Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone

September 6, 2012 updated by: Krishna Pokharel, B.P. Koirala Institute of Health Sciences

Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone: a Randomized, Double Blind Placebo Controlled Study

Background: Benzodiazepine, a common premedicant, suppresses endogenous melatonin levels and thus paradoxically increases episodes of arousal during sleep and thus causes restlessness and hangs over effects. Adding melatonin to it may decrease nocturnal arousal and promote the perception of sound sleep in the perioperative period.

Methods: Eighty patients (ASA 1&2) with anxiety VAS ≥ 2 posted for general anaesthesia will be randomly assigned to receive 0.5 mg alprazolam (Group A), 3 mg melatonin, a combination of 0.5 mg alprazolam and 3 mg melatonin (Group AM), or a similar looking placebo (Group P), approximately 90 minutes before surgery.

Study Overview

Status

Completed

Conditions

Anxiety

Intervention / Treatment

Detailed Description

Review of literature:

Benzodiazepines are among the most popular drugs used for preoperative medication to produce anxiolysis, amnesia, and sedation. However, they negatively influence sleep quality by decreasing the duration of REM sleep and slow wave sleep.

Alprazolam is more anxioselective than the more commonly used ones like midazolam, lorazepam and diazepam.Melatonin (N-acetyl-5-methoxytryptamine) is an emerging premedicant as it possesses anxiolytic and sedative properties without impairing cognitive or psychomotor skills.5 Moreover, it has an excellent safety profile.

We designed this prospective randomized double blind placebo controlled study to assess whether addition of melatonin to alprazolam has any benefit over alprazolam, melatonin or placebo alone as a premedication agent.

Rationale of the study Melatonin facilitates sleep onset and improves the quality of sleep. On the other hand, benzodiazepines suppress endogenous melatonin levels and thus paradoxically increase episodes of arousal during sleep causing restlessness and hang over effects (fatigue).

Hence, the rationale of using melatonin alprazolam combination is melatonin may decrease nocturnal arousal and promote the perception of sound sleep and thus reverse this unwanted side effect of alprazolam. Melatonin does not produce amnesia and adding a benzodiazepine to it may be desirable to achieve this desirable premedication effect.

Research design and methodology:

After getting approval from the institutional research ethics committee and written informed consent, we will study eighty patients. With the help of computer generated random numbers, patients will be assigned to one of the four groups (n=20) to receive vitamin B (Group P), 0.5 mg alprazolam (Group A), 3mg melatonin (Group M) or a combination of 0.5 mg alprazolam and 3 mg melatonin (Group AM) approximately 90 minutes before surgery. In addition to the study drugs, Groups A and AM will also receive vitamin B.

On the preanaesthetic visit one day prior to surgery, the patients will be explained about the nature of the study and the various scales to be used. A 10 cm linear Visual Analogue Scale (VAS) as well as Nepali version of the Amsterdam Preoperative Anxiety and Information Scale (APAIS) will be used to assess their anxiety level. The extremes of the VAS anxiety scale will be marked as 'no anxiety' at the 0 end and 'anxiety as bad as ever can be' at the 10 cm end. Sedation will be assessed with a 5 point scale (0=alert, 1=arouses to voice, 2=arouses with gentle tactile stimulation, 3=arouses with vigorous tactile stimulation, 4=lack of responsiveness) and orientation, with a 3 point scale (0=none, 1=orientation in either time or place, 2=orientation in both). To test for the memory, recall of 5 different simple pictures and 2 events will be assessed. Pictures to be used will be sequentially numbered on the back and their names printed on the front.

Approximately 2 hours prior to surgery, each patient will be taken to a quiet room. Non invasive blood pressure, heart rate, respiratory rate and SpO2 will be monitored. Then picture 1 (cup on a plate) and 2 (fruits) will be shown at 10 min before and just prior to the drug administration respectively. Patients will be asked to take the study medication orally with 15 ml of plain water according to the group assignment by an investigator not involved in the patient management and data collection thereafter. Then anxiety, sedation and orientation will be assessed at 15 min, 30 min and 1 hour after the drug administration. At these time points pictures 3 (bird), 4 (hare) and 5 (car) will also be shown respectively.

In the operating room, intravenous access will be secured and pethidine 1 mg/kg administered. Then intravenous lidocaine 20 mg bolus will be administered followed by propofol with infusion pump at 100 ml per hour till responses to verbal command and eyelash reflex are lost. Vecuronium 0.1 mg/kg and isoflurane in oxygen will be administered to maintain the adequate depth of anaesthesia. After intubation, ventilation will be adjusted to maintain normocapnia. Incremental doses of pethidine and vecuronium will be administered as needed on the discretion of the investigator blinded to the patient's group assignment. No other analgesics will be administered. After completion of surgery, intravenous neostigmine 50 microgram/kg and glycopyrrolate 10 microgram/kg will be given to reverse muscle paralysis. Anaesthesia time (induction to emergence) will be noted.

In the recovery room, patients will receive the standard postoperative care; including oxygen administration via face mask 6 L/min and monitoring of heart rate, respiratory rate, non invasive blood pressure and SpO2. Modified Aldrete score and sedation score will be assessed at 10 min and 30 min after extubation. Also the occurrence of nausea, vomiting, dizziness, headache and restlessness will be recorded till 24 hours. Vomiting will be managed with ondansetron 4 mg intravenously.

The next day, the patients will be asked if they recalled the two events; being transported to operating room and intravenous cannula being inserted. They will also be asked to have a free recall of the five pictures they were shown and the score will represent the numbers of pictures they recalled. Then the first five pictures that they were shown will be mixed with next 5 new pictures (of a horse, shoe, bicycle, elephant and tiger) and they will be asked to recognize those they had already seen. The score will represent the number of pictures correctly identified. They will also be asked whether they felt that premedication drug is required to relieve anxiety and also whether they would like to receive the same premedication drug in the future.

Statistical analysis: Data will be tested for normal distribution using Kolmogorov-Smirnov test. To identify differences between groups, one-way ANOVA will be used for normally distributed continuing data and chi square tests for categorical data. If the data is found to be not normally distributed; they will be analyzed with nonparametric statistical methods. Friedman repeated measures analysis of variance followed by Wilcoxon tests with Bonferroni correction will be used for within-group comparison of values between different time points. Kruskal Wallis tests with post hoc multiple comparisons by Mann Whitney U test will be used for the comparison of values between the groups at each time points. Parametric data will be expressed as the mean±SD and nonparametric data as median (interquartile range). A p value <0.05 will be considered significant.

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Nepal
- Koshi
  - Dharan, Koshi, Nepal, 56700
    - B. P. Koirala Institute of Health Sciences
  - Dharan, Koshi, Nepal, 56700
    - Dr Krishna Pokharel

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

Inclusion Criteria:

(ASA 1&2),
aging 18 to 65 years
having anxiety VAS score of more than 2
posted for general anaesthesia with estimated duration of < 3 hours.

Exclusion Criteria:

patients taking analgesics, sedatives, antiepileptics or antidepressants,
suffering from obesity (BMI ≥ 28) or neuropsychiatric disease,
having allergy to the study drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Melatonin Premedication with 3 mg melatonin (Meloset) tablet orally 1-2 hour prior to anesthesia	Drug: meloset (melatonin) 3 mg melatonin tablet 1-2 hour prior surgery
Placebo Comparator: melatonin and alprazolam premedication Premedication with 3 mg melatonin and 0.5 mg alprazolam (Stresnil) tablet orally 1-2 hrs prior to anesthesia	Drug: stresnil ( melatonin and alprazolam) 3 mg melatonin and 0.5 mg alprazolam 1-2 hr before anesthesia
Placebo Comparator: alprazolam premedication Premedication with 0.5 mg alprazolam (Alprax) tablet orally 1-2 hr prior to anesthesia	Drug: (alprax) alprazolam 0.5 mg alprazolam
Active Comparator: placebo premedication Premedication with a similar looking placebo tablet orally 1-2 hr prior to anesthesia	Drug: placebo similar looking placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in VAS Anxiety Score Relative to Baseline After Premedication Time Frame: Change from baseline in VAS anxiety score at 15 minutes after premedication	VAS (Visual Analogue Score) Anxiety Scale is a 10 cm long scale with two sides, the patient side (front) and the clinicians side (back). The extremes of the front are colored as white and black with a gradual darkening of color from white to black. The back is marked in centimeter from 0 to 10 and 0 correlates with white color (no anxiety at all) and 10 correlates to black color (anxiety as bad as ever can be) on the front. As anxiety is worsened, the color is darker and score is more. The maximum score is 10 and minimum 0. The patient is asked to point on the scale according to his anxiety level. The anxiety score is the correlating number on the clinicians side. The more the reduction in anxiety from baseline, the better the outcome.	Change from baseline in VAS anxiety score at 15 minutes after premedication
Change in VAS Anxiety Score Relative to Baseline at 30 Minutes After Premedication Time Frame: Changes from baseline in VAS anxiety score at 30 minutes after premedication	VAS (Visual Analogue Score) Anxiety Scale is a 10 cm long scale with two sides, the patient side (front) and the clinicians side (back). The extremes of the front are colored as white and black with a gradual darkening of color from white to black. The back is marked in centimeter from 0 to 10 and 0 correlates with white color (no anxiety at all) and 10 correlates to black color (anxiety as bad as ever can be) on the front. As anxiety is worsened, the color is darker and score is more. The maximum score is 10 and minimum 0. The patient is asked to point on the scale according to his anxiety level. The anxiety score is the correlating number on the clinicians side. The more the reduction in anxiety from baseline, the better the outcome.	Changes from baseline in VAS anxiety score at 30 minutes after premedication
Change in VAS Anxiety Score Relative to Baseline at One Hour After Premedication Time Frame: Changes from baseline in VAS anxiety score at one hour after premedication	VAS (Visual Analogue Score) Anxiety Scale is a 10 cm long scale with two sides, the patient side (front) and the clinicians side (back). The extremes of the front are colored as white and black with a gradual darkening of color from white to black. The back is marked in centimeter from 0 to 10 and 0 correlates with white color (no anxiety at all) and 10 correlates to black color (anxiety as bad as ever can be) on the front. As anxiety is worsened, the color is darker and score is more. The maximum score is 10 and minimum 0. The patient is asked to point on the scale according to his anxiety level. The anxiety score is the correlating number on the clinicians side. The more the reduction in anxiety from baseline, the better the outcome.	Changes from baseline in VAS anxiety score at one hour after premedication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sedation Score at One Hour After Premedication Time Frame: Sedation score at 1 hour after the premedication	Sedation level was assessed with a 5 point scale (0=alert, 1=arouses to voice, 2=arouses with gentle tactile stimulation, 3=arouses with vigorous tactile stimulation, 4=lack of responsiveness). Minimum score is 0 and Maximum is 4. The lesser the score, the better the outcome.	Sedation score at 1 hour after the premedication
Orientation Score Time Frame: Orientation score at one hour after premedication	Orientation was assessed with a 3 point scale (0=none, 1=orientation in either time or place, 2=orientation in both). Minimum score is 0 and maximum is 2. The lesser the score, the lesser the effect on patients cognition and the better the outcome.	Orientation score at one hour after premedication
Number of Patients With Intact Memory Time Frame: 24 hour after surgery	Number of patients who recalled or recognized the picture number five shown one hour after premedication. The more the number of patients with intact memory, the better the outcome.	24 hour after surgery
Amount of Propofol Consumption Time Frame: 1 - 2 hour after premedication	Dose of propofol needed for loss of response to verbal command was noted at the time of induction of general anesthesia. The lesser the propofol needed for the loss of response to verbal command, the better the outcome.	1 - 2 hour after premedication
Number of Patients With Loss of Memory for Being Transferred to Operating Room. Time Frame: 24 hour after surgery	Patients were asked whether they recalled the event of being transferred to the operating room before anaesthesia. The lesser the number of patients with amnesia, the better the outcome.	24 hour after surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

B.P. Koirala Institute of Health Sciences

Investigators

Principal Investigator: Krishna Pokharel, MD, B.P. Koirala Institute of Health Sciences
Study Director: Balkrishna Bhattarai, MD, B.P. Koirala Institute of Health Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

about its FDA status

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2011

Primary Completion (Actual)

January 1, 2012

Study Completion (Actual)

January 1, 2012

Study Registration Dates

First Submitted

November 10, 2011

First Submitted That Met QC Criteria

December 4, 2011

First Posted (Estimate)

December 6, 2011

Study Record Updates

Last Update Posted (Estimate)

October 5, 2012

Last Update Submitted That Met QC Criteria

September 6, 2012

Last Verified

September 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

2/18 (Acd. 796/067/068)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Studies a U.S. FDA-regulated device product

product manufactured in and exported from the U.S.

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Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone