Comparing Melatonin to Diazepam as a Premedication: a Triple-blind, Randomized, Placebo Controlled Clinical Trial
Phase: PHASE3
Conditions: Anxiety, Preoperative Anxiety
Sponsor: University of Jordan

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Title page 
 
 
 
 
 
 
 
Comparing the Effect of Melatonin, Diazepam, 
and Placebo on Decreasing the Level of 
Anxiety Preoperatively 
 
NCT06103188 
 
 
Last updated: October 30, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Background 
Surgery carries be a heavy mental burden for the patient and can result in anxiety [1]. Preoperative 
anxiety is typically managed with benzodiazepines which have unpleasant adverse effects and can lead 
to serious complications [2,3]. 
Melatonin is a naturally occurring hormone which has shown promising results as an anxiolytic in 
both experimental and clinical studies [4-7]. Melatonin has not been associated with any 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 as a preoperative anxiolytic. 
 
Study design 
This study is a prospective, randomized, triple-blinded, placebo-controlled clinical trial conducted at 
the Jordan University Hospital. Participants will be recruited from patients undergoing various elective 
surgeries at the Jordan University Hospital. Participants will be selected based on predefined inclusion 
and exclusion criteria. 
 
Participants 
Inclusion criteria: 
- 
Patients with ASA grade 1 or 2 
- 
Age between 18 to 60 
- 
Posted for general anesthesia 
Exclusion criteria: 
- 
Patients with a known allergy to any of the drugs under study 
- 
Pregnancy 
- 
Illiteracy 
- 
Patients with any mental illness 
- 
Patients currently taking antipsychotics or antidepressants 
Withdrawal and drop-out-criteria 
1. 
If the participant 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. 

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3. 
If circumstances not covered by criteria 1-2 occur and the investigator deems it necessary 
regarding the health of the participant. 
  
Study course 
Patients will be approached in the anesthesia clinic and provided with detailed information about the 
study. Contact information about the participants will be collected for future follow-up if needed. 
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. 
Participants will be contacted again in the holding clinic 120 minutes prior to their scheduled surgery. 
They will be asked to complete a questionnaire assessing their anxiety, sedation, and orientation. 
 
Following the baseline assessment, participants will be administered oral 5 mg melatonin, 5 mg 
diazepam, or an identical placebo. The same variables (anxiety, sedation, and orientation) will be 
reassessed after 60 minutes. Any intraoperative or postoperative events will be recorded by the 
corresponding anesthesiologist. 
 
Anxiety will be measured using both the Amsterdam Preoperative Anxiety and Information Scale 
(APAIS) [10] and visual analogue scales (VAS). Sedation will be measured using Ramsay sedation 
scale [11], and orientation to time and place was assessed. 
 
Randomization 
Medications were packaged in identical containers and labeled by an independent investigator. 
Randomization was conducted using Microsoft Excel (Microsoft Corporation, 2021) VBA scripting, 
which assigned treatments and patient codes independently. The script ensured equitable distribution 
of treatments across genders. 
Furthermore, the patients' identity was safeguarded through the utilization of unique fake IDs. 
Participants are randomized at a ratio of 1:1:1. The investigators and data analysts are not aware of the 
content of the containers. An identification key is stored in sealed envelopes. 
 
 
 
 

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OUTCOMES 
Primary outcome 1: 
 
Title: Change in the anxiety score based on VAS 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
VAS (Visual Analogue Score) Anxiety Scale is a 100 mm long scale. The scale is marked in 
millimeters from 0 to 100, where 0 correlates with no anxiety at all, and 100 correlates to anxiety as 
bad as possible. The maximum score is 100 and minimum 0. The patient is asked to point on the scale 
according to his anxiety level. The more the reduction in anxiety from baseline, the better the 
outcome. 
 
Primary outcome 2: 
Title: Change in anxiety score based on The Amsterdam Preoperative Anxiety and Information 
Scale (APAIS) 
Time frame: Before administration of pre-medication, and after 1 hour from the administration 
of premedication. 
Description: 
The Amsterdam Preoperative Anxiety and Information Scale (APAIS) is a self-reported questionnaire. 
The scale consists of six items, four of which assess the patient’s anxiety, while the last two assess the 
patients’ need-for-information and the patient must choose how much he agrees with each item on a 
scale of 1 (not at all) to 5 (very much). The more the reduction in the anxiety score from baseline the 
better the outcome. 
 
Secondary outcome 1: 
Title: Change in sedation 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
Sedation will be assessed with Ramsay sedation scale (RSS) as follows: 
1 – Patient is anxious and agitated or restless, or both 
2 – Patient is cooperative, oriented, and tranquil 
3 – Patient responds to commands only 
4 – Patient exhibits brisk response to light glabellar tap or loud auditory stimulus 
5 – Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus 

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6 – Patient exhibits no response. 
Secondary outcome 2: 
Title: Change in orientation 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
Orientation will be assessed with a three-point scale as follows: 
0 – None 
1 – Orientation in either time or place 
2 – Orientation in both 
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