Anxiolytic and Analgesic Effects of Melatonin (ANAN-Melatonin)

Anxiolytic and Analgesic Effects of Melatonin: A Randomized, Double-blinded, Placebo-controlled Clinical Study

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.

Study Overview

• Status: Completed
• Conditions: Anxiety
• Intervention / Treatment: Drug: Placebo; Drug: Melatonin

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria part one:

• Patients who are candidates for breast surgery.
• BMI between 18 and 30
• Visible veins in the elbow region
• Fertile women use anti-contraception and have performed a negative pregnancy test

Exclusion Criteria part one:

• Patients, who use daily opioids, benzodiazepines or melatonin
• Patients diagnosed with a psychiatric disorder (defined as in medical treatment)
• Patients with severe physical disease (ASA 3-4)
• Patients with previous or ongoing alcohol or drug abuse
• Patients with liver disease (defined as in medical treatment)
• Patients diagnosed sleep disturbances
• Patients who are unable to cooperate according to the protocol
• Patients with allergy to melatonin

Inclusion Criteria part two:

- Male patients who are candidates for inguinal or umbilical hernia reapir

Exclusion Criteria part two:

• Patients, who use daily opioids, benzodiazepines or melatonin
• Patients diagnosed with a psychiatric disorder (defined as in medical treatment)
• Patients with severe physical disease (ASA 3-4)
• Patients with previous or ongoing alcohol or drug abuse
• Patients with liver disease (defined as in medical treatment)
• Patients diagnosed sleep disturbances
• Patients who are unable to cooperate according to the protocol
• Patients with allergy to melatonin

Withdrawal- and drop-out criteria part 2:

• Patients can withdraw at any time during trial

• Complications during surgery occur that lead to:

  1. Immediate reoperation
  2. Hospitalization to intensive care unit
• If it is considered in the best interest of the patients physical- and psychological health to withdraw from the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Melatonin; 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.	Drug: Melatonin; Gelatin capsules
Placebo Comparator: Placebo; Gelatin capsules. Anxiolytic and analgesic study. Evening the day before surgery, the morning before surgery, immediately after surgery and the evening after surgery.	Drug: Placebo; Placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preoperative Anxiety	The "State" scale of the State-Trait Anxiety Inventory (STAI). Construct: Current level of anxiety. Scale range: 20-40 (higher scores indicate higher level of current anxiety) Scores are calculated according to the STAI scoring manual by adding point from each item (possible point for each item is 1-4).	60 minutes preoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Anxiety	State-Trait Anxiety Index	at the preoperative interview, 60 minutes prior to surgery and 4 hours postoperatively.
Pre- and Postoperative Anxiety	Visual analog scale	at the preoperative interview, 60 minutes prior to surgery, 1 and 4 hours postoperatively.
Intraoperative Requirement of Remifentanil	µg/kg/min	intraopeative
Intraoperative Requirement of Propofol	mg/kg/min	intraoperative
Use of Rescue-opioids in the PACU	dose	0-24 hours postoperative
Use of Rescue-opioids in the Ward	dose	0-24 hours postoperative
Perioperative Sleep Quality	Visual analog scale	24 hours
General Well-being and Fatigue	Visual analog scale	24 hours
Plasma Concentrations of Melatonin	pg/ml	baseline, 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 melatonin administration.

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Investigators: Principal Investigator: Dennis B Zetner, MD., Herlev Hospital, Herlev Ringvej 75, Herlev, Denmark

Publications and helpful links

General Publications

• Madsen BK, Zetner D, Moller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD009861. doi: 10.1002/14651858.CD009861.pub3.

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): March 1, 2021
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: March 5, 2015
• First Posted (Estimate): March 11, 2015

Study Record Updates

• Last Update Posted (Actual): September 2, 2021
• Last Update Submitted That Met QC Criteria: August 5, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Melatonin; Surgery; Pharmacokinetic; Anxiolytic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: Melatonin1234