Premedication With Melatonin and Alprazolam Combination Versus Alprazolam or Melatonin Alone
Condition: Anxiety
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

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.
    

Intervention name(s): meloset (melatonin); stresnil ( melatonin and alprazolam); (alprax) alprazolam; placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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
Intervention MeSH terms: Melatonin; Alprazolam; Azaperone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: premedication; premedicants; preoperative anxiety; melatonin; alprazolam