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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 28  |  Issue : 3  |  Page : 229-235

Control of odontogenic pain by diclofenac and meloxicam mucoadhesive patches: A randomized, double-blinded, placebo-controlled, preliminary study


1 Department of Oral Medicine and Radiology, College of Dental Sciences, Davangere, Karnataka, India
2 Department of Pharmaceutics, Bapuji Pharmacy College, Davangere, Karnataka, India

Date of Submission24-Dec-2015
Date of Acceptance28-Nov-2016
Date of Web Publication13-Dec-2016

Correspondence Address:
Dr. Pratik R Pipalia
Department of Oral Medicine and Radiology, College of Dental Sciences, Davangere, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-1363.195669

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   Abstract 

Aims and Objectives: To evaluate and compare the efficacy of diclofenac and meloxicam as mucoadhesive patches in dental pain management. Materials and Method: This study was conducted among 45 adult patients of either sex, who were diagnosed with dental pain and were attending the outpatient department. Written informed consent was obtained from all the patients. A 1 × 1 cm2 mucoadhesive patch of any one (diclofenac, meloxicam or placebo) was applied on the attached gingival region of the tooth with pain. Pain was recorded using a ten point visual analog scale (VAS) score at every 5 min for 30 min. Pain was measured and compared before and after the application of the patch. Results: The results showed that patients with diclofenac patch gained mean pain reduction from 6 ± 1.54 mm to 2.60 ± 1.32 mm after 30 min (P < 0.01), and with meloxicam patch gained mean pain reduction from 6.06 ± 2.72 mm to 2.33 ± 1.23 mm after 30 min (P < 0.01), compared to patients with placebo 6.03 ± 2.09 mm to 5 ± 2.10 mm (P > 0.05). The maximum pain reduction was seen with meloxicam patch. Conclusion: Transmucosal mucoadhesive analgesic patches are a better alternative to oral analgesics to control dental pain. Hence, routine use of mucoadhesive analgesic patch for dental pain reduction is recommended in day to day practice.

Keywords: Dental pain, diclofenac, meloxicam, mucoadhesion, transmucosal patch


How to cite this article:
Pipalia PR, Annegeri RG, Juturu T, Mehta R. Control of odontogenic pain by diclofenac and meloxicam mucoadhesive patches: A randomized, double-blinded, placebo-controlled, preliminary study. J Indian Acad Oral Med Radiol 2016;28:229-35

How to cite this URL:
Pipalia PR, Annegeri RG, Juturu T, Mehta R. Control of odontogenic pain by diclofenac and meloxicam mucoadhesive patches: A randomized, double-blinded, placebo-controlled, preliminary study. J Indian Acad Oral Med Radiol [serial online] 2016 [cited 2019 Nov 17];28:229-35. Available from: http://www.jiaomr.in/text.asp?2016/28/3/229/195669


   Introduction Top


Dental pain may be defined as pain that originates from the innervated tissues within the tooth or immediately adjacent to it.[1] It can have social, psychological and economic consequences on individuals and communities. It has been reported that toothache is the major causal impairment for almost all aspects of daily performance.[2] Individuals who suffer from toothache avoid chewing hard things, are prevented from eating certain foods, and also have trouble sleeping.[3] Literature suggests that the overall prevalence estimates for dental pain ranges from 7–66%.[4]

The drugs most commonly used to manage dental pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and mostly they are administered through peroral route. Diclofenac, meloxicam, etc., are among the most widely used medications in the world because of their demonstrated efficacy in reducing pain and inflammation. Numerous studies have clearly documented that the risk of upper gastrointestinal complications increases with increasing doses as well as increasing frequency of use of NSAIDs.

On the other hand, transmucosal routes of drug delivery offer distinct advantages over oral administration such as less dosing frequency, short treatment period, improved patient compliance, reduction in fluctuation in steady-state levels and therefore, better control of disease condition. In addition, there is reduced intensity of local or systemic side effects, increased safety margin of high potency drugs and maximum utilization of drug enabling reduction in the total amount of drug administered.[5]

Mucoadhesive patch works on the principle of mucoadhesion, which is the phenomenon of the attachment of natural or synthetic macromolecule to the mucin layer of mucosal surface or epithelial surface.[6] The mechanism of mucoadhesion is generally divided in two steps, namely, the contact stage and the consolidation stage, as shown in [Figure 1]. The first stage is characterized by the contact between the mucoadhesive and the mucous membrane, with spreading and swelling of the formulation. In the consolidation step, the mucoadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive molecules to break and to link up by weak Van der Waal forces and hydrogen bonds and after that drug percolation occurs.[7],[8],[9],[10]
Figure 1: Stages of mucoadhesion

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There are very few studies related to dental pain control through oral mucoadhesive patches. Hence, this study was designed to evaluate the effectiveness of diclofenac and meloxicam via oral transmucosal route using mucoadhesive patch for the management of dental pain. The present study was conducted to evaluate and compare the efficacy of diclofenac and meloxicam as mucoadhesive patches in dental pain management.


   Materials and Methods Top


The study protocol was approved by the Institutional Review Board of College of Dental Sciences, Davangere, India (Certificate no. CODS/487/2014-2015). The study was conducted in accordance to the Declaration of Helsinki. Patients of either sex attending the outpatient department were included in the study based on the inclusion and exclusion criteria.

Inclusion criteria: Patients of both sexes aged more than 18 years, clinically diagnosed with odontogenic pain (apical periodontitis), mentally sound to answer the visual analog scale (VAS) score, and who had not taken any type of analgesic drugs, anti-inflammatory drugs, or tranquilizers for one day before the study were included in the study. The exclusion criteria included: (i) Patients allergic to the drug or patch material, (ii) patients with serious renal, hepatic, respiratory, cardiac, endocrine, or metabolic impairment (iii) patients with persistence mental confusion, or (iv) women who were pregnant and lactating.

In the present study, diclofenac sodium and meloxicam (Dr Reddy Labs, Hyderabad) were used. Transmucosal patches were prepared by solvent casting technique(Anders and Merkle, 1989)[11] using film hydroxypropyl methyl cellulose (HPMC) polymer (350 mg). The polymer was weighed accurately and dissolved in 5 ml of acetone. The beaker containing the polymer and ethanol was kept aside for 5 min for swelling of the polymer. Further, 3 ml of acetone was added to the abovementioned polymer solution and the dispersion was stirred. Then, 10 drops of (3.675% w/v) glycerin was added to the polymer solution. Simultaneously, 30 mg of diclofenac was accurately weighed and dissolved in 1 ml of methanol in another beaker. The drug solution was added to the polymer solution and was mixed thoroughly with the help of a magnetic stirrer. The glass mold of size 5 × 3 cm 2 was placed over a flat surface. The entire solution was poured into the glass mold. Inverted funnel was placed over the mold to avoid sudden evaporation. The mold-containing polymeric solution of drug was kept for 12 h at room temperature for drying. After drying, the films were observed and checked for possible imperfections upon their removal from the molds. Similar preparation procedure was used to prepare meloxicam (8 mg) and placebo patches. The composition of each patch is mentioned in [Table 1]. They were covered with wax paper and preserved in desiccator till the evaluation tests were performed. The patches were tested for all quality control measures such as drug content uniformity, thickness uniformity, weight uniformity, sterility, folding endurance, tensile strength, and stability.[11] The patches were cut into 1 × 1cm 2 pieces. The transmucosal diclofenac patch contained 2 mg of the drug on average and the meloxicam patch contained 0.50 mg of the drug. The patches were packed with wax paper and preserved till the day of application. The cut patches were labeled as patch a, patch b, and patch c by the supervisor to facilitate the double blinding.
Table 1: Composition of each patch

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Pain assessment

The first investigator was assigned collection of the data on a detailed proforma wherein the chief complaint, working diagnosis, detailed medical history, the VAS scores, and other related information were recorded. Pain intensity was measured by 10 mm VAS score with 0 being no pain and 10 being worst imaginable pain. The patients were asked by the investigator to describe the degree of pain they experienced at baseline and every 5 min for 30 min. [Figure 2] and [Figure 3] were used to assist the patient to assess the pain.
Figure 2: To assist the patient for degree of pain experienced (Visually)

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Figure 3: To assist the patient for degree of pain experienced (Verbally)

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Randomization was computer assisted. Patients were randomly divided into three groups, Group A, B, and C; and mucoadhesive patch a, b, and c were applied, respectively, over the attached gingiva and alveolar mucosa of the offending tooth, as shown in [Figure 4]. The area was mopped with cotton pallet and patch was placed. Patients were advised not to talk, swallow, or do any tongue movement, which can dislodge the patch. After 30-min patch was removed and discarded. Patients were followed up for any adverse effects for the next 7 days. All the patients proposed to be selected for the present study were made to seat and relax on the dental chair and underwent clinical examination by the oral diagnostician (the second investigator) to assess their sustainability for the enrolment in the present study. Methodology in the form of a flow chart is shown in [Figure 5].
Figure 4: Mucoadhesive patch applied to the attached mucosa of mandibular premolar and molar

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Figure 5: Flow diagram of phases in the study

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Statistical analysis

Statistical analysis was done using the Statistical Package for the Social Sciences version 21.0 (SPSS, Chicago, IL, USA). MS Excel 2010 (Microsoft Corporation, Washington, DC, USA) was used to generate tables and chart. Tests used were one-way analysis of variance (ANOVA) for intergroup comparison, repeated measures ANOVA for intragroup comparison, and descriptive analysis [Mean ± standard deviation (SD)]. To assess the level of significance between the groups, Tukey's post hoc test were used. P value of < 0.05 was considered to be significant.


   Results Top


Demographic characteristics of all the patients are shown in [Table 2]. Recording of the data was done by a single observer to eliminate interobserver bias. In the present study, out of 45 patients with odontogenic pain, 21 were females and 24 were males. The age of the patients ranged between 18 and 55 years, with the mean age of 36.38 ± 12.89 years. After debriefing, it was found that Group A was given diclofenac patch, group B was given placebo patch, and group C was given meloxicam patch.
Table 2: Demographic and clinical characteristics of patients who participated in study

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Intergroup analysis

The mean baseline VAS scores recorded were 6 ± 1.54 mm, 6.03 ± 2.09 mm, and 6.06 ± 2.72 mm for diclofenac group, placebo group, and meloxicam group, respectively, which, at the end of 30 min reduced to 2.60 ± 1.32 mm, 5 ± 2.10 mm and 2.33 ± 1.23 mm, respectively. The results were statistically significant between meloxicam with placebo group and diclofenac with placebo group, as shown in [Table 3] (P < 0.01).
Table 3: Intergroup and intragroup comparison of visual analog scale score for group A, B, and C at baseline (0 min), 5 min, 10 min, 15 min, 20 min, 25 min, and 30 min time interval

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Intragroup analysis

The difference observed in VAS score in the first two time intervals (i.e., 10 min) was not found to be statistically significant in all groups (P > 0.05). For third, fourth, fifth, and sixth time interval (next 20 min), it was found to be significant for the diclofenac group (A) (P < 0.05) and meloxicam group (C) (P < 0.05) but not for placebo group (B) (P > 0.05). There was no significant difference in pain reduction between both drug groups (P > 0.05), however, meloxicam showed better pain reduction than diclofenac group [Graph 1],[Graph 2],[Graph 3],[Graph 4].




   Discussion Top


Oral mucosa is proclaimed to be a leaky epithelium intermediate between that of the epidermis of the skin and the intestinal mucosa.[12] The lamina propria of oral mucosa is endowed with the presence of small capillaries. Their permeability is estimated to be 4 to 4000 times that of the epidermis. The vessels drain absorbed drugs along with the blood into the major veins, which ultimately opens in the jugular vein. Thus buccal route of drug delivery provides a direct access to the systemic circulation painlessly and with a steady rate of delivery bypassing the stomach environment and first pass metabolism, leading to high bioavailability.[13]

Various mucous devices including tablet, ointment, and gels have recently been developed. However, buccal patches offer greater flexibility and comfort than that by other devices. In addition, a patch can circumvent the problem of the relatively short residence time of oral gels on mucosa because gels are easily washed away by saliva.[14],[15] Our study demonstrated that diclofenac and meloxicam mucoadhesive patches have a role in dental pain management as compared with placebo. All the patients in group A (n = 15, 100%) as well as in group C (n = 15, 100%) showed mild to moderate pain reduction compared to Group B in which there was no pain reduction in 12 patients (80%).

Literature suggests that fastest acting analgesics take 17 min to reach its analgesic effects if the drug is being administered by noninvasive route.[16] However, in the present study, significant analgesic effect was achieved in 15 min or even less. A similar study conducted in Assiut University Hospital's Maxillofacial Unit, in which the author studied 40 patients who underwent minor and major surgery using single patch (1 × 5 cm 2) containing 4 mg of lornoxicam daily for 3 days. Pain intensity was measured by 100 mm VAS scale for 3 days. The author observed significant analgesic effect using mucoadhesive patch.[17] Similarly, the present study also revealed significant reduction in dental pain with the use of 1 × 1 cm 2 mucoadhesive patch of diclofenac and meloxicam.

In our study, the diclofenac patch contained approximately 2 mg of the drug on average and the meloxicam patch contained 0.50 mg of drug, which were very low compared to oral administration dosages i.e., diclofenac being 50mg and meloxicam being 7.5mg. This can be explained as the study is directed to the local effect of the drug so that the drug concentration was reduced. It is similar to commercially available diclofenac gel preparation for local application, which also contains less dosage of the drug i.e., 1 w/w%.

NSAIDs work by inhibiting the COX enzyme, to reduce inflammation. However, COX enzyme is also a constitutional enzyme present in the gastric mucosa where it plays a key role in protecting the gastric mucosa by producing mucin. Studies explaining gastric adverse effects of NSAIDs due to local effects of the drugs that can be easily overcome by the transmucosal route have been reported. Similar to our study, 3 patients in group A, 1 in group B, and 3 in group C had history of gastritis, however, none of them experienced any discomfort.

Another study done in Teikyo University, Japan, wherein mucoadhesive indomethacin patches used at 0.5 and 1% concentration in 65 patients diagnosed with various oral conditions associated with pain. The authors stated that the effects were the greatest in the 1% indomethacin group.[18] Future studies can be conducted with larger sample size and correlations of the serum drug concentration with its clinical effect.


   Conclusion Top


Our study established the efficacy of diclofenac and meloxicam mucoadhesive patch in terms of dental pain management with least possible side effects. The study reported statistically significant results in terms of dental pain reduction, and it should be adopted in day to day practice.

Acknowledgement

We gratefully acknowledge Dr. Garima J., Dr. N. Narendra and Mr Mailappa for their contribution towards this study and special thanks to Dr. Parth Thakkar for statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

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Patel VM, Prajapati BG, Patel MM. Design and characterization of chitosan-containing mucoadhesive buccal patches of propranolol hydrochloride. Acta Pharm 2007;57:61-72.  Back to cited text no. 10
    
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Thimmasetty J, Pandey G, Babu P. Design and in vivo evaluation of carvedilol buccal mucoadhesive patches. Pak J Pharm Sci 2008;21:241-8.  Back to cited text no. 11
    
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Patel KV. Buccal Bioadhesive Drug Delivery System: An Overview. Int J Pharmaceutical Biol Arch 2011;2:600-9.  Back to cited text no. 13
    
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Squier C. The permeability of oral mucosa. Crit Rev Oral Biol Med 1991;2:13-32.  Back to cited text no. 14
    
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Rathbone MJ, Tucker IG. Mechanisms, barriers and pathways of oral mucosal drug permeation. Adv Drug Deliv Rev 1993;12:41-60.  Back to cited text no. 15
    
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Sawaddiruk P. Tramadol hydrochloride/acetaminophen combination for the relief of acute pain. Drugs Today 2011;47:763-72.  Back to cited text no. 16
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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