Anaesthesia

Volume 69, Issue 10 p. 1163-1171

Review Article

Free Access

A systematic review of peri-operative melatonin

L. P. H. Andersen,

Corresponding Author

L. P. H. Andersen

PhD Fellow

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

Correspondence to: L. P. H. Andersen

Email: [email protected]

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M. U. Werner,

M. U. Werner

Associate Anaesthetic Professor

Multidisciplinary Pain Center 7612, Neuroscience Center, Copenhagen, Denmark

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J. Rosenberg,

J. Rosenberg

Professor

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

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I. Gögenur,

I. Gögenur

Associate Professor

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

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L. P. H. Andersen,

Corresponding Author

L. P. H. Andersen

PhD Fellow

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

Correspondence to: L. P. H. Andersen

Email: [email protected]

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M. U. Werner,

M. U. Werner

Associate Anaesthetic Professor

Multidisciplinary Pain Center 7612, Neuroscience Center, Copenhagen, Denmark

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J. Rosenberg,

J. Rosenberg

Professor

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

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I. Gögenur,

I. Gögenur

Associate Professor

Department of Surgery D, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

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First published: 19 May 2014

https://doi.org/10.1111/anae.12717

Citations: 64

You can respond to this article at http://www.anaesthesiacorrespondence.com

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Summary

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 I² 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.

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, anxiety 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 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 I² 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; anxiety; sleep quality; oxidative stress; emergence behaviour; anaesthetic doses; steal anaesthetic induction (in a sleeping patient); and safety (Table 2).

Table 1. Risk of bias table, categorising nine methodological domains in each of 24 included RCTs.

	1	2	3	4	5	6	7	8	9
	Bias domain
Acil et al. 2004 17	?	?	?	+	+	?	+	−	−
Almenrader et al. 2013 31	+	+	+	+	+	+	+	+	+
Borazan et al. 2010 13	+	+	+	+	?	?	+	+	+
Capuzzo et al. 2006 20	+	+	+	?	+	?	+	+	−
Caumo et al. 2007 6	+	+	+	+	?	?	+	+	+
Caumo et al. 2009 5	+	+	+	+	+	?	+	+	+
Evagelidis et al. 2009 30	+	+	+	+	?	?	+	−	−
Gögenur et al. 2009 16	+	+	+	+	+	?	+	+	+
Haghjooy et al. 2013 28	+	+	+	+	+	?	+	−	−
Ismail & Mowafi 2009 14	+	+	+	+	?	?	+	+	−
Isik et al. 2008 27	?	?	+	+	?	?	+	+	−
Ionescu et al. 2008 15	?	?	+	+	?	?	+	+	−
Kain et al. 2009 21	+	+	+	+	?	?	+	+	+
Khezri & Merate 2013 4	+	+	+	+	+	?	+	−	+
Kücükakin et al. 2010 25	+	+	?	?	+	+	+	+	+
Kücükakin et al. 2010 26	+	?	?	?	+	−	+	+	+
Naguib & Samarkandi 1999 18	?	?	+	+	?	?	+	+	−
Naguib & Samarkandi 2000 19	?	?	+	+	?	?	+	+	−
Naguib et al. 2006 24	+	+	+	+	?	?	+	−	−
Nickkholgh et al. 2011 32	+	+	+	+	+	+	+	−	+
Mowafi & Ismail 2008 12	+	+	?	+	?	?	+	+	−
Özcengiz et al. 2011 29	+	+	+	+	?	?	+	+	−
Samarkandi et al. 2005 22	+	+	+	+	?	?	+	+	−
Turkistani et al. 2007 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.

Table 2. Details of included RCTs.

	n	Surgery	Anaesthetic	Control	Route	Dose	Timing	Outcomes
Acil et al. 2004 17	66	Laparoscopic cholecystectomy	GA	Midazolam, placebo	SL	5 mg	90 min <	Analgesia, anxiety
Almenrader et al. 2013 31	87	Various	GA	Clonidine	Oral	5 mg	60 min <	Steal induction
Borazan et al. 2010 13	52	Open prostatectomy	GA	Placebo	Oral	6 mg × 2	Night < and 60 min <	Analgesia, sleep
Capuzzo et al. 2006 20	138	Various	GA/Spinal	Placebo	Oral	10 mg	90 min <	Analgesia, anxiety
Caumo et al. 2007 6	33	Open hysterectomy	Epidural	Placebo	Oral	5 mg × 2	Night < and 60 min <	Analgesia, anxiety, sleep
Caumo et al. 2009 5	59	Open hysterectomy	Epidural	Clonidine, placebo	Oral	5 mg × 2	Night < and 60 min <	Analgesia, anxiety
Evagelidis et al. 2009 30	71	Hysteroscopy	GA	Placebo	SL	0.1, 0.25 or 0.5 mg.kg⁻¹	30 min <	Anaesthetic requirement
Gögenur et al. 2009 16	121	Laparoscopic cholecystectomy	GA	Placebo	Oral	5 mg	> for three nights	Analgesia, sleep
Haghjooy et al. 2013 28	30	CABG	GA	Placebo	Oral	10 mg	For one month daily and 60 min <	Oxidative stress
Ismail & Mowafi 2009 14	40	Ophthalmological	Topical	Placebo	Oral	10 mg	90 min <	Analgesia, anxiety
Isik et al. 2008 27	60	Dental	Sedation	Midazolam, placebo	Oral	3 mg or 0.5 mg.kg⁻¹	60 min <	Sedation
Ionescu et al. 2008 15	53	Laparoscopic cholecystectomy	GA	Midazolam, placebo	SL	3 mg × 2	Night < and 90 min <	Analgesia, anxiety
Kain et al. 2009 21	148	Various	GA	Midazolam	Oral	0.05, 0.2 or 0.4 mg.kg⁻¹	45 min <	Anxiety, emergence
Khezri & Merate 2013 4	60	Ophthalmological	Topical	Placebo	SL	3 mg	60 min <	Analgesia, anxiety
Kücükakin et al. 2010 25	41	Laparoscopic cholecystectomy	GA	Placebo	IV then oral	10 mg	At incision	Oxidative stress
Kücükakin et al. 2010 26	50	Major vascular	GA/ Epidural	Placebo	IV then oral	50 mg then 10 mg	At incision and > for 3 nights	Oxidative stress
Naguib & Samarkandi 1999 18	75	Laparoscopic gynaecological	GA	Midazolam, placebo	SL	5 mg	100 min <	Analgesia, anxiety
Naguib & Samarkandi 2000 19	84	Laparoscopic gynaecological	GA	Midazolam, placebo	SL	0.05, 0.1 or 0.2 mg.kg⁻¹	100 min <	Analgesia, anxiety
Naguib et al. 2006 24	200	Various	GA	Placebo	Oral	0.2 mg.kg⁻¹	50 min <	Anaesthetic requirement, anxiety
Nickkholgh et al. 2011 32	36	Hepatic	GA	Placebo	Oral	50 mg.kg⁻¹	After intubation	Safety
MowafI & Ismail 2008 12	40	Hand	IVRA	Placebo	Oral	10 mg	90 min <	Analgesia, anxiety
Özcengiz et al. 2011 29	100	Oesophageal dilatation	GA	Dex’, midazolam, placebo	Oral	0.1 mg.kg⁻¹	45 min <	Emergence
Samarkandi et al. 2005 22	105	Various	GA	Midazolam, placebo	Oral	0.1, 0.25 or 0.5 mg.kg⁻¹	60 min <	Anxiety, emergence, sleep
Turkistani et al. 2007 23	45	Various	GA	Placebo	Oral	3 or 5 mg	100 min <	Anaesthetic requirements, anxiety

CABG, coronary artery bypass grafting; GA, general anaesthesia; IVRA, intravenous regional analgesia; Dex', dexmedetomidine; SL, sublingual; IV, intravenous; <, before surgery; >, after surgery.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

PRISMA flowchart.

Most studies gave 3–10 mg (0.05–0.5 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 30–100 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 placebo 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 placebo 23. Participants had various operations: abdominal 15-17, 25, 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).

Table 3. The effect of melatonin compared with placebo on intra-operative pain scores.

Effect of melatonin on pain score
Capuzzo et al. 2006 20	→
Ismail & Mowafi 2009 14	↓
Khezri & Merate 2013 4	→
Mowafi & Ismail 2008 12	↓

→, no statistical difference; ↓, statistically less pain after melatonin vs placebo.

Table 4. The effect of melatonin, compared with placebo, on intra-operative and postoperative analgesic doses reported in nine and six RCTs, respectively.

	Intra-operative	Postoperative
	Analgesic dose
Borazan et al. 2010 13	↓	↓
Caumo et al. 2007 6	→	↓
Caumo et al. 2009 5	→	↓
Ionescu et al. 2008 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 placebo.

Fourteen studies (n = 1146) investigated anxiety before, during and after surgery using four different scales: VAS 4, 12, 14, 17-19, 23, 24; NRS 20; state-trait anxiety inventory 5, 6, 15; Yale pre-operative anxiety scale 21, 22. Melatonin reduced pre-operative anxiety, 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 anxiety or was no different to control (Table 5).

Table 5. The effect of melatonin, compared with placebo, on intra-operative and postoperative anxiety scores reported in two and eight RCTs, respectively.

	Intra-operative	Postoperative
	Anxiety score
Acil et al. 2004 17		↓
Capuzzo et al. 2006 20		→
Caumo et al. 2007 6		↓
Caumo et al. 2009 5		↓
Ionescu et al. 2008 15		↓
Ismail & Mowafi 2009 14	↓
Khezri & Merate 2013 4	↓	↓
Naguib & Samarkandi 1999 18		→
Naguib & Samarkandi 2000 19		→

→, no statistical difference; ↓, statistically less anxiety after melatonin vs placebo.

Only one study in children intended to record sedation as an outcome (n = 60), and found no difference between melatonin and placebo 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 placebo 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 placebo 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 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 placebo, melatonin reduced postoperative pain and pre-operative anxiety. 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.

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).

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 (MT₁ and MT₂) and interaction with opioid, ?-aminobutyric acid (GABA) or N-methyl-D-aspartate 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 dose-response relationship for melatonin has yet to be demonstrated in humans, which might be provided in non-clinical settings 38, 39.

Peri-operative anxiety 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 anxiety 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 peri-operative polysomnography.

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 15–30 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 anxiety, including subsequent anaesthetics. Melatonin has not been compared with placebo, but appears to be inferior to clonidine 31.

Several studies have demonstrated that melatonin is without the adverse effects associated with opioids, non-steroidal 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 anxiety 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.

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Volume69, Issue10

October 2014

Pages 1163-1171

A systematic review of peri-operative melatonin

Summary

Introduction

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Discussion

Acknowledgements

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A systematic review of peri-operative melatonin

Summary

Introduction

Methods

Results

Discussion

Acknowledgements

Competing interests

References

Citing Literature

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References

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