BJA
Editorial III
British Journal of Anaesthesia 112 (1): 7–8 (2014) doi:10.1093/bja/aet332
EDITORIAL III
Perioperative melatonin: not ready for prime time L. P. H. Andersen*, J. Rosenberg and I. Go¨genur Department of Surgery, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark * Corresponding author. E-mail: [email protected]
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.2 4 7 13 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.22 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,3 5 6 8 – 11 13 – 15 19 22 or missing prestudy power calculations.8 14 15 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.1 2 4 6 The exact mechanisms of melatonin for these indications are still being investigated, but animal studies have shown specific receptormediated effects and interaction with multiple other receptor systems such as the GABA, benzodiazepine, and opioid system.23 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 mg administered intrathecally, up to 300 mg kg21 bodyweight administered orally across several animal models documenting dose-dependent anxiolytic and anti-nociceptive effects.23 24 The correct dosage of melatonin in humans seems largely unknown and should be investigated further, documenting dose –response curves for the individual indications.
7
Downloaded from http://bja.oxfordjournals.org/ by guest on March 24, 2015
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.1 – 21 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.1 – 3 5 6 8 – 15 These studies have documented that melatonin is effective in treating perioperative anxiety, showing significant anxiolytic effects in 11 of the 13 studies.1 – 3 5 6 8 – 10 13 – 15 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.1 6 8 – 10 13 The analgesic effects of melatonin have been investigated in 11 randomized studies.1 – 11 Six studies have documented significantly improved analgesia, reduced analgesic requirements in the perioperative period, or both,1 – 6 whereas five studies could not document an analgesic effect of melatonin administration.7 – 11
BJA
Declaration of interest None declared.
References 1 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. J Pain 2009; 10: 100–8 2 Caumo W, Torres F, Moreira NL Jr, et al. The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg 2007; 105: 1263– 71 3 Mowafi HA, Ismail SA. Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesth Analg 2008; 107: 1422– 6 4 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. J Anesth 2010; 24: 155– 60 5 Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg 2009; 108: 1146–51 6 Ionescu D, Badescu C, Ilie A, Acalovschi I. Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebocontrolled study. SAJAA 2008; 57: 8–11
8
7 Go¨genur I, Ku¨cu¨kakin B, Bisgaard T, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial. Anesth Analg 2009; 108: 1152–6 8 Acil M, Basgul E, Celiker V, Karago¨z AH, Demir B, Aypar U. Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance. Eur J Anaesthesiol 2004; 21: 553– 7 9 Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth 1999; 82: 875–80 10 Naguib M, Samarkandi AH. The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000; 91: 473– 9 11 Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg 2006; 103: 121–3 12 Kain ZN, MacLaren JE, Herrmann L, et al. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology 2009; 111: 44– 9 13 Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol 2005; 22: 189–96 14 Turkistani A, Abdullah KM, Al-Shaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol 2007; 24: 399–402 15 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. Anesth Analg 2006; 103: 1448–52 16 Ku¨cu¨kakin B, Klein M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Go¨genur I. No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebo-controlled trial. Acta Anaesthesiol Scand 2010; 54: 1121– 7 17 Ku¨cu¨kakin B, Wilhelmsen M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Go¨genur I. No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebocontrolled trial. Eur J Vasc Endovasc Surg 2010; 40: 461–7 18 Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam in anxious children. Paediatr Anaesth 2008; 18: 635–41 ¨ zcengiz D, Gunes Y, Ozmete O. Oral melatonin, dexmedetomidine, 19 O and midazolam for prevention of postoperative agitation in children. J Anesth 2011; 25: 184–8 20 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. Singapore Med J 2009; 50: 78– 81 21 Nickkholgh A, Schneider H, Sobirey M, et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res 2011; 50: 381–8 22 Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008; 12: R52 23 Srinivasan V, Pandi-Perumal SR, Spence DW, et al. Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Res Bull 2010; 81: 362–71 24 Papp M, Litwa E, Gruca P, Mocae¨r E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol 2006; 17: 9– 18 25 DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr. Absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40: 781–4
Downloaded from http://bja.oxfordjournals.org/ by guest on March 24, 2015
Melatonin has an extensive first-pass metabolism of 85%, and a limited half-life of 1 h. The inter-subject differences in bioavailability are however low.25 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 bestdocumented 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.
Editorial III
Editorial III
British Journal of Anaesthesia 112 (1): 7–8 (2014) doi:10.1093/bja/aet332
EDITORIAL III
Perioperative melatonin: not ready for prime time L. P. H. Andersen*, J. Rosenberg and I. Go¨genur Department of Surgery, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark * Corresponding author. E-mail: [email protected]
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.2 4 7 13 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.22 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,3 5 6 8 – 11 13 – 15 19 22 or missing prestudy power calculations.8 14 15 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.1 2 4 6 The exact mechanisms of melatonin for these indications are still being investigated, but animal studies have shown specific receptormediated effects and interaction with multiple other receptor systems such as the GABA, benzodiazepine, and opioid system.23 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 mg administered intrathecally, up to 300 mg kg21 bodyweight administered orally across several animal models documenting dose-dependent anxiolytic and anti-nociceptive effects.23 24 The correct dosage of melatonin in humans seems largely unknown and should be investigated further, documenting dose –response curves for the individual indications.
7
Downloaded from http://bja.oxfordjournals.org/ by guest on March 24, 2015
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.1 – 21 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.1 – 3 5 6 8 – 15 These studies have documented that melatonin is effective in treating perioperative anxiety, showing significant anxiolytic effects in 11 of the 13 studies.1 – 3 5 6 8 – 10 13 – 15 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.1 6 8 – 10 13 The analgesic effects of melatonin have been investigated in 11 randomized studies.1 – 11 Six studies have documented significantly improved analgesia, reduced analgesic requirements in the perioperative period, or both,1 – 6 whereas five studies could not document an analgesic effect of melatonin administration.7 – 11
BJA
Declaration of interest None declared.
References 1 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. J Pain 2009; 10: 100–8 2 Caumo W, Torres F, Moreira NL Jr, et al. The clinical impact of preoperative melatonin in postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg 2007; 105: 1263– 71 3 Mowafi HA, Ismail SA. Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesth Analg 2008; 107: 1422– 6 4 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. J Anesth 2010; 24: 155– 60 5 Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg 2009; 108: 1146–51 6 Ionescu D, Badescu C, Ilie A, Acalovschi I. Melatonin as premedication for laparoscopic cholecystectomy: a double-blind placebocontrolled study. SAJAA 2008; 57: 8–11
8
7 Go¨genur I, Ku¨cu¨kakin B, Bisgaard T, et al. The effect of melatonin on sleep quality after laparoscopic cholecystectomy: a randomized, placebo-controlled trial. Anesth Analg 2009; 108: 1152–6 8 Acil M, Basgul E, Celiker V, Karago¨z AH, Demir B, Aypar U. Perioperative effects of melatonin and midazolam premedication on sedation, orientation anxiety scores and psychomotor performance. Eur J Anaesthesiol 2004; 21: 553– 7 9 Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth 1999; 82: 875–80 10 Naguib M, Samarkandi AH. The comparative dose–response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000; 91: 473– 9 11 Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg 2006; 103: 121–3 12 Kain ZN, MacLaren JE, Herrmann L, et al. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology 2009; 111: 44– 9 13 Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol 2005; 22: 189–96 14 Turkistani A, Abdullah KM, Al-Shaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol 2007; 24: 399–402 15 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. Anesth Analg 2006; 103: 1448–52 16 Ku¨cu¨kakin B, Klein M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Go¨genur I. No effect of melatonin on oxidative stress after laparoscopic cholecystectomy: a randomized placebo-controlled trial. Acta Anaesthesiol Scand 2010; 54: 1121– 7 17 Ku¨cu¨kakin B, Wilhelmsen M, Lykkesfeldt J, Reiter RJ, Rosenberg J, Go¨genur I. No effect of melatonin to modify surgical-stress response after major vascular surgery: a randomised placebocontrolled trial. Eur J Vasc Endovasc Surg 2010; 40: 461–7 18 Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam in anxious children. Paediatr Anaesth 2008; 18: 635–41 ¨ zcengiz D, Gunes Y, Ozmete O. Oral melatonin, dexmedetomidine, 19 O and midazolam for prevention of postoperative agitation in children. J Anesth 2011; 25: 184–8 20 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. Singapore Med J 2009; 50: 78– 81 21 Nickkholgh A, Schneider H, Sobirey M, et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res 2011; 50: 381–8 22 Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008; 12: R52 23 Srinivasan V, Pandi-Perumal SR, Spence DW, et al. Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Res Bull 2010; 81: 362–71 24 Papp M, Litwa E, Gruca P, Mocae¨r E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol 2006; 17: 9– 18 25 DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr. Absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40: 781–4
Downloaded from http://bja.oxfordjournals.org/ by guest on March 24, 2015
Melatonin has an extensive first-pass metabolism of 85%, and a limited half-life of 1 h. The inter-subject differences in bioavailability are however low.25 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 bestdocumented 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.
Editorial III
