Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 129-135

Efficacy of Curcumin and Piperine as Antioxidant Adjuvant to Intralesional Dexamethasone Injection for Management of Oral Submucous Fibrosis: A Clinical Trial


1 Department of Dentistry, HIMSR & HAH Centenary Hospital, Hamdard Nagar, New Delhi, India
2 Department Of Radiodiagnosis, HIMSR & HAH Centenary Hospital, Hamdard Nagar, New Delhi, India
3 Department of Otorhinolaryngology, HIMSR & HAH Centenary Hospital, Hamdard Nagar, New Delhi, India
4 Department of Public Health Dentistry, ESIC Dental College, Rohini, New Delhi, India

Date of Submission04-Oct-2021
Date of Acceptance10-Nov-2021
Date of Web Publication14-Jan-2022

Correspondence Address:
Dr. Nilima Sharma
Department of Dentistry, HIMSR & HAH Centenary Hospital, Hamdard Nagar, New Delhi-110062
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jofs.jofs_218_21

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  Abstract 


Introduction: Oral submucous fibrosis (OSMF) is a well-recognized potentially malignant disorder of the oral mucosa with malignant potential estimated to be 7% to 13%. Both conservative and surgical treatment methodologies have been tried to bring relief from burning sensation, to decrease fibrous bands and to improve mouth opening. The role of curcumin as an anti-inflammatory, antioxidant has not been well established for the treatment of OSMF. Therefore, this study is undertaken. Materials and methods: The patients of OSMF attending the outpatient department of dentistry and otorhinolaryngology constituted the subjects for this study. Both groups were injected twice a week with dexamethasone sodium phosphate 4 mg/mL for 12 weeks. In addition, the test group was asked to take orally tablet TurmixR (curcumin 300 mg and piperine 5 mg) tablet 300 mg thrice daily orally for 3 months. The following outcome variables were measured 3 months posttreatment [burning sensation on visual analog scale, mouth opening (in millimeters) by vernier calipers, percentage relief in symptoms from pretreatment stage, and ultrasonographic evaluation of thickness of fibrotic bands]. Results: The mean change in burning sensation and mouth opening at weeks 3, 5, 7, 9, and 12 was significantly more among test group. The mean change in band length on ultrasonography on both right and left side from pre to mid and posttreatment was significantly more among test group. Conclusion: The commercially prepared avatar of Curcuma longa (turmeric) shows promise in reduction of signs and symptoms of patients with OSMF.

Keywords: Burning, fibrotic bands, ultrasonography


How to cite this article:
Sharma N, Jain A, Bahudar S, Oberoi SS. Efficacy of Curcumin and Piperine as Antioxidant Adjuvant to Intralesional Dexamethasone Injection for Management of Oral Submucous Fibrosis: A Clinical Trial. J Orofac Sci 2021;13:129-35

How to cite this URL:
Sharma N, Jain A, Bahudar S, Oberoi SS. Efficacy of Curcumin and Piperine as Antioxidant Adjuvant to Intralesional Dexamethasone Injection for Management of Oral Submucous Fibrosis: A Clinical Trial. J Orofac Sci [serial online] 2021 [cited 2022 Dec 5];13:129-35. Available from: https://www.jofs.in/text.asp?2021/13/2/129/335842




  Introduction Top


Oral submucous fibrosis (OSMF) is a premalignant condition predominantly reported in people of Asian descent. OSMF in initial stages presents as stomatitis, blanching of the oral mucosa with progressive perioral vertical and circular palpable fibrous bands and a mottled, marble-like appearance of the buccal mucosa.[1]

Betel quid chewing, excessive use of chilies and spices, poor nutrition, and vitamin and iron deficiency are suggested as causative agents. The habit of chewing areca nuts is recognized as the most important etiologic agent in the pathogenesis of this condition. Number of epidemiologic surveys, case–series reports, case–control studies, cohort, and interventional studies provide evidence that areca nut is the main etiologic factor for OSMF.[2]

The four main alkaloids in betel (i.e., arecoline, arecaidine, guvacine, and guvacoline) stimulate fibroblasts to produce collagen.[3]

Hydrolysis of arecoline to arecaidine is further accelerated by addition of slaked lime to betel nut; the latter amplifies fibroblastic proliferation and increases collagen formation.[4]

Significant variation in the prevalence of OSMF in different communities, regions, and countries is directly attributable to the patterns of areca nut usage, age of onset of the habit and variations in product availability.

Data indicate that more than 5 million people in India have OSMF (0.5% of the Indian population).[5]

The rate varies from 0.2% to 2.3% in males and 1.2% to 4.57% in females in Indian communities.[5]

Various treatment modalities both conservative and surgical have been tried to bring relief from burning sensation, to decrease fibrous bands and to improve mouth opening. These include intralesional injections of corticosteroids, placental extracts or hyaluronidase either alone or in combination, micronutrient supplementation, physiotherapy, and surgery.[6],[7],[8],[9],[10]

Immunosuppressive action of steroids helps in prevention or suppression of the fibroproductive inflammation found in OSMF lesions, thus ameliorating this myofibrocollagenous condition.[8]

As long, intralesional injections of dexamethasone (4 mg/mL) and hyaluronidase 1500 IU and 0.5 mL of lignocaine 2% have been the treatment modality in the management of patients with OSMF with variable success rates in different clinical studies.[11],[12]

Curcumin is an anti-inflammatory, antioxidant but its role in treatment of OSMF has not been well established. Low aqueous solubility and extensive first pass metabolism following oral dosing is an attribute of this molecule. Its absorption is enhanced by formulating it with naturally occurring UGT inhibitors such as piperine, quercetin, tangeretin, and silibinin; thus increasing its oral bioavailability. Piperine is a known inhibitor of hepatic and intestinal glucuronidation, inhibits several enzymes responsible for metabolism of curcumin thereby making more active form of curcumin available. This study was undertaken to evaluate the efficacy of curcumin and piperine as an antioxidant adjuvant to corticosteroid injections in the management of OSMF.[13]


  Materials and Methods Top


Source of data

The patients of OSMF attending the outpatient Department of Dentistry and Otorhinolaryngology of HIMSR & HAHC Hospital constituted the subjects for this study. Detailed patient history was recorded with regards to the onset, severity, and duration of symptoms. Patients were equally distributed among control and test groups.

Previous history of addiction to tobacco/pan masala intake was carefully noted. Local examination was performed to assess the OSMF according to the guidelines of clinical and functional staging by Haider et al.[14] The trial was registered with Clinical Trial Registry of India CTRI/2015/07/006001.

Ethical clearance (protocol no. 17/14) was given by the Jamia Hamdard Institutional Ethics Committee, New Delhi on December 1st, 2014.

Sample size calculation

Sample size:

From among those attending the clinic, initially we will take a sample as per the formulae:

n = z2p(1 ‒ p) /d2

where n is the sample size, z = 1.96 (95% confidence interval), p is the prevalence (5%), 1 ‒ p = 95%, and d is the allowable absolute error (5%).

Allocation of groups

Fifty patients were randomly divided into two groups by draw of chits. Both groups were injected twice a week with dexamethasone sodium phosphate 4 mg/mL for 12 weeks.

Group A (curcumin and piperine): Intralesional dexamethasone sodium phosphate 4 mg/mL injection biweekly and tablet TurmixR (curcumin 300 mg and piperine 5 mg) tablet 300 mg thrice daily orally for 3 months.

Group B (control): Intralesional dexamethasone sodium phosphate 4 mg/mL steroid injection Chart 1.



Inclusion and exclusion criteria

The inclusion criteria were as follows: patients of either sex above 20 years of age and positive history of chewing areca nut or one of its commercial preparations. Diagnosis of OSMF was made on the basis of natural history and characteristic clinical features which included the presence of burning sensation in the mouth, intolerance to spicy food, blanching and loss of suppleness of oral mucosa, presence of palpable fibrous bands, and decreased mouth opening.

Exclusion criteria

The exclusion criteria were as follows: patients with systemic diseases (diabetes, hypertension, liver disorders, kidney disorders, autoimmune disorders), other mucosal lesions, pregnant and lactating women, patients with a known allergy or contraindication to the study drugs, association of malignant neoplasm in oral cavity/or oropharynx and temporomandibular joint problems such as temporomandibular joint arthrosis, and fracture mandible ramus.

Study procedure

Only buccal mucosa was considered for our study. All individuals were subjected to clinical, ultrasonographic evaluation before the treatment.

Ultrasonographic estimation of submucous fibrosis was performed in all the subjects. B-mode ultrasonography on Samsung HS-70 5D machine (Samsung Medison Co. Ltd., Seoul, Korea) was used to measure the thickness of submucosa with high frequency linear probe. The standard digital caliper was used for measurement. All patients were examined with standard protocol using a shoulder support in supine position with radiologist conducting ultrasound on right side of examination table.

Copious amount of sterile coupling gel (cellulose dextrose gel) was used for smooth interface between the probe and buccal and labial surfaces extra orally. As scanning, the gloved index finger of subjects was placed intraorally against the lining mucosa to help in delineation of the empty spaces of the oral.[11]

Single trained radiologist acquired the images for all the patients. Three readings were obtained at each spot to reduce intraobserver variations. All measurements were obtained in millimeters. Three points were selected for these measurements, the anterior, middle, and posterior for buccal mucosa.

The mean submucosal thickness of three points was calculated for the mucosa. The study included 40 clinically confirmed cases of oral submucous fibrosis which were randomly allocated to the two study groups.

Patients were counseled for deleterious habit and advised to discontinue the same before initiation of treatment. Basic therapy comprising of scaling was performed. Evaluation of the dentition for new stains was carried out to assess the patient’s compliance of cessation of habit.

Parameters assessed

The following parameters were evaluated at preoperative and every patient visit [burning sensation on visual analog scale and interincisal distance was measured to assess the mouth opening (in millimeters) by vernier calipers].[15] The following parameters were evaluated at every patient visit (percentage relief in symptoms from pretreatment stage and percentage relief in symptoms from last visit). The following parameters were evaluated at start of treatment, midtreatment and end of treatment (ultrasonographic evaluation thickness of fibrotic bands in OSMF lesions) [Figure 1]a,b.
Figure 1 (a) Line joining the ear lobule with commissure. (b) Probe placement. High frequency probe with finger inside oral cavity pushing the buccal mucosa out in proximation to the probe.

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The following outcome variables were measured 3 months posttreatment (burning sensation on visual analog scale, interincisal distance was measured to assess the mouth opening (in millimeters) by vernier calipers, percentage relief in symptoms from pretreatment stage, and ultrasonographic evaluation of thickness of fibrotic bands.

Statistical analysis

Descriptive statistics was performed by calculating mean and standard deviation for the continuous variables. The software used for the statistical analysis was Statistical Package for Social Sciences (SPSS) (IBM) version 25.0 and MedCalc software (WINDOWS for MedCalc). Unpaired or independent t-test was used for comparison of mean value between two groups when the data followed normal distribution. Repeated measures analysis of variance test was used for comparison of mean values obtained over more than two time intervals from the same sample when the data followed normal distribution.


  Results Top


The mean burning sensation at baseline (week 1), week 3, week 5, week 7, week 9, week 12, change at week 3, change at week 5, change at week 7, change at week 9, and change at week 12 was compared between test and control groups using the unpaired t test. The mean burning sensation at weeks 3, 5, 7, 9, and 12 was significantly more among control group. The mean change in burning sensation at weeks 3, 5, 7, 9, and 12 was significantly more among test group [Table 1].
Table 1 Comparison of mean burning sensation between control and experimental group

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The mean mouth opening at week 3, week 5, week 7, week 9, week 12, change at week 3, change at week 5, change at week 7, change at week 9, and change at week 12 was compared between test and control groups using the unpaired t test. The mean mouth opening at weeks 3, 5, 7, 9, and 12 was significantly more among test group. The mean change in mouth opening at weeks 3, 5, 7, 9, and week 12 was significantly more among test group [Table 2].
Table 2 Comparison of mean mouth opening between control and experimental group

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The mean band thickness on ultrasonography (right side) at baseline, midtreatment, posttreatment, change from pre to mid, and posttreatment was compared between test and control groups using the unpaired t test. The mean band length on ultrasonography (right side) at midtreatment and posttreatment was significantly more among control group. The mean change in band length on ultrasonography (right side) from pre to mid and posttreatment was significantly more among test group [Table 3].
Table 3 Comparison of Mean band thickness Right side between control and experimental group

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The mean band length on ultrasonography (left side) at baseline, midtreatment, posttreatment, change from pre to mid, and posttreatment was compared between test and control groups using the unpaired t-test. The mean band thickness on Ultrasonography (Left side) at mid-treatment and post-treatment was significantly more among control group. The mean change in band thickness on ultrasonography (left side) from pre to mid and posttreatment was significantly more among test group [Table 4], [Figure 2]a,b.
Table 4 Comparison of Mean band thickness left side between control and experimental group

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Figure 2 (a) (in experimental group) Thickening of submucosa measuring approx. 3.2 mm pretreatment. (b) Reduced submucosal thickness measuring approx. 1.3 mm posttreatment.

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  Discussion Top


Curcuma longa (turmeric) is an age old Ayurvedic medicine for treatment for inflammatory conditions. Curcumin interacts with numerous molecular targets involved in inflammation and has antioxidant and antimicrobial properties.

Our study reported that mean change in burning sensation at weeks 3, 5, 7, 9, and 12 was significantly more among test group (P < 0.001), which is in conjunction with studies which report either reduction in symptoms such as burning,[16] a complete resolution of burning sensation with curcumin.[17]

The alleviation of burning sensation in the turmix group could be attributed to its anti-inflammatory properties. Curcumin modulates the inflammatory response by:
  1. Downregulating the activity of cyclooxygenase-2 (COX-2), lipoxygenase, and inducible nitric oxide synthase (iNOS) enzymes.
  2. Inhibiting the production of the inflammatory cytokines, tumor necrosis factor-alpha, proinflammatory interleukin (IL) such as IL-1, IL-2, IL-6, IL-8, and IL-12, monocyte chemoattractant protein, and migration inhibitory protein.[13]


Though the gold standard for diagnosis of any oral lesion would always be histopathologic examination, ultrasonography being a noninvasive, nonionizing technique is suitable for visualization of changes in the superficial structures such as buccal and labial mucosa[18] and serving as a better diagnostic tool compared to clinical and histopathologic examination.

In our study, both mean mouth opening and the mean change in mouth opening at weeks 3, 5, 7, 9, and 12 was significantly more among test group when compared with control group [Table 2]. In addition, the mean change in the submucosal band thickness of right and left buccal mucosa from pre to mid and posttreatment was significantly more among test group when compared with controls [Table 3] and [Table 4].

Fibrosis is a resultant of reduced collagen clearance by collagen stabilization and inhibition of phagocytosis. Formation of cross-links between collagen peptide chains renders the collagen resistant to degradation by collagenases.[19] The active constituents in betel nut induce substantial amounts of collagen synthesis in the oral mucosal cells.

The myofibroblasts detected in OSMF-affected tissues not only synthesize collagen, but also produce numerous inflammatory mediators, chemokines, and growth factors intensifying and prolonging the inflammation in OSMF by activating the inflammatory cells.[16] This self-excitation of inflammation increases the expression of fibrogenic cytokines such as transforming growth factorβ1, and enhances fibrosis.[20]

High levels of copper in areca nut, a major etiologic factor in OSMF, play an initiating role in stimulation of fibrogenesis by upregulation of lysyl oxidase and thereby causing inhibition of degradation of collagen.[21]

Curcumin is reported to induce apoptosis. It ability to act as a photosensitizers on exposure to visible light, in the presence of oxygen can be utilized for photodynamic therapy, especially in precancerous oral diseases.[22]

In vitro study postulates that curcumin inhibits proliferation of fibroblasts and myofibroblasts, the latter being more sensitive to its actions. It also disturbs the cell cycle, induces apoptosis, and decreases the generation of collagen types I and III in myofibroblasts. It may therefore be of potential for the treatment of OSMF.[23] This can be attributed to the improvement in mouth opening observed in experimental group in which curcumin was used as adjunct to conventional treatment.

Inhibition of proliferation and induction of apoptosis in myofibroblasts offers a new paradigm in the treatment of OSMF. Curcumin a potent scavenger of reactive oxygen species; mediates antiprecancer activities by increasing levels of vitamins C and E in saliva and prevents lipid peroxidation and DNA damage.[24]

Potent analgesic and anti-inflammatory activities of Piper nigrum L have been demonstrated in animal model study.[25]

A randomized controlled trial reports greater effect of curcuminoids–piperine combination in elevating reduced glutathione, reducing malonedialdehyde. The promising effects of curcuminoids on the measures of systemic oxidative stress enable them to be used as safe adjuvants.[26]


  Conclusion Top


Oral antioxidant curcuminan essential condiment in all the Indian households can be used as an adjuvant therapy in the initial management of patients with OSMF, though commercially available curcumin preparations with an agent to increase its bioavailability are recommended. The patients will be encouraged to consume this molecule as it is well tolerated by patients with OSMF without any side effects.

Larger patient sample size, with longer period of treatment follow-up, will strengthen the hypothesis of our study in the treatment of OSMF.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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