Melatonin possesses sedative, hypnotic, analgesic, antiinflammatory, antioxidative, and chronobiotic properties that distinguish it as an attractive alternative premedicant. A qualitative systematic review of the literature concerning the perioperative use of melatonin as an anxiolytic or analgesic in adult patients was carried out using the recommended guidelines provided by the Cochrane Handbook for Systematic Reviews of Interventions. Nine of the 10 studies showed statistically significant reduction of preoperative anxiety with melatonin premedication compared with placebo. An opioid-sparing effect or reduced pain scores were evident in five studies whereas three studies were contradictory. Thus, melatonin premedication is effective in ameliorating preoperative anxiety in adults, but its analgesic effects remain controversial in the perioperative period. Additional well designed randomized controlled trials are necessary to compare melatonin premedication with other pharmacological interventions, investigate its effect on more varied surgical populations, and to delineate its optimal dosing regimen.

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Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials.

Background
Since the early 1980s, it has become more and more common to carry out surgical procedures on a day case basis. Many patients are anxious before surgery yet there is sometimes a reluctance to provide sedative medication because it is believed to delay discharge from hospital.This is an updated version of the review first published in 2000 (previous updates 2003; 2006).

Objectives
To assess the effect of anxiolytic premedication on time to discharge in adult patients undergoing day case surgery under general anaesthesia.

Search methods
We identified trials by computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2009 Issue 1 ); MEDLINE (1980 to January 2009); EMBASE (1980 to January 2009). We also checked the reference lists of trials and review articles and handsearched three main anaesthesia journals.

Selection criteria
We included all identified randomized controlled trials comparing anxiolytic drug(s) with placebo before general anaesthesia in adult day case surgical patients.

Data collection and analysis
We collected data on anaesthetic drugs used; results of psychomotor function tests where these were used to assess residual effect of premedication; and on times from end of anaesthesia to ability to walk unaided or readiness for discharge from hospital. Formal statistical synthesis of individual trials was not performed in view of the variety of drugs studied.

Main results
We included 17 studies. Methodological quality of included studies was poor. Of these 17, only seven studies specifically addressed the discharge question; none found any delay in premedicated patients. Two other studies used clinical criteria to assess fitness for discharge, though times were not given. Again, there was no difference from placebo. Eleven studies used tests of psychomotor function with or without clinical measures as indicators of recovery from anaesthesia. In none of these studies did the premedication appear to delay discharge, although performance on tests of psychomotor function was sometimes still impaired. Three studies showed no impairment in psychomotor function, six showed some impairment which had resolved by three hours or time of discharge and two showed significant impairment.

Authors' conclusions
We found no evidence of a difference in time to discharge from hospital, assessed by clinical criteria, in patients who received anxiolytic premedication. However, in view of the age and variety of anaesthetic techniques used and clinical heterogeneity between studies, inferences for current day case practice should be made with caution.

Premedication for anxiety in adult day surgery.

We systematically reviewed randomised controlled trials of peri-operative melatonin. We included 24 studies of 1794 participants that reported eight peri-operative outcomes: anxiety; analgesia; sleep quality; oxidative stress; emergence behaviour; anaesthetic requirements; steal induction; and safety. Compared with placebo, melatonin reduced the standardised mean difference (95% CI) pre-operative anxiety score by 0.88 (0.44-1.33) and postoperative pain score by 1.06 (0.23-1.88). 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.

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/pdf/10.1111/anae.12717

A systematic review of peri‐operative melatonin

Background
Anxiety in relation to surgery is a well-known problem. Melatonin offers an atoxic alternative to benzodiazepines in ameliorating this condition in the pre- and postoperative period.

Objectives
To assess the effect of melatonin on pre- and postoperative anxiety in adults when comparing melatonin with placebo or when comparing melatonin with benzodiazepines.

Search methods
The following databases were searched on 19 April 2013: CENTRAL, MEDLINE, EMBASE, CINAHL and Web of Science. For ongoing trials and protocols we searched clinicaltrials.gov, Current Controlled Trials and the World Health Organization (WHO) International Clinical Trials Registry Platform. We reran the search in October 2014. We will deal with any studies of interest when we update the review.

Selection criteria
Randomized, placebo-controlled or standard treatment-controlled, or both, studies that evaluated the effect of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both genders (15 to 90 years of age) undergoing any kind of surgical procedure in which it was necessary to use general, regional or topical anaesthesia.

Data collection and analysis
Data were extracted independently by two review authors. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimen, preoperative anxiety outcome measures and postoperative anxiety outcome measures.

Main results
This systematic review identified 12 randomized controlled trials (RCTs) including 774 patients that assessed melatonin for treating preoperative anxiety, postoperative anxiety or both. Four of the 12 studies compared melatonin, placebo and midazolam, whereas the remaining eight studies compared melatonin and placebo only.

The quality of the evidence for our primary outcome (melatonin versus placebo for preoperative anxiety) was high. More than half of the included studies had a low risk of selection bias and at least 75% of the included studies had a low risk of attrition, performance and detection bias. Most of the included studies had an unclear risk of reporting bias.

Eight out the 10 studies that assessed the effect of melatonin on preoperative anxiety using a visual analogue scale (VAS) (ranging from 0 to 100 mm, higher scores indicate greater anxiety) showed a reduction compared to placebo. The reported estimate of effect (relative effect -13.36, 95% confidence interval (CI) -16.13 to -10.58; high quality evidence) was based on a meta-analysis of seven studies. Two studies did not show any difference between melatonin and placebo. Two studies comparing melatonin with midazolam using a VAS found no evidence of a difference in preoperative anxiety between the two groups (relative effect -1.18, 95% CI -2.59 to 0.23; low quality evidence).

Eight studies assessed the effect of melatonin on postoperative anxiety. Four of these studies measuring postoperative anxiety 90 minutes postoperatively using a VAS did not find any evidence of a difference between melatonin and placebo (relative effect -3.71, 95% CI -9.26 to 1.84). Conversely, two studies showed a reduction of postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) when comparing melatonin with placebo (relative effect -5.31, 95% CI -8.78 to -1.84; moderate quality evidence). Two studies comparing melatonin with midazolam using a VAS did not find any evidence of a difference between the two groups in postoperative anxiety (relative effect -2.02, 95% CI -5.82 to 1.78).

Authors' conclusions
When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults (measured 50 to 100 minutes after administration). The effect of melatonin on postoperative anxiety (measured 90 minutes and 6 hours after surgery) in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.

Melatonin for pre‐ and postoperative anxiety in adults

This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

Pharmacokinetics of high-dose intravenous melatonin in humans.

Background: There are only a few studies involving the use of melatonin for premedication for anaesthesia. The goal of our study was to compare the effects of melatonin and midazolam administered a...

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Melatonin as premedication for laparoscopic cholecystectomy: a double-blind, placebo-controlled study

Background There are only a few studies involving the use of melatonin for premedication for anaesthesia. The goal of our study was to compare the effects of melatonin and midazolam administered as premedication for laparoscopic cholecystectomy. 
Methods This double-blind, placebo-controlled study included 53 patients (ASA I, II) undergoing laparoscopic cholecystectomy under general anaesthesia. The patients were divided into three groups : group 1 (n = 18) included patients receiving 3 mg melatonin the night before and as premedication; group 2 (n = 17) included the patients receiving 3,75 mg midazolam (1 / 2 of a 7,5 mg tablet) by the same protocol as for melatonin; and group 3 (n = 18) included patients receiving placebo tablets. Preoperatively, the anxiety and sedation scores, as well as the quality of preanaesthetic sleep, were evaluated. Postoperatively, the anxiety and sedation scores and the number of remembered pictures were evaluated at 15 and 60 minutes and 6, 12 and 24 hours respectively. The intra-anaesthetic opioid requirements were also evaluated. 
Results Preoperatively the lowest anxiety score was registered in the midazolam group; also the difference between the melatonin and midazolam groups was not significant. In the placebo group the anxiety score was significantly higher as compared with melatonin or midazolam. Postoperatively anxiety scores were lowest in the melatonin group at every time interval. The scores for the remembered pictures were consistently better in the melatonin group. The sedation score was lower in the melatonin group as compared with midazolam, as were the intra-anaesthetic opioid requirements. 
Conclusions Melatonin (3 mg) can be successfully used as premedication for laparoscopic cholecystectomy, especially for day case surgery. Advantages over midazolam and placebo include better perioperative anxiolysis, and a better recovery profile as assessed by sedation and memory.

I. Miclutia

Papers

Melatonin as premedication for laparoscopic cholecystectomy: a double-blind, placebo-controlled study

Melatonin as premedication for laparoscopic cholecystectomy : a double-blind, placebo-controlled study : scientific letter