Abstract: 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). 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.

Plain-language summary: The evidence was current to April 2013. We found 12 studies involving 774 patients. The age of the participants, in the studies, ranged from 19 to 80 years. Types of surgery and anaesthesia varied. The melatonin doses varied from 3 to14 mg and were administered 50 to 100 minutes before surgery. Midazolam (a benzodiazepine) doses ranged from 3.5 to 15 mg. We reran the search in October 2014. We will deal with any studies of interest when we update the review. Four studies compared melatonin, placebo and midazolam; eight studies compared melatonin and placebo only. Comparing the effect of melatonin with placebo, melatonin may reduce preoperative anxiety. It may also reduce postoperative anxiety compared with placebo, measured six hours after surgery. When comparing the effect of melatonin with midazolam preoperatively, there was no difference in anxiety. Postoperatively, there was no difference when comparing the effect of melatonin with placebo on anxiety measured 90 minutes after surgery or when comparing the effect of melatonin with midazolam. The quality of the evidence varied by outcome. We are confident that melatonin reduces anxiety preoperatively from the short term data in the review. We are less certain of this effect six hours postoperatively. Whether the anxiety reducing effect of melatonin can be applied to all surgical patients remains unclear, as many factors influence the risk of anxiety; among these are age, gender, type of surgery, type of anaesthesia, and cultural and religious differences. Younger age and female gender are independent risk factors for anxiety and this may be a limitation as four studies only included women and three only included patients older than 60 years. Eight studies were carried out in Middle-East countries; this might be a limitation with regard to generalizability. Melatonin compared to placebo, given as premedication (tablets or under the tongue (sublingually)) reduced preoperative anxiety (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety (measured 50 to 100 minutes after administration). When compared to placebo, melatonin may reduce postoperative anxiety (six hours after surgery).