Clinical trial NCT02386319
Conditions: Anxiety
Keywords: Melatonin Surgery Pharmacokinetic Anxiolytic
Sponsor: Herlev Hospital
Start date: 2016-08-01; Completion date: 2021-04-01
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study's main objective is to investigate melatonin's anxiolytic and sleep-regulating effects in patients undergoing surgery. Moreover, the investigators intend to investigate the pharmacokinetic parameters of melatonin in this patient population.

Detailed description:
The study is separated into two parts. In the first part the patients are undergoing cosmetic breast surgery, and in the second part the patient undergo inguinal og umbilical surgery.

The first part is a cohort at 12 patients undergoing breast surgery. All patients in this group will be treated with melatonin, and the investigators intend to investigate the pharmacokinetic parameters of melatonin. Melatonin will be administrated 60 min. before surgery and the evening after surgery at 9 pm.

All patients will receive an intravenous catheter. The intravenous catheter will be used for blood sampling. A baseline blood sample will be taken 65 min before surgery (baseline) and thereafter blood samples will be obtained 0 min., 15 min., 30 min., 45 min., 60 min., 90 min., 120 min., 180 min., 240 min., 300 min., 360 min. and 420 min. after administration of melatonin. Blood samples will be obtained again after administration of melatonin at 9 pm. in the evening in the same manner as described above. Plasma samples will be stored at minus 80 C and analyzed at the research laboratory of the Department of surgery, Herlev Hospital. The analysis will be preformed with the RIA-technique.

The second part is a randomized, double-blind, placebo-controlled study with a total of 32 participants divided into a intervention group (16) and a placebo group (16). In this part the investigators intend to investigate the anxiolytic and sleep-promoting effects of melatonin. Melatonin and placebo will be administrated at 9 pm. the evening before surgery, 120 min. before surgery, immediately after surgery in the PACU and at 9 pm the evening after surgery.

Anxiety will be measured by the State-Trait Anxiety Inventory (STAI) and a VAS-scale (0 mm = no anxiety and 100 mm = worst anxiety). Quality of sleep will be measured at the VAS-scale as well (0 mm = best sleep and 100 = worst sleep).

Randomization will be performed by a computer at randomization.com. The "first generator" function is used. The randomization will be preformed in blocks of 4 patients in each.

Manufacturing of medications and randomization will be made by an independent pharmacist.

The primary outcome is preoperative anxiety as measured on the STAI. A previous study investigated preoperative anxiety before hernia surgery and found a mean of 35.4 (SD 10.0) on the STAI scale. There does not exist any generally accepted measure of how large a change on the STAI scale constitutes a clinically important difference. However, a change equal to one standard deviation has been suggested. In the present study, this corresponds to a minimal relevant difference (MIREDIF) of 10 points on the STAI scale or 28%. A power of 80% was defined, a significance level of 5% and a minimal relevant difference (MIREDIF) of 28%. From these assumptions, 16 patients in each treatment group is needed

Statistics Anxiety and sleep quality will be compared at individual timepoints between groups Comparison will be performed either by Mann-whitheys-test or unpaired t-test, depending on the distribution of data. Values are considered significant at a p-value at 5% or less. Data will be reported as mean (SD) or median (IQR) depending on the distribution of data.

Data for the blood samples will be presented as AUC plasma concentrations, half-life, maximum concentration and time to maximum concentration.

Arms: arm 1: Melatonin 10 mg, gelatin capsules. Pharmacokinetic study: 10 mg x 2. In the morning before surgery and in the evening after surgery.

Anxiolytic and analgesic study: 10 mg x 4. Evening the day before surgery, the morning before surgery, immediately after surgery and the evening after surgery. arm 2: Gelatin capsules. Anxiolytic and analgesic study. Evening the day before surgery, the morning before surgery, immediately after surgery and the evening after surgery.
Interventions: intervention 1: Melatonin intervention 2: Placebo
Intervention descriptions: intervention 1: Gelatin capsules intervention 2: Placebo capsules

Protocol documents:
Prot_SAP_000.pdf: 
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Title page 
Study Title: Anxiolytic and Analgesic Effects of Melatonin 
NCT02386319 
Last updated: 2 September 2020 
 


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Background 
Surgery can be a serious mental strain for the patient and can result in anxiety [1]. Anxiety is usually treated 
with benzodiazepines which have unpleasant adverse effects and can lead to serious complications [2,3]. 
Melatonin is a naturally occurring hormone which has documented anxiolytic effects in both experimental 
and clinical studies [4-7]. Melatonin does not have any known serious adverse effects [8], and the known 
adverse effects are dizziness, headache, nausea, and fatigue. Melatonin could potentially be an effective 
anxiolytic drug for treating perioperative anxiety [9]. 
Objective        
To investigate the effect of oral melatonin on perioperative anxiety.  
Study design 
Randomized, double-blinded, placebo-controlled trial involving patients undergoing elective 
inguinal/umbilical hernia repair. Outcomes of interest are anxiety, well-being, and sleep quality. Participants 
will be allocated to either melatonin or placebo in a 1:1 ratio and will be randomized in blocks of 4. 
Participants 
Inclusion criteria: 
• 
Male patients undergoing elective inguinal or umbilical repair. 
Exclusion criteria: 
• 
Patients with regular consumption of opioids, benzodiazepines, or melatonin. 
• 
Patients with psychiatrics comorbidity (ongoing treatment) or patients classified as ASA 3 or 4 
• 
Patients with an ongoing abuse of alcohol or recreational drugs´ 
• 
Patients suffering from liver disease (ongoing treatment)´ 
• 
Patient diagnosed with a sleeping disorder 
• 
Allergy towards melatonin 
• 
Patients incapable of participating in accordance with the study protocol 
Withdrawal and drop-out-criteria 
1. If the participants wishes to withdraw from the trial at any timepoint  
2. If the participant suffers from any treatment complication the results in a reoperation or admission 
to an intensive care unit 
3. If circumstances not covered by criteria 1-2 occur and the investigator deems it necessary in regard 
to the health of the participant 


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Study course 
Participants will be recruited according to the above criteria by study personnel after their preoperative 
consultation with the surgeon. Patients are given written and verbal information about the purpose and 
conduct of the study, and are required to give written and verbal consent to participate. Baseline data are 
collected. 
Participants will be administered oral 10 mg melatonin at four different timepoints: at 9 pm the evening 
before surgery, 120 minutes before surgery, immediately after surgery, and at 9 pm the evening on the day 
of surgery. 
Anxiety will be measured at different timepoint using both the State-Trait Anxiety Inventory (STAI) [10] and 
visual analogue scales (VAS). All data will be collected electronically using the platform Research Electronic 
Data Capture (REDCap). 
Pharmacology 
Pharmaceuticals are produced and packaged according to Good Manufacturing Practice guidelines by and 
authorized manufacturer. The applied drugs are tablets containing 10 mg melatonin or placebo. Tablet are 
identical in size, shape, color, and flavor. Labelling is performed by the manufacturer in accordance with 
Good Manufacturing Practice guidelines. 
Randomization 
Randomization, blinding, and labelling is performed by the authorized manufacturer. Randomization is 
performed trough Randomization.com using the first generator functionality. Participants are randomized in 
blocks of 4 and in a ratio of 1:1. The investigator are not aware of the content of the tablets. An identification 
key is stored in sealed envelopes. 
OUTCOMES 
Primary outcomes 
• 
Preoperative anxiety 1 hour before surgery using STAI [10] 
Secondary outcomes 
• 
Postoperative anxiety using STAI [10] 
• 
Pre- and postoperative anxiety using VAS 
• 
Length of stay 
• 
Quality of sleep the night before and after surgery 
• 
Intraoperative use of remifentanil 
• 
Intraoperative use of propofol  
• 
Use of rescue-opioid (0-6 hours postoperatively) 


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• 
Use of rescue-opioid (0-24 hours postoperatively) 
• 
General well-being 
• 
Fatigue 
MÅLINGER  
Perioperative anxiety 
Perioperative anxiety is measured using both STAI and VAS at recruitment, 60 minutes before surgery, and 4 
hours after surgery. 
Sleep quality 
Quality of sleep is measured using a VAS where higher score equals better quality of sleep. Data on length of 
sleep and number of awakenings will also be collected. 
Karolinska sleepiness scale 
This is a 9-point interval scale (1 = very awake; 9 = very sleepy) used to measure the degree of sleepiness. 
Will be administered on the morning before and after surgery. 
Fatigue and well-being 
Subjective fatigue will be measures on a 10-point scale (higher score indicates more fatigue). Well-being will 
be measured using as VAS (higher score indicates less well-being). Will be administered on the morning 
before and after surgery. 
Power and sample size 
The primary outcome is preoperative anxiety measured using STAI. A previous study investigated anxiety in 
relation to inguinal hernia surgery and found a mean preoperative STAI of 35.4 (SD 10.0) [11]. The are no 
generally agreed recommendation for what constitutes a clinically significant change on the STAI, but a 
change of one SD has been proposed [12]. In the current study, this equals a minimal relevant difference 
(MIREDIF) of 10 point in the STAI or 28%. Necessary power is set at 0.80 and level of significance at 5%. This 
results in a necessary sample size of 16 participants in each group. 
Statistics 
Level of anxiety will be compared using Mann-Whitney’s test or unpaired T test depending on the 
distribution of data. Data will be analyzed using Graphpad Prism (Graphpad Software, La Jolla, CA) and/or 
SPSS (IBM SPSS, Statistics for Windows, Version 20.0, Armonk, NY, IBM Corp). A p value of 0.05 will be 
considered significant. Data will be reported as mean (SD) or median (IQR) depending on distribution. 
Ethical considerations 
This trial will be conducted in accordance with the Helsinki Declaration and with the permission of the Medical Ethics 
Committee of the Capital Region of Denmark. The study will contribute to the understanding of melatonin’s anxiolytic 


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benefits and will be conducted using a randomized double-blinded design. The safety of oral administration of 
melatonin is well-established [13-27]. All participants will give written and verbal informed consent to participate. 
Participants can withdraw from the trial at any timepoint.


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The trial will be conducted in accordance with the current protocol, ICH-GCP guidelines, and applicable 
legislation. The sponsor will allow direct access to the collected data throughout the monitoring of the trial by 
the applicable authorities. Permissions will be obtained from the Danish Data Protection Agency, the Danish 
Medicines Agency, and the Medical Ethics Committee of the Capital Region of Denmark. 
This document is an abbreviated and translated version of the original protocol approved by the Danish 
authorities. The translation was performed on 5 August 2021 at the request of ClinicalTrials.gov.