Clinical trial NCT02386319: Anxiolytic and Analgesic Effects of Melatonin
Official title: Anxiolytic and Analgesic Effects of Melatonin: A Randomized, Double-blinded, Placebo-controlled Clinical Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anxiety
Keywords: Melatonin
Surgery
Pharmacokinetic
Anxiolytic
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
First posted: 2015-03-11
Enrollment: 36
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Preoperative Anxiety
timeFrame: 60 minutes preoperative
Secondary outcomes:
measure: Postoperative Anxiety
timeFrame: at the preoperative interview, 60 minutes prior to surgery and 4 hours postoperatively.
measure: Pre- and Postoperative Anxiety
timeFrame: at the preoperative interview, 60 minutes prior to surgery, 1 and 4 hours postoperatively.
measure: Intraoperative Requirement of Remifentanil
timeFrame: intraopeative
measure: Intraoperative Requirement of Propofol
timeFrame: intraoperative
measure: Use of Rescue-opioids in the PACU
timeFrame: 0-24 hours postoperative
measure: Use of Rescue-opioids in the Ward
timeFrame: 0-24 hours postoperative
measure: Perioperative Sleep Quality
timeFrame: 24 hours
measure: General Well-being and Fatigue
timeFrame: 24 hours
measure: Plasma Concentrations of Melatonin
timeFrame: 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.
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Herlev Hospital
Study officials:
affiliation: Herlev Hospital, Herlev Ringvej 75, Herlev, Denmark
name: Dennis B Zetner, MD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.