A Phase 4 interventional study of meloset (melatonin) and stresnil ( melatonin and alprazolam) in Anxiety, sponsored by B.P. Koirala Institute of Health Sciences. Completed at 2 sites in Nepal. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2012-10-05.
Sponsored by B.P. Koirala Institute of Health Sciences · Phase 4, Interventional, and Treatment
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.
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.
B.P. Koirala Institute of Health Sciences is the lead sponsor of 53 studies on the registry; 6 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Premedication with 3 mg melatonin (Meloset) tablet orally 1-2 hour prior to anesthesia
Drug: meloset (melatonin)
Premedication with 3 mg melatonin and 0.5 mg alprazolam (Stresnil) tablet orally 1-2 hrs prior to anesthesia
Drug: stresnil ( melatonin and alprazolam)
Premedication with 0.5 mg alprazolam (Alprax) tablet orally 1-2 hr prior to anesthesia
Drug: (alprax) alprazolam
Premedication with a similar looking placebo tablet orally 1-2 hr prior to anesthesia
Drug: placebo
3 mg melatonin tablet 1-2 hour prior surgery
3 mg melatonin and 0.5 mg alprazolam 1-2 hr before anesthesia
0.5 mg alprazolam
similar looking placebo tablet
Change in VAS Anxiety Score Relative to Baseline 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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: Changes from baseline in VAS anxiety score at one hour after premedication
Sedation Score at One Hour After 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.
Time frame: Sedation score at 1 hour after the premedication
Orientation Score
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.
Time frame: Orientation score at one hour after premedication
Number of Patients With Intact Memory
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.
Time frame: 24 hour after surgery
Amount of Propofol Consumption
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.
Time frame: 1 - 2 hour after premedication
Number of Patients With Loss of Memory for Being Transferred to Operating Room.
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.
Time frame: 24 hour after surgery
Recruitment period was of three months. Approximately 90 minutes prior to surgery, each patient was taken to a quiet room inside the operation theater complex.
| Milestone | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Started | 20 | 20 | 20 | 20 |
| Completed | 20 | 19 | 18 | 18 |
| Not completed | 0 | 1 | 2 | 2 |
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.
| Centimeter | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Change in VAS Anxiety Score Relative to Baseline After Premedication | 0.35 ± 0.8 | 0.70 ± 1.6 | 0.65 ± 1.2 | 0.25 ± 0.8 |
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.
| units on a scale | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Sedation Score at One Hour After Premedication | 0.5 (0 to 1) | 1 (1 to 2.75) | 1 (0 to 1.75) | 0 (0 to 1) |
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.
| units on a scale | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Orientation Score | 2 (2 to 2) | 2 (2 to 2) | 2 (2 to 2) | 2 (2 to 2) |
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.
| Participants | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Number of Patients With Intact Memory | 13 | 4 | 5 | 14 |
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.
| mg | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Amount of Propofol Consumption | 79.2 ± 4 | 65.5 ± 21 | 59.0 ± 21 | 75.8 ± 25 |
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.
| centimeter | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Change in VAS Anxiety Score Relative to Baseline at 30 Minutes After Premedication | 1.15 ± 1.4 | 1.72 ± 2.2 | 1.62 ± 1.6 | 0.82 ± 1.6 |
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.
| Centimeter | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Change in VAS Anxiety Score Relative to Baseline at One Hour After Premedication | 1.80 ± 1.7 | 2.92 ± 2.3 | 2.35 ± 2.1 | 0.85 ± 1.9 |
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.
| Participants | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| Number of Patients With Loss of Memory for Being Transferred to Operating Room. | 1 | 5 | 4 | 0 |
Collected over 24 hours after premedication. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Melatonin | — | 0/20 (0%) | 13/20 (65%) |
| Melatonin and Alprazolam | — | 0/19 (0%) | 12/19 (63.2%) |
| Alprazolam | — | 0/18 (0%) | 14/18 (77.8%) |
| Placebo | — | 0/18 (0%) | 16/18 (88.9%) |
| Event | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo |
|---|---|---|---|---|
| RestlessnessGeneral disorders | 6/20 | 7/19 | 9/18 | 8/18 |
| Nausea and VomitingGastrointestinal disorders | 6/20 | 7/19 | 8/18 | 9/18 |
| HeadacheNervous system disorders | 4/20 | 4/19 | 3/18 | 5/18 |
| DizzinessNervous system disorders | 5/20 | 3/19 | 2/18 | 4/18 |
| Age, Categorical(Participants) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 20 | 20 | 20 | 20 | 80 |
| >=65 years | 0 | 0 | 0 | 0 | 0 |
| Age Continuous(years) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| Mean | 33.8 ± 10.9 | 38.0 ± 13.5 | 36.9 ± 10.0 | 36.2 ± 12.9 | 36 ± 12 |
| Sex: Female, Male(Participants) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| Female | 16 | 14 | 16 | 15 | 61 |
| Male | 4 | 6 | 4 | 5 | 19 |
| Region of Enrollment(participants) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| Nepal | 20 | 20 | 20 | 20 | 80 |
| Vas baseline (cm)(centimeters) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| Median | 5 (4 to 6) | 5 (3.6 to 6) | 5 (4.2 to 7) | 5 (4 to 6) | 5 (4 to 6) |
| Anaesthesia time(minutes) | Melatonin | Melatonin and Alprazolam | Alprazolam | Placebo | Total |
|---|---|---|---|---|---|
| Mean | 65.8 ± 18.1 | 77.2 ± 34.3 | 73.7 ± 21.0 | 71.7 ± 17.6 | 71.6 ± 23.7 |
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B.P. Koirala Institute of Health Sciences