We reviewed the evidence from randomized controlled trials about the effects of melatonin on preoperative and postoperative anxiety in adults undergoing surgery when compared with placebo or benzodiazepine sedative drugs.
People often feel uneasy and apprehensive both before and after surgery. Anxiety occurs in up to 80% of individuals undergoing surgery. They may be concerned about their illness, the need for hospitalization and being incapacitated, anaesthesia, surgery, pain, and the situation.
Factors that can influence risk of anxiety include age (younger age), being female, surgery type, type of anaesthesia, and cultural and religious differences. Being anxious can lead to increased pain and the need for additional pain management.
Interventions to reduce the level of anxiety include anxiolytic-sedative drugs such as benzodiazepines, information and effective communication around the time of surgery, cognitive-behavioural therapy, music, and massage therapy.
Benzodiazepines can cause cognitive problems such as trouble remembering and concentrating and daytime sleepiness, and they can interfere with coordination and physical movement, even after single doses.
Melatonin is a hormone produced in the pineal gland in the brain that regulates circadian rhythms. These are the body and behavioural changes that follow a daily cycle and help to determine sleep patterns. Studies have shown that melatonin can reduce anxiety. It causes few or no cognitive problems and has no known serious side effects. This means it could be a worthy alternative to medical treatment.
Evidence for this review update is current to July 2020.
We found 27 randomized studies involving 2319 adult participants that looked at the effects of melatonin given before surgery on the level of anxiety both before and after surgery. Most studies were conducted in developing countries. We included any kind of surgical procedure in which general, regional, or topical anaesthesia was used.
Melatonin doses varied from 3 to 10 mg or from 0.05 to 0.4 mg/kg. Benzodiazepine (midazolam, oxazepam, or alprazolam) doses ranged from 0.25 to 15 mg or from 0.05 to 0.2 mg/kg.
None of the studies reported receipt of funding from drug manufacturers or agencies with commercial interests.
Twenty-four studies compared melatonin with placebo, and 11 studies compared melatonin with benzodiazepine drugs. Gabapentin, pregabalin, and clonidine were also compared with melatonin in some studies.
Melatonin reduced anxiety before surgery when compared to placebo (18 studies, 1264 participants; moderate-certainty evidence).
The reduction in anxiety after surgery was small compared with that seen with placebo (7 studies, 524 participants; low-certainty evidence), including at six hours after surgery (2 studies, 73 participants; low-certainty evidence).
Melatonin may have similar effects to benzodiazepines on the level of anxiety before surgery (7 studies, 409 participants; moderate-certainty evidence) and immediately after surgery (3 studies, 176 participants; low-certainty evidence).
Fourteen studies did not report on adverse events, six studies reported that no side effects were observed, and seven studies reported cases of nausea, sleepiness, dizziness, and headache. Benzodiazepines interfered with psychomotor and cognitive function more than placebo and melatonin (in 11 studies). They caused the greatest degree of sedation, although melatonin also showed sedation compared to placebo (14 studies). No serious adverse events were reported.
Quality of the evidence
We are moderately confident that melatonin reduces anxiety preoperatively compared with placebo. Effects on immediate and delayed postoperative anxiety after surgery are less clear when compared with placebo (low-quality evidence).
We did not find any evidence that melatonin differs in antianxiety effects from benzodiazepines (moderate- and low-quality evidence).
It remains unclear whether the anxiety-reducing effects of melatonin apply to all surgical patients.
Giving melatonin before surgery may effectively reduce anxiety before surgery, but any reduction in anxiety after surgery with melatonin is less clear when compared with placebo.
When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults.
Anxiety in relation to surgery is a well-known problem. Melatonin offers an alternative treatment to benzodiazepines for ameliorating this condition in the preoperative and postoperative periods.
To assess the effects of melatonin on preoperative and postoperative anxiety compared to placebo or benzodiazepines.
We searched the following databases on 10 July 2020: CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science. For ongoing trials and protocols, we searched clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform.
We included randomized, placebo-controlled or standard treatment-controlled (or both) studies that evaluated the effects of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both sexes (15 to 90 years of age) undergoing any kind of surgical procedure for which it was necessary to use general, regional, or topical anaesthesia.
One review author conducted data extraction in duplicate. 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 regimens, preoperative anxiety outcome measures, and postoperative anxiety outcome measures.
We included 27 randomized controlled trials (RCTs), involving 2319 participants, that assessed melatonin for treating preoperative anxiety, postoperative anxiety, or both.
Twenty-four studies compared melatonin with placebo. Eleven studies compared melatonin to a benzodiazepine (seven studies with midazolam, three studies with alprazolam, and one study with oxazepam). Other comparators in a small number of studies were gabapentin, clonidine, and pregabalin.
No studies were judged to be at low risk of bias for all domains. Most studies were judged to be at unclear risk of bias overall. Eight studies were judged to be at high risk of bias in one or more domain, and thus, to be at high risk of bias overall.
Melatonin versus placebo
Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo (mean difference (MD) -11.69, 95% confidence interval (CI) -13.80 to -9.59; 18 studies, 1264 participants; moderate-certainty evidence), based on a meta-analysis of 18 studies.
Melatonin may reduce immediate postoperative anxiety measured on a 0 to 100 mm VAS compared to placebo (MD -5.04, 95% CI -9.52 to -0.55; 7 studies, 524 participants; low-certainty evidence), and may reduce delayed postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) (MD -5.31, 95% CI -8.78 to -1.84; 2 studies; 73 participants; low-certainty evidence).
Melatonin versus benzodiazepines (midazolam and alprazolam)
Melatonin probably results in little or no difference in preoperative anxiety measured on a 0 to 100 mm VAS (MD 0.78, 95% CI -2.02 to 3.58; 7 studies, 409 participants; moderate-certainty evidence) and there may be little or no difference in immediate postoperative anxiety (MD -2.12, 95% CI -4.61 to 0.36; 3 studies, 176 participants; low-certainty evidence).
Fourteen studies did not report on adverse events. Six studies specifically reported that no side effects were observed, and the remaining seven studies reported cases of nausea, sleepiness, dizziness, and headache; however, no serious adverse events were reported. Eleven studies measured psychomotor and cognitive function, or both, and in general, these studies found that benzodiazepines impaired psychomotor and cognitive function more than placebo and melatonin. Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo. Several studies did not report on adverse events; therefore, it is not possible to conclude with certainty, from the data on adverse effects collected in this review, that melatonin is better tolerated than benzodiazepines.