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British Journal of Anaesthesia
BJA

III. Perioperative melatonin: not ready for prime time

      Melatonin is an endogenous sleep hormone produced in the pineal gland. The primary physiological role of melatonin is the regulation of circadian rhythms in mammals. Pharmacological doses of melatonin have been shown to be effective in treatment of sleep disorders and circadian rhythm disorders. In recent years, melatonin has been tested in various clinical conditions such as hypertension, diabetes, metastasizing cancer, fibromyalgia, irritable bowel syndrome, and chronic obstructive pulmonary disease. Moreover, a total of 21 randomized trials have investigated the use of melatonin in the perioperative period.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Borazan H
      • Tuncer S
      • Yalcin N
      • Erol A
      • Otelcioglu S
      Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Gögenur I
      • Kücükakin B
      • Bisgaard T
      • et al.
      The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Capuzzo M
      • Zanardi B
      • Schiffino E
      • et al.
      Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.
      • Kain ZN
      • MacLaren JE
      • Herrmann L
      • et al.
      Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      • Turkistani A
      • Abdullah KM
      • Al-Shaer AA
      • Mazen KF
      • Alkatheri K
      Melatonin premedication and the induction dose of propofol.
      • Naguib M
      • Samarkandi AH
      • Moniem MA
      • et al.
      The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study.
      • Kücükakin B
      • Klein M
      • Lykkesfeldt J
      • Reiter RJ
      • Rosenberg J
      • Gögenur I
      No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebo-controlled trial.
      • Kücükakin B
      • Wilhelmsen M
      • Lykkesfeldt J
      • Reiter RJ
      • Rosenberg J
      • Gögenur I
      No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebo-controlled trial.
      • Isik B
      • Baygin O
      • Bodur H
      Premedication with melatonin vs midazolam in anxious children.
      • Özcengiz D
      • Gunes Y
      • Ozmete O
      Oral melatonin, dexmedetomidine, and midazolam for prevention of postoperative agitation in children.
      • Evagelidis P
      • Paraskeva A
      • Petropoulos G
      • Staikou C
      • Fassoulaki A
      Melatonin premedication does not enhance induction of anaesthesia with sevoflurane as assessed by bispectral index monitoring.
      • Nickkholgh A
      • Schneider H
      • Sobirey M
      • et al.
      The use of high-dose melatonin in liver resection is safe: first clinical experience.
      A perioperative course incorporating principles for fast-track recovery requires optimal pain relief and rapid mobilization, and a multimodal focus on the reduction in fatigue, postoperative nausea and vomiting (PONV), cognitive impairment, and sleep disturbances. A possible clinical effect and an appealing safety profile makes melatonin an interesting new drug for the perioperative setting. Moreover, widely used analgesics, anxiolytics, and sedatives are associated with risk of side-effects such as respiratory depression, postoperative delirium, and PONV and might increase the risk of serious complications in the perioperative period. The development of effective analgesics, anxiolytics, and sedatives is therefore still relevant to ensure safety for the patient. Melatonin has shown promising result, but one essential question still remains; what is the evidence for the use of melatonin in the perioperative setting and should it be applied in our daily clinical practice?
      Thirteen studies have explored the anxiolytic effects of melatonin in the perioperative period.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Capuzzo M
      • Zanardi B
      • Schiffino E
      • et al.
      Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.
      • Kain ZN
      • MacLaren JE
      • Herrmann L
      • et al.
      Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      • Turkistani A
      • Abdullah KM
      • Al-Shaer AA
      • Mazen KF
      • Alkatheri K
      Melatonin premedication and the induction dose of propofol.
      • Naguib M
      • Samarkandi AH
      • Moniem MA
      • et al.
      The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study.
      These studies have documented that melatonin is effective in treating perioperative anxiety, showing significant anxiolytic effects in 11 of the 13 studies.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      • Turkistani A
      • Abdullah KM
      • Al-Shaer AA
      • Mazen KF
      • Alkatheri K
      Melatonin premedication and the induction dose of propofol.
      • Naguib M
      • Samarkandi AH
      • Moniem MA
      • et al.
      The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study.
      The anxiolytic effects have been documented before operation, intraoperatively, and after operation, on multiple widely accepted anxiety scales (state trait anxiety inventory, Yale preoperative anxiety scale, visual analogue scale, and numerical rating scale), and in comparison with inactive placebo and other anxiolytics/sedatives.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      The analgesic effects of melatonin have been investigated in 11 randomized studies.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Borazan H
      • Tuncer S
      • Yalcin N
      • Erol A
      • Otelcioglu S
      Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Gögenur I
      • Kücükakin B
      • Bisgaard T
      • et al.
      The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Capuzzo M
      • Zanardi B
      • Schiffino E
      • et al.
      Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.
      Six studies have documented significantly improved analgesia, reduced analgesic requirements in the perioperative period, or both,
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Borazan H
      • Tuncer S
      • Yalcin N
      • Erol A
      • Otelcioglu S
      Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      whereas five studies could not document an analgesic effect of melatonin administration.
      • Gögenur I
      • Kücükakin B
      • Bisgaard T
      • et al.
      The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Capuzzo M
      • Zanardi B
      • Schiffino E
      • et al.
      Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.
      Four studies have investigated the effects of melatonin on sleep in relation to surgery, but only documented minor, although significant, effects on subjective and objective sleep parameters.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Borazan H
      • Tuncer S
      • Yalcin N
      • Erol A
      • Otelcioglu S
      Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial.
      • Gögenur I
      • Kücükakin B
      • Bisgaard T
      • et al.
      The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      Moreover, a positive effect of melatonin on objectively measured sleep parameters was found in a small randomized clinical trial in mechanically ventilated patients in the intensive care unit.
      • Bourne RS
      • Mills GH
      • Minelli C
      Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.
      The sleep-regulating effect of melatonin in surgical patients still remains to be established.
      The previously described studies investigating anxiety, analgesia, and sleep quality were all randomized double-blinded placebo-controlled trials. However, the quality of the described studies is heterogeneous and often with a lack of documentation of primary outcomes,
      • Mowafi HA
      • Ismail SA
      Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia.
      • Ismail SA
      • Mowafi HA
      Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Naguib M
      • Samarkandi AH
      Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam.
      • Naguib M
      • Samarkandi AH
      The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study.
      • Capuzzo M
      • Zanardi B
      • Schiffino E
      • et al.
      Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.
      • Samarkandi A
      • Naguib M
      • Riad W
      • et al.
      Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study.
      • Turkistani A
      • Abdullah KM
      • Al-Shaer AA
      • Mazen KF
      • Alkatheri K
      Melatonin premedication and the induction dose of propofol.
      • Naguib M
      • Samarkandi AH
      • Moniem MA
      • et al.
      The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study.
      • Özcengiz D
      • Gunes Y
      • Ozmete O
      Oral melatonin, dexmedetomidine, and midazolam for prevention of postoperative agitation in children.
      • Bourne RS
      • Mills GH
      • Minelli C
      Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial.
      or missing prestudy power calculations.
      • Acil M
      • Basgul E
      • Celiker V
      • Karagöz AH
      • Demir B
      • Aypar U
      Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance.
      • Turkistani A
      • Abdullah KM
      • Al-Shaer AA
      • Mazen KF
      • Alkatheri K
      Melatonin premedication and the induction dose of propofol.
      • Naguib M
      • Samarkandi AH
      • Moniem MA
      • et al.
      The effects of melatonin premedication on propofol and thiopental induction dose–response curves: a prospective, randomized, double-blind study.
      Furthermore, none of the studies has adhered to ‘CONSORT’ guidelines concerning randomized clinical trials. The numbers of patients in the studies were generally low, and the inclusion criteria restrictive, reducing the external validity of the results.
      A general issue concerning the studies investigating melatonin has been the time of administration in relation to the wanted effect. Four of the studies investigating anxiety and pain administered melatonin the night before surgery and documented significant positive effects.
      • Caumo W
      • Levandovski R
      • Hidalgo MP
      Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy; a double-blind, randomized, placebo-controlled study.
      • Caumo W
      • Torres F
      • Moreira Jr, NL
      • et al.
      The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy.
      • Borazan H
      • Tuncer S
      • Yalcin N
      • Erol A
      • Otelcioglu S
      Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial.
      • Ionescu D
      • Badescu C
      • Ilie A
      • Acalovschi I
      Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebo-controlled study.
      The exact mechanisms of melatonin for these indications are still being investigated, but animal studies have shown specific receptor-mediated effects and interaction with multiple other receptor systems such as the GABA, benzodiazepine, and opioid system.
      • Srinivasan V
      • Pandi-Perumal SR
      • Spence DW
      • et al.
      Potential use of melatonergic drugs in analgesia: mechanisms of action.
      Furthermore, in humans, the anxiolytic, analgesic, and hypnotic effects may be inter-related. More detailed knowledge concerning mechanisms of action and correct timing of administration are therefore needed to target maximal effects of melatonin in humans.
      Another matter is the choice of effective dosage. In clinical studies investigating anxiety and pain, 3–10 mg of melatonin has shown significant results. Animal studies have used doses ranging from 0.3 µg administered intrathecally, up to 300 mg kg−1 bodyweight administered orally across several animal models documenting dose-dependent anxiolytic and anti-nociceptive effects.
      • Srinivasan V
      • Pandi-Perumal SR
      • Spence DW
      • et al.
      Potential use of melatonergic drugs in analgesia: mechanisms of action.
      • Papp M
      • Litwa E
      • Gruca P
      • Mocaër E
      Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety.
      The correct dosage of melatonin in humans seems largely unknown and should be investigated further, documenting dose–response curves for the individual indications.
      Melatonin has an extensive first-pass metabolism of ∼85%, and a limited half-life of 1 h. The inter-subject differences in bio-availability are however low.
      • DeMuro RL
      • Nafziger AN
      • Blask DE
      • Menhinick AM
      • Bertino Jr, JS
      Absolute bioavailability of oral melatonin.
      It should however be mentioned that earlier studies have reported very variable bio-availability after melatonin administration and findings of DeMuro and colleagues should be confirmed in future studies. The previously mentioned studies have investigated oral or sublingual administration. Future studies should take proper consideration to the pharmacokinetics of melatonin and examine the potential efficacy differences in the various administration forms.
      The lack of studies documenting a strong dose–effect relation in humans, and the absence of preclinical studies (such as human experimental models) raise several questions before melatonin can be used routinely in the clinical setting. Furthermore, an investigation of the link between mechanisms of action and clinical effects should be elaborated in humans. Moreover, a limited number of clinical studies have investigated the perioperative use of melatonin in relation to analgesia and sleep quality, and their findings have been contradictory. Thus, the currently available studies do not support routine perioperative clinical use of melatonin.
      The anxiolytic effect of melatonin before surgery is the best-documented effect, and, when used as an anxiolytic agent, melatonin has negligible side-effects. Based on previously described studies investigating anxiety and the pharmacokinetics of melatonin, it would appear that 5–10 mg of oral melatonin 30–60 min before operation may have useful effect, but there have been limited data on the dosage.

      Declaration of interest

      None declared.

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