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Authors:
Michael T. Madsen, Bachelor of Medicine, Medical Student 1, Herlev Hospital, University of Copenhagen, Department of Surgery, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
 Phone: (work) +45 38 68 94 96. Fax number: +45 38 68 36 02. E-mail:  HYPERLINK "mailto:Michael_madsen88@hotmail.com" Michael_madsen88@hotmail.com. 
Jacob Rosenberg, DMSc., Professor, Senior Consultant 1, Herlev Hospital, University of Copenhagen, Department of Surgery, Herlev Ringvej 75, DK-2730 Herlev, Denmark 
Phone: (work) +45 38 68 36 00. Fax number: +45 38 68 36 02. E-mail:  HYPERLINK "mailto:jacob.rosenberg@regionh.dk" jacob.rosenberg@regionh.dk
Ismail G�genur, DMSc., Professor, Senior Consultant 1, Herlev Hospital, University of Copenhagen, Department of Surgery, Herlev Ringvej 75, DK-2730 Herlev, Denmark
 Phone: (work) +45 38 68 95 01. Fax number: +45 38 68 36 02. E-mail:  HYPERLINK "mailto:goegenur@dadlnet.dk" goegenur@dadlnet.dk.


Corresponding author and reprints request to:
Michael Tvilling Madsen, Herlev Hospital, University of Copenhagen, Department of Surgery, Herlev Ringvej 75, DK-2730 Herlev, Denmark, cellphone: +45 2785 7247, Fax number: +45 38 68 36 02, E-mail:  HYPERLINK "mailto:michael_madsen88@hotmail.com" michael_madsen88@hotmail.com

Short Title: Melatonin and sleep after cholecystectomy  

Funding and contributions:
This study was independently performed hence no funding to declare. 
MTM: Analyzed the data and interpreted the data, prepared the first draft of the manuscript, revised and coordinated revision of the manuscript. 
JR: Planned and designed the study, interpreted the data, and revised the manuscript.
IG:  Planned and designed the study, collected the data, interpreted the data, and revised the manuscript.  
Abstract 
Objective: We set out to investigate whether administration of an oral dose of 5 mg melatonin in the evenings after laparoscopic cholecystectomy could reduce sleep disturbances measured by actigraphy.  
Methods: We performed a double-blinded, placebo-control, randomised clinical trial where patients were received 5 mg melatonin or placebo approximately 30 minutes before bedtime three nights postoperative. Participants were monitored with actigraphy two nights preoperatively and three nights postoperatively. Likewise sleep, pain, general wellbeing, and fatigue were measured via visual analogue scales.
Results: Melatonin administration in the postoperative period did not affect any of the objectively determined sleep parameters compared with placebo. No group difference was observed during the nighttime or daytime even though the overall sleep was disturbed postoperatively. Melatonin intervention did not result in improvements in the subjective parameters.   
Conclusions: We did not show an effect of 5 mg melatonin administration on sleep in the postoperative period. 



Keywords: Actigraphy, Sleep, Melatonin, Cholecystectomy, and Randomized clinical trial.





1. INTRODUCTION
Postoperative sleep and circadian disturbances are frequent after surgery1 and may be associated with prolonged postoperative convalescence,2-4 cardiovascular and respiratory morbidity, 3-5 cognitive dysfunction,6,7 and impaired immune function.8 The degree of sleep disturbances are positively correlated to the surgical stress response, and it has been shown that minimally invasive surgery causes less pronounced sleep disturbances than open abdominal surgery.9 
  	In patients undergoing laparoscopic cholecystectomy, polysomnography (PSG) measurements have shown decreased slow-wave-sleep (SWS) with corresponding increase in sleep stage 2 (N2) on postoperative night one.3 Another way to objectively quantify sleep is by using actigraphy, which measures sleep by detecting movements. 10,11   Actigraphy has been validated in many different medical populations 10,12,13 including patients undergoing abdominal surgery. 14 Actigraphy has also been used to measure sleep after laparoscopic cholecystectomy.14-17 Advantages of actigraphy in the surgical setting compared to PSG is that it is a non-invasive measuring technique with uncompromised patient mobility, low cost, and the data-analysis requires minimal manual data editing.18-20    
Melatonin is an endogenous hormone which coordinates the internal circadian rhythm and is by some considered to be a �sleep hormone�. 21 Melatonin has been shown to be reduced in the postoperative period in a gynaecological surgical population22 which has later been confirmed in both major and minor abdominal surgery.23,24 Specifically after laparoscopic cholecystectomy a phase-delay and reduction in amplitude of melatonin is present.24 Melatonin used as exogenous supplementation has very low levels of toxicity, therefore making it an attractive therapeutic option. 25 It has primarily been used to reduce jetlag-related symptoms and as treatment for different sleep disorders.26 Melatonin�s hypnotic effect does not follow a simple dose response relationship and timing of administration is important.25  In the perioperative setting it has been used as an anxiolytic, analgesic, sedative, and as a potent antioxidant.27;28  
We set out to investigate whether administration of an oral dose of 5 mg of melatonin at bedtime in the postoperative period could reduce sleep disturbances measured by actigraphy.


2. METHODS
The study was a double-blinded, placebo-controlled, randomised clinical trial where all healthcare professionals interacting with the patients were blinded to the given treatment. The randomization and blinding process were previously described by G�genur et al.29 The Regional Ethics Committee approved the study and patients signed an informed consent form after both oral and written information before entering the study. The study was approved by the Danish Medicines Agency, and monitored by the regional Good Clinical Practice unit. The study was registered on ClinicalTrial.gov (NCT00113906).   
 	The patients included in the study were recruited from two surgical departments in the greater Copenhagen area. Inclusion criteria were planned ambulatory laparoscopic cholecystectomy, age between 18 to 80 years, and ASA-risk class I-III. The exclusion criteria were daily alcohol consumption above 5 units of alcohol (12 g of ethanol/unit), preoperative use of beta-blockers, continuous use of opioids or anxiolytics in the week before surgery, diagnosed sleep disorder, foreseeable poor compliance (not fluent in Danish or diagnosed with psychiatric disease), and lack of written consent. The presence of postoperative complications which could be expected to result in postoperative pain or unexpected sickness in the postoperative week, conversion to open procedure, or treatment with psychotropic drugs were all considered to be grounds for withdrawal from the study. The current study population represents a subgroup from the original study.29 Due to a limited number of available Actipgrahs and logistic challenges in the timing of measurement it was not possible to monitor all patients in the original study with actigraphy. Hence patients ultimately monitored with Actigraphy were selected only depending on the availability of an actigraph, and as such at random. 
	The patients received standardized general anaesthesia consisting of induction bolus of propofol 2  EMBED Equation.3   and 5  EMBED Equation.3   for maintenance. Rocuronium 0.5  EMBED Equation.3  was given for neuromuscular blockade at induction and prophylactic antibiotic consisted of 160 mg gentamicin administered intravenously preoperatively. Bupivacaine was used as local infiltration analgesia in the trocar incisions and details for postoperative care were as previously described.29
  	At the point of discharge (the procedures were all day case procedures) the postoperative interventional medicine was given to the patient. This was capsules of melatonin (5 mg, Penn Pharmaceutical Services, Tredegar, Gwent, Wales, UK) or placebo (identical capsules, 200 mg of lactose and 3 mg magnesium stearate, Penn Pharmaceutical Services). Patients were instructed to take the medicine 30 minutes before expected bedtime on the first three postoperative nights.
  	The measurement of activity was made by an Actigraph, which is a small wrist-born device containing an accelerometer in the form of a piezoelectric transducer.30 The data are stored on an internal memory in the watch and later downloaded to a personal computer for further analysis. By using a computer generated algorithm, the data are converted to information about sleep or sleep-wake rhythm. The patients met three days before planned surgery and were randomized to either placebo or melatonin.  At this initial meeting the Actigraph (octagonal basic Motionlogger, ambulatory monitoring, Inc, New York, USA) was fitted on the patients non-dominant arm. The Actigraph was worn 24 hours a day for approximately three days preoperatively to three days postoperatively. The zero crossing mode (ZCM) setting was used for data collection and sleep was scored in 30 second epochs according to the Cole-Kripke sleep algorithm.11 
	Actigraphy can measure a wide variety of sleep parameters, and in this study we chose to look at six outcomes as our primary outcome. Total sleep time (TST) is the duration of the sleep period based on the actual sleep start and end, and not the time spent in bed. Wake time (WT) is the time spent awake during the measuring period. Sleep efficiency (SE) is the percentage of actual sleep while being in bed at night. Sleep latency (SL) is the time from �lights-off� until the actual time of sleep onset. Wake after sleep onset (WASO) is the number of wake minutes during the night period. Number of awakenings (NOA >5 minutes) is the number of awakenings lasting a minimum of 5 minutes during the sleep period. During the day period we measured wake-time and total sleep time. The day time period was defined as 07.00 to 23.00 hours and the night time period was defined as 23.00 to 07.00 hours. The night-time measurements two nights preoperatively (PRE2) were compared to postoperative nights one, two and three (PO1, PO2, and PO3). For day-time measurements the preoperative day-time was compared to the day-time on postoperative days 1, 2 and 3.
Self-reported sleep quality was evaluated via a visual analog scale (VAS, 0 mm = best possible sleep and 100 mm = worst possible sleep). Level of discomfort was determined by using questionnaires about general well-being, pain, and fatigue. General well-being and pain were also assessed by using a VAS-scale (0 mm = extremely well / no pain and 100 mm = extreme malaise / worst conceivable pain). Fatigue was measured using a 10-point ordinal scale (1 = fit and 10 = fatigued).31 The parameters were determined on the morning the day before surgery and on postoperative mornings one, two and three which means that scoring on the night preceding surgery was not used. The reported subjective sleep outcomes represent a subgroup based on the available patients with actigraphy measurement in the original study.29              
 	Data in tables are presented as median (range) unless stated otherwise. Normal distribution of the data was tested by Kolmogorov-Smirnov test and the appropriate statistics were used accordingly.  P< 0.05 was considered to be statistically significant.  For statistical analyses SPSS 20.0 (SPSS Chicago, IL) was used. When comparing groups for binominal data, Fisher�s exact test was used. Intergroup comparisons were made with Mann-Whitney test. For Intraday comparison Friedman test including post hoc testing was used, and results were adjusted with a Bonferroni correction to minimise the risk of a Type 1 Error. 
3. RESULTSFrom the original study29 54 patients were included in this analysis and completed the study according to the study protocol. These 54 patients were the only ones with available actigraphy data hence the smaller study population compared to the original study (Figure 1). 29 patients received placebo treatment and 25 patients were received melatonin intervention. As seen in Table 1 no significant statistical difference in baseline parameters was present between the placebo and the melatonin groups (Table 1).
 	When comparing the nighttime sleep parameters WT, TST, SE, NOA5, WASO and SL for the melatonin and placebo groups, there were no significant differences between preoperative values (Table 2). There were no differences between the melatonin and placebo group on any of the measured parameters on any of the postoperative days (Table 2). With regard to actigraphy measurements for the daytime period no significant differences was found for WT or TST (Table2).  
Significant differences were found when comparing pre- versus postoperative (PO1, PO2, and PO3) values for WT, TST, SE, NOA5, and WASO for the entire group (Table 3). WT was significantly increased on PO1 and PO2 compared to PRE2, however on PO3 significant difference was not present after Bonferroni correction. TST was significantly increased on PO1 compared to PRE2 but not on PO2 and PO3. SE was significantly decreased on PO1 compared to PRE2, but not on PO2 and PO3 after Bonferroni correction (Table 3). NOA5 was significantly increased on all postoperative days compared to PRE2 and the same was true for WASO except on PO3. SL was not significantly changed in the postoperative period (Table 3). With regard to the daytime measurements both WT and TST were in the entire postoperative period significantly changed compared to PRE2. WT showed a marked decrease on PO1 but rebounded toward preoperative values on PO2 and PO3 (Table 3). TST during the daytime increased on PO1 with a decline toward PRE2 values on PO2 and PO3 (Table 3).
	For subjectively measured parameters (subjective sleep, morning fatigue, pain and general wellbeing) no significant differences were observed between the melatonin and placebo groups on the postoperative mornings 1, 2 and 3 (Table 4). 
Subjective outcomes were significantly different when preoperative and postoperative values were compared. Subjective sleep became significantly worse on PO1 but no difference was observed on PO2 and PO3 compared with preoperatively (Figure 2a). General wellbeing became worse on PO1 and rebounded on PO2 and PO3 compared to preoperative values (Figure 2b). Fatigue was significantly increased on PO1, and then decreased toward preoperative values on PO2 and PO3 (Figure 2c). Pain was significantly increased on all postoperative days compared with preoperatively (Figure 2d).   
4. DISCUSSION 
Administration of 5 mg melatonin approximately 30 minutes before bedtime on postoperative day one, two, and three did not affect any of the objectively determined sleep parameters compared with placebo. Melatonin did not affect any of the objective sleep outcomes measured during the day nor during the night. Melatonin intervention did not result in an improvement in any of the subjective parameters on postoperative days one, two or three.  	
 	Melatonin is a multi-potent hormone that functions both as a hypnotic25 and as a chronobiotic21 modulator of human sleep. The acute hypnotic effects of melatonin can promote sleep within 30-60 minutes.32 One should note that these effects are present in physiological levels of melatonin, and large doses does  not yield further effect possibly due to desensitization of melatonin receptors.25 According to the most recent update of the Cochrane systematic review on melatonin substitution for treatment of jetlag from 200833 doses of 0,5 � 5 mg show similar hypnotic effects although 5 mg having a more pronounced effect. A dose above 5 mg does not seem to be more effective.33 Hence, we chose a dose of 5 mg quick release melatonin to be administrated approximately half an hour before bedtime so the acute hypnotic effect could be the intended mechanism. Despite of this we could not demonstrate this effect with the study setup used in our study. 
	The literature regarding melatonin as a hypnotic is not uniform and conflicting opinions exists.25,34 One of the factors influencing the effect of melatonin is age. Melatonin has varying effect in different ages generally with children responding more strongly than elderly.25 Melatonin production peaks around puberty and with increasing age the endogenous production of melatonin decrease.35,36 Correlation between decreased production and insomnia has been reported37 and increased age may also be associated with reduced receptor sensitivity for melatonin. 25 It should, however, be noted that there exists great inter-individual variation in melatonin levels across age groups. 25 The typical participant in our study was a woman in her mid to late forties which may imply reduced melatonin production and sensitivity. Interestingly, it has also been shown that older women are less responsive to the soporific effect of melatonin.34 Likewise, varying sleep inducing effect of melatonin has been shown throughout the menstrual cycle.38 
	Another confounder in the picture is the way melatonin is administered and metabolised. When melatonin is administered orally it goes through a large first pass effect39 which leads to varying blood levels among study participants. Oral administration of e.g. 10 mg melatonin leads to supra-physiological blood levels25 but no dose-dependent hypnotic effect seems to be present between 0.5 mg � 10 mg.40 In our case with the administration of 5 mg oral melatonin, one must assume that participants had supra-physiological blood levels of melatonin, although systemic absorption could have been altered due to bowel dysfunction after abdominal surgery. This was not monitored and future studies should specifically investigate systemic absorption of orally administered melatonin after various surgical procedures. 
	Timing of administration is a crucial element in the effect of melatonin. In most of the studies showing a sleep promoting effect of melatonin, melatonin was primarily administered during the daytime.34 Exogenous melatonin seems to have most pronounced hypnotic effect when blood levels of melatonin are low.25 We administered the 5 mg of melatonin approximately 30 minutes before bedtime which is when endogenous melatonin production is increasing. This should in theory mimic the natural evening increase in melatonin production and therefore induce a sleep promoting effect. The administration 30 minutes before bedtime instead of a standardized time-point (e.g. 21:00 hours) should synchronize the administration of melatonin to the individual�s sleep-wake rhythm. As such we believe that the chosen administration point is ideal for the intended hypnotic effect of melatonin.  
	The methodology of actigraphy has been validated in healthy populations and good correlation with polysomnography (PSG) has been shown.10,41 A validation of actigraphy was performed in patients undergoing major abdominal surgery compared to healthy controls14, and different methodological aspects of actigraphy were addressed. However no comparison with the golden standard was performed, and no epoch by epoch comparison was performed which is needed fore thorough validated in a surgical population.14 With Actigraphy one can not measure sleep architecture and compared to PSG, which is the golden standard in the field, actigraphy only describes absolute sleep parameters and not detailed sleep architecture. Melatonin administration in patients with reduced REM sleep has been shown to increase the amount of REM sleep.42;43 Actigraphy would not have been able to determine this effect, however as previously shown, REM sleep does not seem to be disturbed after laparoscopic cholecystectomy.3
A small limitation to actigraphy measurements were the use of a standardized night period (i.e. 23-07 hours) and daytime (i.e. 07-23 hours). This standardized time does not take into account the individual participants� varying sleep-wake rhythm which could be a confounding factor.  One could have used sleep diaries in an attempt to correct for this individual dependent factor. A more pronounced limitation to this study was that the data represents a subgroup analysis and was thus not powered to examine actigraphically measured sleep parameters. However, we chose to do analyses of this subgroup based on vast amount of literature describing sleep disturbances and the possibility that we, by objectively measured sleep parameters, possibly would find a difference between the melatonin and placebo group. 
	 
5. Conclusion
 In conclusion, our study did not show an effect of melatonin on sleep in the postoperative period even though the sleep for the entire group was disturbed. Future clinical trials with larger study populations are needed to clarify the sleep promoting effect of melatonin in patients undergoing laparoscopic cholecystectomy, and similar studies should be performed in other surgical populations. 

6. Acknowledgments
Research nurses Dorthe Greve J�rgensen, Jeanette Juncker Madsen, and Irene Tarp J�rgensen are thanked for invaluable help and enthusiasm during the study.

7. Funding 
This study was independently performed hence no funding to declare. 

8. Conflict of Interest
MTM: No conflict of interest to declare.
JR: No conflict of interest to declare.
IG: No conflict of interest to declare.
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