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Table of Contents   
ORIGINAL RESEARCH  
Year : 2021  |  Volume : 32  |  Issue : 4  |  Page : 438-442
Sedative effect of midazolam in different vehicles for oral administration


1 Pharmacology Laboratory, Faculty of Health Sciences, Universidad Científica del Sur; School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru
2 Research Group “Investigación en Ciencias Básicas Estomatológicas (ICBEST)”, Lima, Peru
3 Research Group “Investigación en Ciencias Básicas Estomatológicas (ICBEST)”; Faculty of Dentistry, Bromatology and Toxicology, Universidad Nacional Mayor de San Marcos, Lima, Peru
4 Pharmacology Laboratory, Faculty of Health Sciences, Universidad Científica del Sur, Lima; Research Group “Investigación en Ciencias Básicas Estomatológicas (ICBEST)”, Lima, Peru
5 Department of Pharmacology, Bromatology and Toxicology, Universidad Nacional Mayor de San Marcos, Lima, Peru

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Date of Submission11-Oct-2020
Date of Decision06-Nov-2021
Date of Acceptance03-Mar-2022
Date of Web Publication18-May-2022
 

   Abstract 


Context: Oral administration of midazolam is one of the most important protocols for producing adequate conscious sedation; however, it has an unpleasant taste and is poorly tolerated by pediatric patients. Aim: The aim of this study was to evaluate the sedative effect of diluted midazolam in different vehicles used to mask its unpleasant taste. Methods and Material: A total of 30 male mice (BALB-c) were randomly distributed in five groups. They were administered diluted midazolam in different vehicles (saline solution, paracetamol syrup, diclofenac suspension, multi-vitamin syrup, and boxed juice). All suspensions were administered orally (0.6 mg/Kg). The pH variation was evaluated with a digital pH meter, and the quality of sedation was evaluated in three tests: hole board test, grip strength test, and forced swimming test. Results: The paracetamol syrup vehicle was found to be the only vehicle which did not change its pH over time after dilution of midazolam. When evaluating the perforated platform, the greatest sedative effect was observed in the midazolam group with the paracetamol syrup (P > 0.05). Regarding grip strength, a difference was evident in all study groups at 45 minutes (P = 0.006); the midazolam group with the multi-vitamin syrup was less effective. Regarding the response time to forced swimming, the midazolam group with the paracetamol syrup presented the longest time at 15 and 30 minutes (5.39 ± 0.93 and 6.29 ± 0.83, respectively). Conclusion: The suspension of midazolam diluted in the paracetamol syrup is the most suitable for performing conscious sedation efficiently.

Keywords: Midazolam, sedation, suspension, syrup

How to cite this article:
Franco-Quino C, Chavez-Rimache L, Aponte-Laban A, Borda-Mendoza E, Gonzales-Camacho C, Chumpitaz-Cerrate V, Herrera-Calderon O. Sedative effect of midazolam in different vehicles for oral administration. Indian J Dent Res 2021;32:438-42

How to cite this URL:
Franco-Quino C, Chavez-Rimache L, Aponte-Laban A, Borda-Mendoza E, Gonzales-Camacho C, Chumpitaz-Cerrate V, Herrera-Calderon O. Sedative effect of midazolam in different vehicles for oral administration. Indian J Dent Res [serial online] 2021 [cited 2022 Jun 27];32:438-42. Available from: https://www.ijdr.in/text.asp?2021/32/4/438/345434



   Introduction Top


Conscious sedation is a protocol for drug-induced depression of the central nervous system, characterised by maintaining verbal contact with the patient. Furthermore, studies have shown that conscious sedation is more effective in controlling anxiety compared to non-pharmacological protocols.[1],[2],[3]

In dentistry, pulp and tooth treatments are frequent; these procedures generate pain and anxiety in patients, and if they are not managed correctly, they can cause long-lasting emotional trauma.[3] For this reason, benzodiazepines are used, which have proven to be safe and effective in achieving conscious sedation.[4],[5],[6]

Midazolam is frequently used as a pre-anaesthetic medication agent, showing beneficial effects because it has a fast onset of action and is short-lived.[2] In conscious sedation with midazolam, an anxiolytic effect is achieved; it prevents psychological stress, which allows the separation of children and parents, and produces anterograde amnesia.[2],[7],[8],[9],[10],[11] At a single dose, midazolam (0.2–0.6 mg/kg) has been shown to provide adequate sedative effects in pediatric patients undergoing dental surgical procedures.[12]

Before 1998, liquid dosage forms for oral administration of midazolam were not available; these conditions are maintained in some countries.[13] One of the main problems with oral presentation of midazolam is its unpleasant taste, because of which drinks, juices, and syrups are flavoured in order to mask its unpleasant taste.[4],[8]

Currently, there is insufficient information on the effect of midazolam combined with pain relievers, such as the paracetamol syrup, and with non-steroidal anti-inflammatory drugs, such as diclofenac, or with multi-vitamin complexes.

Therefore, the present study aims to evaluate the sedative effect of diluted midazolam in different vehicles used to mask its unpleasant taste.


   Methods and Material Top


Registration with the ethics committee was not performed, but it was evaluated by the expert committee (2019). For the care and use of experimental animals, the guidelines proposed by the Institute for Laboratory Animal Research (ILAR, 2010) were considered. In addition, topics for the care and use of laboratory animals, proposed by the Institutional Committee for the Care and Use of Animals (CICUA, ILAR), are in compliance with our current regulations of the Animal Protection Law (Law No. 27265).[14] In total, we used 30 male mice (BALB-C) of 25 ± 5 g, purchased from the bioterium of the Faculty of Medicine of the Universidad Nacional Mayor de San Marcos (Lima – Peru). All mice were conditioned for 7 days in light/dark cycles of 12 hours at 22 ± 2°C and subjected to fasting for 12 hours prior to the treatments, and water consumption was available at all times.

The preparation of the oral midazolam suspensions was carried out using five vehicles:

  1. Saline solution (NaCl 0.9%, BRAUN – Peru),
  2. Paracetamol syrup (160 mg/5 mL, Panadol® – GLAXOSMITHKLINE – Costa Rica),
  3. Diclofenac suspension (9 mg/5 mL, Dolo Liviolex® pediatric – TEVA – Peru),
  4. Multi-vitamin syrup (Mucovit® - HERSIL – Peru),
  5. Boxed juice (Pulp® – Peru).


First, the enteric coating of the midazolam tablet (Dormonid® - ROCHE - Brazil) was removed and crushed in a mortar; then, 5 mL was extracted from the vehicles and mixed until a suspension of 15 mg/5 mL was obtained. A digital pH meter was used to determine the pH of the vehicle before and after mixing with midazolam.

Subsequently, they were randomly distributed into five groups: Group A was midazolam suspension with saline solution (NaCl 0.9%), Group B was midazolam suspension with the paracetamol syrup (160 mg/5 mL), Group C was midazolam suspension with the multi-vitamin syrup, Group D was midazolam suspension with diclofenac suspension (9 mg/5 mL), and Group E was midazolam suspension with boxed juice. All suspensions were administered by using an oral cannula at a dose of 0.6 mg/Kg.

To determine the quality of sedation, we used three tests: the first was the hole board test.[15] It was used to determine the depressant effects of midazolam. It was carried out on a grey surface of 40 x 40 cm and 2.2 cm thick, with 16 holes of 3 cm in diameter equally distributed. The platform was placed at a height of 15 cm; the animals were placed in the centre of the platform, and the number of times the animal stuck its head out of the holes was evaluated taking as reference the ears (head dipping) for 5 minutes. The second method was the grip strength test;[16] mice were placed with its horizontal torso on a metal grid to allow the legs to adhere to the grid. Subsequently, the tail was gently pulled back and the grip force was determined by means of a dynamometer, which was previously calibrated. This procedure was performed repeatedly on three occasions. Finally, we used the forced swimming test;[17] for this test, a 20 cm diameter cylindrical tank was used with the water heated to 24 ± 2°C. The mice were placed in the central part of the tank, and the time in which the mouse completely left the cylinder was evaluated. This procedure was performed repeatedly on three occasions.

The STATA v15 statistical package was used to analyse the data. All data were expressed with a mean and standard deviation. For multiple comparisons, the Kruskall–Wallis analysis was used, and P < 0.05 was considered significant, with a confidence level of 95%.


   Results Top


Regarding pH changes, it was observed that the paracetamol syrup was the only vehicle that did not change its pH over time [Figure 1].
Figure 1: Variation of the pH of the vehicles used to dilute midazolam

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When evaluating the hole board test, it was found that the anxiolytic and sedative effect appeared in all groups after 30 minutes, and this effect is more intense in group B; however, no significant difference was evidenced; P = 0.961 [Table 1].
Table 1: Hole board test according to the study group

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Regarding the grip strength test, it was observed that at 15 minutes, all the groups presented lower strength; with the exception of group C, which showed an increase in grip strength compared to the baseline group (from 148.33 ± 17.22 to 155.01 ± 28.81 g). Furthermore, no significant difference was found at 15 and 30 minutes (p = 0.69 and P = 0.153, respectively) between the study groups; however, after 45 minutes, group C showed the highest grip strength (p = 0.006) [Table 2].
Table 2: Grip strength test according to the study group

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Regarding the response time to forced swimming, a progressive effect was observed. At 15 minutes, group B had the most intense effect (5.39 ± 0.93 s) and group C had the least intense effect (1.58 ± 0.12 s); P = 0.004.

At 30 minutes, group B maintained a response to slow forced swimming (6.29 ± 0.83 s) and the fastest response was observed in groups C and D (2.28 ± 0.53 and 2.09 ± 0.68, respectively); P = 0.005. At 45 minutes, all study groups had a longer time for forced swimming, except group C (4.10 ± 3.87 s); however, no significant difference was observed between all experimental groups [Table 3].
Table 3: Test of response to forced swimming in mice

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   Discussion Top


The results showed a sedative effect in all the study groups, but group B (midazolam with the paracetamol syrup) showed better results compared to the others.

Marçon et al.[18] mention that orally administered midazolam produces conscious sedation quickly (<45 minutes) without showing a significant effect on recovery time. For this reason, it is commonly used in the dental area for pulp treatments and serial tooth extractions.

The stability of the active ingredient is very important to achieve adequate bioavailability; midazolam is highly soluble and permeable. For this reason, its absorption is modified mainly by gastric emptying.[18],[19] Midazolam contains an alkaline nitrogen atom which facilitates the formation of water-soluble salts (pKa = 6.15), and this is formed when the pH of the medium is less than 4. Therefore, the solution of midazolam can give rise to 2 forms: the first is a lipophilic molecule with a closed diazepine ring (pH = 4.5), and the second is a water-soluble and polar molecule that contains an open diazepine ring (pH = 2.5). However, once administered to a patient (7.4 physiological pH), the fraction of midazolam in the lipophilic state increases, and this has the ability to cross different membranes. Therefore, the pH of the medium is very important to achieve good bioavailability.[20],[21],[22]

In the present study, it was observed that the paracetamol syrup (pH = 4.5) is the only one that maintains the pH before and after the dilution of midazolam; unlike vehicles with a pH ≤3.5, such as diclofenac, boxed juice, or a multi-vitamin syrup, this could reduce the bioavailability of midazolam by increasing the water-soluble fraction. This was similar to that found by Zhang et al.,[23] who orally administered 25 mg of midazolam solution at different pHs (2.8, 3.2, and 3.9) and observed a direct relationship with plasma concentrations.

Another limitation that prevents adequate bioavailability is the use of injectable solutions, which, when subjected to an acid pH, decrease their bioavailability. Furthermore, its bitter taste makes it difficult to administer.[8]

Studies have been carried out on the safety and effectiveness of the administration of midazolam intra-nasal, which is commonly used in a pediatric emergency department, showing good bioavailability; however, administration of this route causes significant irritation to the mucosa and other adverse effects, such as respiratory depression.[3],[10],[24] The European Union (EU) authorizes the use of the intra-venous formulation for sedation in pediatric patients who undergo minor surgical procedures in medicine and dentistry.

Furthermore, they mention that midazolam tablets are contraindicated because of the limited information on their safety and efficacy.[12] However, they also report that intra-muscular or intra-venous administration is rejected in many cases because it is painful because of fear of needles and the need for more resources; all this limits its use on an outpatient basis. Hence, we are looking for other options that are administered orally and that maintain clinical efficacy.

The administration of midazolam in a single dose aims to achieve conscious sedation, which generates a state of drowsiness and relaxation and maintains the response to stimuli.[1] This was simulated in the present pre-clinical model by the response time to forced swimming, used to assess reaction to a stressful situation.[16] Also, the grip strength test was used to assess muscle performance, and the hole board test was used as an indicator of changes in general locomotion.[15],[25]

It is very frequent that surgical procedures in medicine and dentistry generate pain; this causes anguish, anxiety, and agitation in pediatric patients. Midazolam is the most widely used benzodiazepine in conscious sedation, but it does not have an analgesic effect. For this reason, its combination with paracetamol is beneficial because it offers an analgesic effect, reducing the consumption of post-operative pain relievers and adverse effects, compared to when using another vehicle such as a multi-vitamin syrup or boxed juice.[26]

This work tries to establish an alternative of conscious sedation protocol with the administration of midazolam and the paracetamol syrup; however, it is recommended that for future research, randomised clinical trials should evaluate the effect of midazolam with different vehicles to determine its safety and efficacy during clinical work in dentistry.


   Conclusion Top


Under study conditions, administration of midazolam diluted in the paracetamol syrup is adequate to perform the conscious sedation protocol effectively.

Statement of funding/grants

This study was conducted with the FONDECYT/CIENCIACTIVA EF033-235-2015 grant and TW007393 training grant awarded by the Fogarty International Center of the National Institute of Health, USA.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Dr. Cesar Franco-Quino
Urb., Valle La Molina., Jirón Río Amazonas 234 - Lima
Peru
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdr.IJDR_977_20

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