Non-Surgical Management of Mouth Opening in Oral Sub Mucous Fibrosis: A Network Meta-Analysis

Introduction

Oral cancer is one of the most preventable cancers with a typical sequence of origin as a potentially malignant disorder, promotion, and transformation into cancer. The progression of precancerous lesions into cancerous form can be prevented if they are treated early on. Oral submucous fibrosis (OSMF) is an important precancerous condition mainly attributed to alkaloids, polyphenols and trace elements present in areca nuts.¹ Chewing areca as a component of betel quid is a common practice in most Asian countries and hence OSMF is commonly seen in these parts of the world. It manifests predominantly with a burning sensation of oral mucosa and the inability to open the mouth wide. It is preferable to treat OSMF in its initial stages non-surgically. However, OSMF has never been successfully treated by any single medication so far. Practitioners have tried various combinations of the drugs with variable results.² Hence, we conducted this meta-analysis to assess which treatment modality gives a better result with regard to improvement in mouth opening in OSMF patients.

Materials and Methods

Study design

Considering the availability of a wide variety of non-surgical interventions for OSMF, we decided to carry out a Network Meta Analysis (NMA) to determine the comparative effectiveness of the treatments mainly with respect to mouth opening.

Protocol and registration

This NMA was performed based on the guidelines given by the Preferred Reporting Items for Systematic Reviews and Meta Analyses Protocols (PRISMA-P)³ and has been registered in PROSPERO with ID, CRD42020193681

Criteria for considering reviews for inclusion

Randomized controlled trials (RCTs) performed on patients in the initial stages of OSMF with limited mouth opening were considered for the study.

Search strategy

A systematic literature review was conducted for English language publications through various search engines like Pubmed, Google Scholar, Science direct, Web of Science, Medknow journals, Jaypee journals, Wiley publications as well as a variety of other journals, accessible via the internet platform, using the keywords “oral submucous fibrosis” or “OSMF” using the filter “randomized control trial” wherever possible from January 2020 to October 2021. Only the publications in the English language were considered.

Selection Criteria

Participants: RCTs with human participants diagnosed to be suffering from OSMF.

Type of interventions: Study and patient characteristics - RCTs of non-surgical interventions performed on OSMF patients.

Control: Studies which have compared the interventions either with placebo or with another treatment intervention.

Outcomes: The outcome assessed was an increase in the mouth opening in millimeters. Adverse reactions if any were also recorded.

Exclusion criteria

The following exclusion criteria were applied:

(1) Studies with missing data required to perform a meta-analysis such as mean with standard deviation of the improvement in mouth opening.

(2) Publications using duplicated data.

Data extraction

Two researchers independently screened and extracted the data. Data on study design, population, sample size, interventions, outcomes, and adverse effects were gathered from the included studies.

Assessment of risk of bias

The risk of bias of RCTs was investigated independently by both the authors using the modified version of Cochrane's tool for assessing the risk of bias using Revman 5 software.⁴

Statistical analysis

Frequentist NMA was performed using program R studio software (RStudio Version 1.2.5033).

Data synthesis

We had to analyze whether one intervention is more or less effective than another type of intervention. In NMA, comparison among the interventions was performed indirectly. To overcome variations among the selected studies, the effect size of each study was considered for analysis. The effect size was calculated based on the standardized mean difference (SMD).⁵ The consistency in the entire network was assessed using Cochran’s Q statistics. The treatment ranking was presented by P-scores based on the point estimates and standard errors of the network assesses.

Results

Study selection

As per the PRISMA guidelines, among 2043 articles selected from all databases (Figure 1), a total of 29 RCTs met our inclusion criteria and were accepted for the NMA which included 25 treatments, 47 pair wise comparisons and 26 designs involving 1586 subjects. All the studies were published after 2009. Among the selected RCTs, nine were multiarmed trials. Selected RCTs had subjects of age group ranging from the second decade to the fifth decade and male predominance was seen in all of them. For simplifying the analysis, RCTs with interventions involving antioxidants or multivitamin were considered as multivitamin (Table 1).

Characteristics of outcomes

Method of measurement of mouth opening

Out of the 29 RCTs, 24 trials had mentioned the method of measurement of mouth opening. The interincisal mouth opening was measured using a Vernier caliper or a centimeter-scale from the mesioincisal angle of the upper central incisor to the mesioincisal angle of the lower central incisor. Five trials did not mention the method of measurement of mouth opening.

Adverse reactions

Among the 29 RCTs, seven trials had mentioned about the side effects. Few subjects of the curcumin group had experienced gastric irritation, facial flushing and erythema of the palms.^9,17 Few patients on pentoxifylline had experienced mild side effects related to gastrointestinal and central nervous system.²⁶ No other major side effects were observed. Ten trials had not made any mention about the side effects.

NMA

Using the package “metacont”, treatment effect and standard error were estimated. Package “netmeta” was used to perform NMA. Based on the level of heterogeneity (tau^2 = 0.5649; I^2 = 85.2%), random effect model was considered for NMA. Tests of heterogeneity (within designs) and inconsistency (between designs) was assessed using Cochran’s Q statistics. As the p-value was <0.001, there was statistically significant inconsistency between the trials. Network geometry was obtained (Figure 2) and treatment ranking was assessed through P-SCORE (Table 2). Forest plot was drawn (Figure 3). Results indicated that the intralesional steroid and hyaluronidase with vitamin E supplementation gave better result with P-SCORE as 0.9978 than all the other interventions, Intralesional Steroid and Hyaluronidase with Lycopene (P-SCORE= 0.8752) being the second best.

Discussion

OSMF is a chronic preneoplastic condition, which results in irreversible damage to the oral mucosa. Even though several etiologies have been identified in the past literature, the areca nut is thought to be the primary causative agent. Areca nut alkaloids promote hyalinization and fibrosis of juxta epithelial connective tissue, resulting in oral mucosa blanching and loss of elasticity, as well as decreased capacity to open the mouth.³⁵ Copper levels in processed areca products are much greater than in raw areca nuts. The rising prevalence of OSMF may be linked to the rise in copper content in the processed areca and appealing commercials promoting the use of processed areca.³⁶

OSMF management has always been a challenge over the years because the changes seen are not completely reversible. Excessive deposition of collagen and subsequently decreased vascularity is the major challenge faced by oral physicians in the management of OSMF. Various modalities have been tried, but not a single modality has so far been able to reverse the condition completely. Each modality, however, has demonstrated some advantages over the others.² The most prevalent reason OSMF patients seek dental help is trouble opening their mouth owing to oral mucosal stiffness. As a result, the primary goal of OSMF treatment is to improve mouth opening by nonsurgical or surgical means. Nonsurgical treatments can be used to treat mild to moderately severe cases. We performed this network meta-analysis on multiple nonsurgical modalities to see which one works best on these patients.

The non-surgical modalities that have been tried are intralesional steroids, hyaluronidase, placental extract, colchicine, pentoxifylline, spirulina, lycopene, curcumin capsules, Aloe vera, Nigella sativa, multivitamin, ultrasound and physiotherapy. These modalities have been tried either singly or in combination. Intralesional steroids act locally at the site of injection and have anti-inflammatory as well as immune suppressant action. Corticosteroids such as hydrocortisone, triamcinolone acetonide, betamethasone, and dexamethasone have been used in the management of OSMF. Hyaluronidase and placentrex are also administered intralesionally. Hyaluronidase breaks down hyaluronic acid, degrades the hyaluronic acid matrix, decreases the viscosity of the intercellular cement substances and also reduces collagen formation.² Placental extract accelerates cellular metabolism, aids in absorption of exudates, stimulates regenerative processes and promotes wound healing.²⁵ Intralesional steroids have also been given as a combination with hyaluronidase and placentrex.

Colchicine is an alkaloid found in the crocus like plant, Colchicum autumnale mainly used in the treatment of gout. It exhibits anti-inflammatory action by preventing the migration of neutrophils.³⁷ Oral pentoxifylline has been proved to have beneficial result in treating OSMF because of its anti‑inflammatory, fibrinolytic, immunomodulatory, and rheologic modifying property. Interleukin‑1‑induced fibroblast proliferation is also inhibited by pentoxifylline.²⁶ Spirulina is a microalgae which contains phenolic acid, tocopherols, and beta‑carotene which are known to exhibit antioxidant properties.²¹ Lycopene is a carotenoid phytochemical found predominantly in tomatoes. It is a potent antioxidant.¹¹ Lycopene group showed significant decrease in post-treatment juxtaepithelial collagen deposition and chronic inflammatory infiltrate.¹⁶

Curcumin is a yellowish compound extracted from the rhizomes of turmeric. It has a wide spectrum of biological action. It possesses anti-inflammatory, antibiotic, anticancer, antioxidant and many more properties.³⁸ Nigella sativa exhibits antibacterial, antifungal activity, antioxidant, anticancer, anti- inflammatory, analgesic activity, immunomodulatory, and antifibrotic properties.^15,39 Probably its anti-inflammatory and immunomodulatory properties are helpful in the management of OSMF. Aloe vera is a mannoprotein having anti-inflammatory, immunomodulatory, and antioxidant properties. They have a strong ability to inhibit inflammation similar to the action of cortisone without any side effects.¹⁴

Antioxidant vitamins stabilize and deactivate the free radicals before they attack the cells. Vitamins A, B complex, C, D, E and minerals like iron, copper and magnesium are effective in controlling the signs and symptoms of OSMF.⁴⁰ Ultrasound is proven to have deep heating capacity. They alter the signal-transduction pathways and gene products associated with inflammatory response. Ultrasound decreases inflammation, increases vasodilatation and increases the extensibility of collagen fibers. Heating the tissues using ultrasound when combined with physiotherapeutic exercises causes loosening and softening of adherent fibrous tissues by separation of collagen fibers and thus leads to the increased pliability of oral mucosa and improves mouth opening.²⁸ Oral physiotherapy includes simple mouth opening exercises that can be performed with or without certain appliances. Performing exercises repeatedly in physiotherapy helps to loosen the contractures and thus the mouth opening.

Intralesional steroids along with hyaluronidase or placentrex have been routinely used in the treatment of early stages of OSMF for the last few decades. This treatment, however, necessitates frequent patient visits, and as a result, patient compliance. Many different approaches have been explored with varying degrees of success. Herbal derivatives have recently become more popular in the treatment of OSMF since they are patient-friendly and have demonstrated good effects. They are mainly used for their antioxidant properties. Findings of this NMA show that a combination of drugs gives better results rather than being given singly. Intralesional steroids and hyaluronidase when given along with vitamin E capsules gave a better result in comparison to all the other modalities. However, findings from only one study were available on this particular combination. If the patient’s compliance is questionable for intralesional injections, then oral pentoxifylline, aloe vera or a combination of lycopene & vitamin E can be advised. Results of this NMA show that vitamin E has an added advantage when given along with other drugs either intralesional steroids or lycopene. This may be attributed to the potent antioxidant efficacy of Vitamin E.²³ Results also show that the therapeutic efficacy of intralesional steroids increases when combined with hyaluronidase & multivitamins or antioxidants. Intake of pentoxifylline may cause mild gastric and central nervous system side effects, whereas side effects have not been reported with lycopene and vitamin E.²⁶ Physiotherapeutic jaw exercises may be recommended in addition to other medications as it may provide additional benefits, even though physiotherapy alone is ineffective.

Conclusion

OSMF is an important potentially malignant condition that cannot be completely reversed. It hampers the daily activities because of rigid mucosa and restricted mouth opening. It affects the entire oral mucosa and treating this condition is a major challenge for oral physicians. Our NMA on 29 RCTs and 25 treatments showed that intralesional injection of corticosteroids and hyaluronidase with vitamin E capsules are more effective in the management of mouth opening in OSMF patients. Management should also focus on prevention by patient education and motivation about ill-effects of processed areca products as well as attempting to improve the mouth opening by patient-friendly treatment approach. The major limitation for this NMA was non uniform method of reporting of findings by different authors. Even though 154 trials were available, only 29 trials met our inclusion criteria. It is important that RCTs should be conducted and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement.

Conflict of Interest

None