is associated wit more excessive sedation, disorientation, impaired psycomotor performance, and amnesia compared wit melatonin. 23,24,26,30 32 It is still unclear weter te anxiolytic effect is applicable to all surgical patients because a possible gender and procedure bias exists in te currently available literature. Most of te included studies consisted of female patients undergoing laparoscopic colecystectomies or laparoscopic gynecological procedures. Te only contradictory study exaed an elderly population more tan 65 yr old. 23 Te elderly population as been sown to be refractory to te ypnotic and anxiolytic effects of melatonin. 34 Furtermore, several confounding variables existed in tis study, including different anestetic tecniques and different types of surgical procedures. 23 Altoug statistical significance was not reaced, te absolute level of anxiety scores did decrease by 33% after melatonin premedication versus a decrease of 21% in te placebo group. 23 Te clinical impact of melatonin on pain as not been sufficiently explored to justify its use widely. From te current available literature, conflicting evidence exists. Melatonin premedication was associated wit an analgesic effect in te studies wit pain as a primary outcome, wereas te lack of analgesic effect was observed in studies wit pain as a secondary outcome. 25,27 29 Tis migt reflect inadequate power and a type II error (false negative) finding in te latter. Moreover, te positive studies for analgesia consisted of studies wit a narrow and select group of population, mainly females wit low body mass indexes, and surgeries wit ig anticipated postoperative pain (VAS mm). 25,27 Te analgesic effect of melatonin as been demonstrated in particular for te subgroup of igly anxious patients, wit commendable number-needed-to-treat of less tan 3. 25,27 A dual-dosing regimen (nigt before and before surgery) was utilized in te two studies by Caumo et al. and in one study by Ionescu et al., wic reported reduced pain scores or an opioid-sparing effect in te melatonin group. 24,25,27 In contradistinction, a single preoperative dose was adistered in te studies refuting te analgesic effects of melatonin. 26,30,31 Terefore, it appears tat a dual-dosing regimen of 3 5 mg melatonin (for female patients) may ave a greater impact on pain tan a single preoperative dose of melatonin. Tere are a few limitations of our systematic review wic must be addressed. Our systematic review was confined to te studies publised in te Englis language only. Te data retrieved from te reviewed studies was not suitable for metaanalysis because te data were largely expressed in a grapical fasion or in median and range. Conversion of te data presented in median and interquartile range to mean and SD format can potentially compromise its accuracy and terefore was not attempted. In addition, te population studied, time of assessment of outcomes, and te dosing of melatonin varied among te reviewed studies, making it difficult to syntesize te data quantitatively. Baseline pain assessments were not performed, and terefore te validity of pain assessments in te reviewed trials may be questionable. Moreover, our qualitative analysis was limited by te small sample size of te reviewed clinical trials and te deficiencies of metodological quality, tereby exposing te study to a moderate risk of bias. However, te existing clinical evidence proposes tat melatonin wit its anxiolytic and possible analgesic effects may serve as te ideal alternative for premedication, potentially leading to better patient care and less opioidrelated morbidity. Conclusion Review of te literature provides compelling evidence tat melatonin premedication is effective in ameliorating perioperative anxiety in adults. Te analgesic effects of melatonin in te adult population during te perioperative period remain controversial. Additional well designed randomized controlled trials are necessary to compare melatonin premedication wit oter parmacological interventions, investigate its effect on more varied surgical populations, and delineate its optimal dosing regimen. References 1. Norris W, Baird WL: Pre-operative anxiety: A study of te incidence and aetiology. Br J Anaest 1967; 39: Jonson M: Anxiety in surgical patients. Psycol Med 1980; I0: Warfield CA, Kan CH: Acute pain management. 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