Drug treatment for oral submucous fibrosis: a systematic review

doi:10.21203/rs.3.rs-2956996/v1

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Drug treatment for oral submucous fibrosis: a systematic review

https://doi.org/10.21203/rs.3.rs-2956996/v1

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published 12 Oct, 2023

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Objective

The aim of this review is to evaluate the different medicinal interventions available for the management of oral submucous fibrosis (OSF).

Materials and methods

We searched a comprehensive electronic search on PubMed, Web of Science, and Cochrane Library databases for articles related to OSF patients treated with medications from December 2011 to September 2022. GRADE system was used to evaluate the evidence quality.

Results

Twenty-nine randomized controlled trials (RCTs), six non-RCT studies were included, and the use of drugs for OSF treatment were evaluated. The main outcomes were improvement in mouth opening, burning sensation, cheek flexibility, and tongue protrusion. Drugs like steroids, hyaluronidase, pentoxifylline, lycopene, curcumin, dpirulina, aloe vera, omega3, oxitard, allicin, colchicine have been used. It was found that drugs with evidence high quality were SMI combined with triamcinolone acetonide, lycopene, pentoxifylline, curcumin, and aloe vera, and those with evidence moderate quality were allicin, colchicine, omega 3, and oxitard.

Conclusion

Based on the results of our comprehensive analysis, for long-term treatment, we found lycopene with low side effects, whereas for relieving the symptoms of severe burning sensation, aloe vera is the most effective. Although the resent review has made some progress, drug therapy for OSF remains unclear, and more high-quality RCTs are needed to identify better treatments for OSF.

Oral submucous fibrosis

Drug treatment

Clinical trials

Oral submucous fibrosis (OSF) is an insidious and chronic oral mucosal disease. It is a potentially malignant disorder of the oral mucosa with a malignant transformation rate between 6% and 9%[1]. The initial manifestations of OSF are inflammation, fibrosis occurring after inflammation, and marble-like lesions in the oral mucosa[2]. The late stage of this disease is characterized by a fibrous band that limits mouth opening, which can further cause problems with oral hygiene, speaking, and chewing.

The etiology of OSF has not yet been fully elucidated but may be related to betel nut chewing, capsaicin, autoimmunity, allergies, genetic predisposition, and chronic vitamin and micronutrient deficiencies[3]. The current mainstream view is that betel nut chewing is closely associated with the occurrence of OSF[4]. Excessive use of areca nut, collagen synthesis increases and collagen degradation decreases, increased collagen cross-linking, and insufficient collagen phagocytosis and fibrokine action[5], this eventually leads to OSF. Moreover, the long-term use of areca nut can induce the production of free radicals and reactive oxygen species, leading to a high rate of oxidation/peroxidation of unsaturated fatty acids, which affects the essential components of cell membranes[6]. The study showed that the composition of betel nut products, the frequency and duration of betel nut consumption may all affect the malignant transformation rate of the disease[7] Currently, the treatment of OSF mainly includes physical therapy, hyperbaric oxygen therapy, drug therapy, and surgical treatment[8]. Drug therapy is the most common treatment, and available drug treatments include steroids, exogenous enzymes, multivitamins and micronutrients, peripheral vasodilators, human placental extracts, and other therapeutic agents. Although various treatments have been proposed for OSF over the past few decades, satisfactory results have not been achieved with most methods.

In 2012, Chole et al.[9] reviewed the literature on drug treatment for OSF to identify the role of various drugs in the treatment of OSF. With the emergence of new drugs for the treatment of OSF, we summarize the available pharmacological interventions for the treatment of OSF, describe the efficacy of contemporary and newly developed treatment modalities attempts to provide reference strategies for future research. Therefore, in this review, we collected relevant studies conducted in the past 10 years from 2012 to the present to systematically identify published randomized controlled trials (RCTs), non-RCT studies, and meta-analyses on various drugs for the treatment of OSF since December 2011 and update the literature with new clinical studies.

Sources of data

Detailed literature searches of PubMed, Web of Science, and Cochrane Library from December 2011 to September 2022 were conducted. In addition, we performed a manual search for other references in published reviews.

Search strategy

The search strategy was based on the recommendations of the Oxford Centre for Evidence-Based Medicine and performed using subject headings, free-text terms for OSF, and relevant interventions to identify relevant RCTs, clinical trials, and meta-analyses. The detailed search strategy was ((("Oral Submucous Fibrosis"[Mesh]) OR ((submucous fibrosis) OR (submucous fibroses))) AND (("randomized controlled trial*" OR "randomised controlled trial*" OR "randomized" OR "controlled trial") OR (clinical trials))) AND (("Drug Therapy"[Mesh]) OR (treatment) OR (therapy*) OR (management))

Inclusion Criteria

1)Type of study: RCT, non-RCT studies were included; 2) Subjects: patients diagnosed with OSF according to pathological diagnosis or clinical manifestations, regardless of gender and race; 3) Intervention: the experimental group was treated with drugs; 4)The study was conducted from December 2011 to September 2022; 5) Studies were reported in English only.

Exclusion criteria

(1) incomplete data (2) full text not available (3) Studies with unclear evaluation criteria; (4) Cannot be obtained Bureau index data, literature with incomplete data and wrong data.

Quality analysis

In this review, quality was assessed independently and in duplicate by two independent reviewers using a standardized critical appraisal method for quality evaluation. All disagreements were settled through discussion, which included the participation of a third review author.

The quality of the findings generated by our review were classified as high, moderate, low, or very low in accordance with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system[10]. Authors independently screened the titles and abstracts of studies that fulfilled the selection criteria and checked for agreement.

Figure 1 shows the process of the literature search. The database search yielded a total of 270 studies, and the manual search yielded 9 studies. After eliminating duplicate studies, 117 studies were selected for further title and abstract screening. After screening, 68 studies were excluded as they did not meet the inclusion criteria. The remaining 49 studies were selected for full-text screening, and among the 49 studies, 35 met the criteria and were accepted. These 35 studies included 29 RCTs, 6 clinical trials, a total of 2176 patients were included in the study. Four studies reported the use of steroids, and two reported the use of hyaluronidase. Four studies reported the use of peripheral vasodilators, including isoxsuprine and pentoxifylline. The use of antioxidants was also found to be very common: three studies reported the use of spirulina, eight studies reported the use of curcumin, and four studies reported the use of lycopene. In addition, other drugs such as omega 3, allicin, colchicine, and oxitard were used to treat OSF. Table 1 presents the results of all the included studies. The included studies were all published between 2011 and 2022 and mainly reported data from Asia including China and India. The minimum duration of the intervention was 1.5 months and the maximum duration was 10 months. The main outcomes were improvement in mouth opening, burning sensation, cheek flexibility, and tongue protrusion. The results shows that drugs with evidence high quality were SMI combined with triamcinolone acetonide, lycopene, pentoxifylline, curcumin, and aloe vera, and those with evidence moderate quality were allicin, colchicine, omega 3, and oxitard.

Table 1

Characteristics of the studies included
Study	Study design	Sample (n)	Therapeutic agents	Duration(mouths)	Outcomes (Improvement in signs/symptoms)	Level of evidence
Datarkar et al (2020)	RCT	32	prednisolone mouthwash and antioxidant capsule	9	mouth opening − 10.46 mm Relief of burning sensation - within 12.81 days Relief of recurrent ulceration - within 10.93 days	High
		32	antioxidant capsule	9	mouth opening − 1.04 mm Relief of burning sensation - within 21.56 days Relief of recurrent ulceration - within 20.06 days
Jiang, X. W et al (2013)	RCT	14	triamcinolone acetonide (2 mg)	10	mouth opening − 2.00 ± 1.21 mm burning sensation − 3.05 ± 0.76	High
		14	salvianolic acid B (4 mg)	10	mouth opening − 3.48 ± 2.23 mm burning sensation − 4.96 ± 0.97
		14	TA (2 mg) and SA-B (4 mg)	10	mouth opening − 5.50 ± 1.80 mm burning sensation − 6.11 ± 0.93
Goel, S et al (2015)	Clinical trials	90	Control group	6	Stage I mouth opening 0.00 ± 0.00 (range 1–5 mm) stage II mouth opening 0.00 ± 0.00 (range 3–9 mm) stage III mouth opening 0.00 ± 0.00 (range 4–10 mm)	Moderate
		90	Lycopene group (4 mg/day)	6	Stage I mouth opening 3.00 ± 1.11 (range 1–5 mm) stage II mouth opening 6.07 ± 2.00 (range 3–9 mm) stage III mouth opening 6.53 ± 1.45 (range 4–10 mm)
		90	Betamethasone group (4 mg/ml weekly	6	Stage I mouth opening 3.30 ± 1.51 (range 1–5 mm) stage II mouth opening 9.47 ± 2.47 (range 5–14 mm) stage III mouth opening 3.27 ± 1.36 (range 1–5 mm)
Tp B et al (2019)	RCT	20	Lycopene capsule of 2 mg per day	3	mouth opening − 23.88 ± 0.66	High
		20	Lycopene capsule of 2 mg per day for 3 months and intralesional injection of 0.5 mL of local anesthesia with 2 mL of dexamethasone twice weekly	3	mouth opening − 25.12 ± 0.91
		20	intralesional injection of 0.5 mL of local anesthesia with 2 mL of dexamethasone and 1500 I.U of hyaluronidase biweekly	3	mouth opening − 26.43 ± 0.22
Joseph J. et al. (2019)	Clinical trials	15	LycoRed 16 mg daily in two equally divided dose	3	Mouth opening − 100% Burning sensation − 100% partial response	Moderate
		15	LycoRed along with Hyaluronidase intralesional injection 1500 IU twice weekly	3	Mouth opening − 100% Burning sensation − 92.8% partial response, 7.2% complete response
		15	placebo capsules	3	Mouth opening − 46.2% Burning sensation − 38.5% partial response, 30.8% stable, 30.8% progression
Karemore. et al. (2012)	RCT	46	8mg softgel Lycored TM orally per day in two divided doses of 4mg	3	There was a significant difference in maximum mouth opening between the study and placebo group with Z calculated value of 5.56 mm at the exit in maximum mouth opening. Wherein the lycopene group showed a significant decrease in post-treatment juxta-epithelial collagen deposition and chronic inflammatory infiltrate, whereas the placebo group at exit showed a significant decrease in the chronic inflammatory infiltrate	High
		46	Softgel placebo twice a day orally	3
Piyush. et al. (2019)	RCT	30	a tablet with a combination of Curcumin and Piperine 300mg 1 tablet two times daily	6	Burning sensation - − 4.8 ± 2.6 Mouth opening − 3.95 ± 4.9 Cheek flexibility − 0.36 ± 0.71 Tongue Protrusion − 5 ± 7.2%	High
		30	Lycopene capsules 8mg 1 tablet two times daily	6	Burning sensation − 5 ± 2.3 Mouth opening − 4.1 ± 4.2 Cheek flexibility − 0.66 ± 0.80 Tongue Protrusion − 2.4 ± 3.4
		30	Placebo capsules	6	Burning sensation − 1.5 ± 1.5 Mouth opening − 1.4 ± 2.3 Cheek flexibility − 0.03 ± 0.55 Tongue Protrusion − 2.3 ± 4.3
Saran. et al.(2018)	RCT	30	4 mg of lycopene thrice daily	3	Mouth opening − 11.1 ± 1.0%	High
		30	300 mg of curcumin thrice daily	3	Mouth opening − 6.2 ± 0.4%
Alora R et al. (2015)	RCT	15	hyaluronidase (1500 I.U)	6	Burning Sensation − 2.60 ± 1.60 Pain while opening mouth − 1.00 ± 1.69 Tightness of mucosa − 3.73 ± 1.67 Mouth opening − 6.67 ± 3.74	High
		15	dexamethasone (8 mg)	6	Burning Sensation − 3.20 ± 1.52 Pain while opening mouth − 0.33 ± 0.72 Tightness of mucosa − 2.00 ± 1.51 Mouth opening − 4.27 ± 1.58
		15	hyaluronidase (750 I.U) + dexamethasone 4 mg	6	Burning Sensation − 2.80 ± 1.20 Pain while opening mouth − 1.93 ± 2.15 Tightness of mucosa − 2.53 ± 1.19 Mouth opening − 5.80 ± 2.60
Leena J. et al. (2015)	Clinical trials	28	hyaluronidase 1500 IU mixed in 1.5 ml of dexamethasone and 0.5 ml of lignocaine HCL injected intralesionally biweekly for 4 weeks	9	Limited mouth opening − 92.85% Burning sensation − 89.28% Painful ulceration − 78.57% Blanching of oral mucosa − 71.42%	Moderate
Bhadage, C. J. et al. (2013)	Clinical trials	15	10 mg isoxsuprine tablets four times per day	1.5	mouth opening - differed significantly only between groups B and C (p00.004) with group B patients have more restricted mouth opening. burning sensation - The time to obtain complete relief was significantly shorter (p00.001) in group B compared to group A. None of the patients in group C obtained complete relief	Moderate
		15	Biweekly 2ml dexamethasone with 1500 IU hyaluronidase intralesional injections	1.5
		10	placebo tablets	1.5
Sadaksharam, J. et al. (2017)	RCT	15	oral pentoxifylline 400 mg thrice daily	6	mouth opening − 4.53 ± 1.18723 burning sensation − 0.00 ± 0.00 submucosal thickness − 0.494 ± 0.146 mm	High
		15	2 ml of dexamethasone and 1500 I.U of hyaluronidase biweekly for 6 weeks	6	mouth opening − 2.73 ± 0.70373 burning sensation − 0.13 ± 0.35 submucosal thickness − 0.598 ± 0.181 mm
Prabhu, N. et al. (2015)	RCT	15	Pentoxifylline 2 tablets daily	4	On the assessment of mouth opening and tongue protrusion, there was no significant improvement in either of the groups individually or in comparison. But both groups showed quite a significant improvement individually in burning sensation	High
		15	placebo tablets	4
Ravi. et al. (2011)	RCT	30	placebo	7	Burning sensation − 39.4% Ulceration improved − 35.5% Ankyloglossia improved − 22.6% Fibrotic bands improved − 19.5% Improvement in trismus − 6mm	High
		32	400 mg. Pentoxifylline for a period of 7 months	7	Burning sensation − 86.6% Ulceration improved − 84.1% Ankyloglossia improved − 39.3% Fibrotic bands improved − 32.9% Improvement in trismus − 10mm
Prathima et al. (2013)	Clinical trials	20	antioxidants (Spirulina 500 mg) orally twice daily for 3 months + biweekly treated with steroid injection (Betamethasone 4 mg/ml)	3	mouth opening − 5.7500 ± 2.73140 Burning sensation − 4.7000 ± 1.65752	Moderate
		20	placebo capsules daily two times for 3 months + biweekly treated with steroid injection (Betamethasone 4 mg/ml)	3	mouth opening − 2.8500 ± 1.34849 Burning sensation − 2.6500 ± 1.38697
Mulk, B. S., et al. (2013)	RCT	20	pentoxifylline 400mg twice daily	4	Mouth opening − 0.30 ± 0.0725 Burning sensation − 4.45 ± 1.191 Tongue protrusion − 0.18 ± 0.089	High
		20	spirulina capsules 0.5gm twice daily	4	Mouth opening − 0.36 ± 0.27 Burning sensation − 5.40 ± 1.353 Tongue protrusion − 0.16 ± 0.1095
Patil, S.et al. (2015)	RCT	21	500 mg spirulina in 2 divided doses	3	Mouth opening Baseline 19.9 ± 2.1 After 3 months 25.8 ± 2.5	High
		21	5 mg aloe vera gel to be applied topically thrice daily	3	Mouth opening Baseline 19.1 ± 2.7 After 3 months 23.9 ± 1.9
Aditi. et al. (2021)	Clinical trials	20	Curcumin gel. Approximately 5 mg (quantified by a scoop) of the gel was to be applied to bilateral buccal mucosa twice daily, after food intake.	2	Burning sensation − 100% Mouth opening − 5.45 ± 1.64 mm Cheek flexibility − 2.65 ± 0.57 mm Tongue Protrusion − 5.05 ± 2.13 mm	Moderate
		20	Curcumin mucoadhesive patch. One patch was to be placed on the right and left buccal mucosa each,8 weeks twice daily after food intake.	2	Burning sensation − 100% Mouth opening − 5.9 ± 2.00 mm Cheek flexibility − 2.66 ± 0.53 mm Tongue Protrusion − 3.45 ± 2.52 mm
Vinay. et al. (2015)	RCT	15	Longvida lozenges (Mfg Lic.: GA/1482) (400 mg lozenges) 2 g/day	3	Mouth opening − 5.93 ± 2.37 mm VAS with normal food − 36 (24-65.5) VAS with spicy food − 45 (37.5–74.5)	High
		15	topical steroid 3 times daily	3	Mouth opening − 2.66 ± 1.76 mm VAS with normal food − 15 (7-26.5) VAS with spicy food − 23 (13.5–31.5)
Lanjekar, A. B. et al. (2020)	RCT	40	1% curcumin mucoadhesive gel over the lesion on the affected mucosa 3 times daily	1.5	Mouth opening − 51.813 Burning sensation − 60.563 Color of Oral Mucosa − 0.38 ± 0.49	High
		40	triamcinolone acetonide and hyaluronidase mucoadhesive semisolid gel 3 times daily	1.5	Mouth opening − 44.250 Burning sensation − 63.950 Color of Oral Mucosa − 0.25 ± 0.44
		40	professionally prepared mucoadhesive semisolid the gel of curcumin along with triamcinolone and hyaluronidase mucoadhesive semisolid gel on the affected mucosa 3 times daily	1.5	Mouth opening − 85.438 Burning sensation − 56.988 Color of Oral Mucosa − 0.68 ± 0.47
Pipalia. et al. (2016)	RCT	20	turmeric (400mg) with black pepper(100mg), 2 capsules TID	3	Burning sensation − 87.90% Mouth opening − 14.37% Cheek flexibility − 29.03% Tongue Protrusion − 7.98%	High
		20	nigella sativa, 2 capsules of 500 mg TID	3	Burning sensation − 78.91% Mouth opening − 13.75% Cheek flexibility − 44.12% Tongue Protrusion − 8.95%
Rai. et al. (2019)	RCT	49	Antioxidant (Capsule S M Fibro; WARREN NXGEN DIVISION, Indoco Remedies Limited, Mumbai, Maharashtra, India) twice daily	3	Burning sensation − 71.32% Mouth opening − 22.51% Tongue Protrusion − 28.1%	High
		49	Turmix Tablet (tablet containing curcumin 300 mg and piperine 5 mg; Sanat Products Ltd., Bulandshahar, Uttar Pradesh, India) 3 times per day	3	Burning sensation − 73.58% Mouth opening − 17.07% Tongue Protrusion − 28.12%
		49	urmix Tablet (tablet containing curcumin 300 mg and piperine 5 mg; Sanat Products) 3 times per day	3	Burning sensation − 90% Mouth opening − 21.26% Tongue Protrusion − 34.51%
Srivastava. et al. (2021)	RCT	40	curcumin lozenges three times daily	3	Burning sensation − 0.48 ± 0.506 Mouth opening − 4.0 ± 0.981 Tongue Protrusion − 3.85 ± 0.362	High
		40	2 mL dexamethasone + hyaluronidase 1500 IU twice a week	3	Burning sensation − 0.38 ± 0.401 Mouth opening − 3.28 ± 0.552 Tongue Protrusion − 3.00 ± 0.14
Yadav. et al. (2014)	RCT	20	4 mg Dexamethasone & 1500 I.U Hyaluronidase	3	Burning sensation − 15.6 (11.2) Interincisal distance − 1.5 (1) Tongue protrusion − 0.9 (0.9)	High
		20	Two Curcumin tablets (Turmix 300 mg) per day	3	Burning sensation − 0 (0) Interincisal distance − 0.82 (1.1) Tongue protrusion − 0.23 (0.66)
Chandrashekar A. et al. (2021)	RCT	20	Curcumin gel. Approximately 5 mg (quantified by a scoop) of the gel was to be applied to bilateral buccal mucosa twice daily, after food intake.	2	Mouth opening − 5.45 ± 1.64 mm Tongue Protrusion − 5.05 ± 2.13 Cheek flexibility − 2.65 ± 0.57	High
		20	Curcumin mucoadhesive patch. One patch was to be placed on the right and left buccal mucosa each, twice daily after food intake.	2	Mouth opening − 5.9 ± 2.00 mm Tongue Protrusion − 3.45 ± 2.52 Cheek flexibility − 2.66 ± 0.53 mm
Alam, S. et al. (2013)	RCT	30	medicinal treatment + aloe vera gel over the buccal mucosa, palate, the retromolar region, and the floor of the mouth twice daily	3	Burning sensation 5 ± 0 to 1.73 ± 1.01 Mouth opening − 13.74 mm Tongue protrusion 26.00 ± 5.83 mm to 31.67 ± 6.66 mm	High
			surgical treatment + aloe vera gel over the buccal mucosa, palate, the retromolar region, and the floor of the mouth twice daily	3	Burning sensation 5 ± 0 to 3.66 ± 0.97 Mouth opening 37.46 ± 2.50 mm to 38.93 ± 3.32 mm Tongue protrusion 22.86 ± 5.08 mm to 27.10 ± 2.46 cm
		30	medicinal treatment + No aloe vera gel	3	Burning sensation 5 ± 0 to 3.53 ± 1.17 Mouth opening 24.0 ± 7.53 to 30.0 ± 7.41 mm Tongue protrusion 32.46 ± 6.35 mm to 36.66 ± 5.31 mm
			surgical treatment + No aloe vera gel	3	Burning sensation 5 ± 0 to 4.23 ± 0.75 Mouth opening 37.33 ± 2.12 to 34.0 ± 3.18 Tongue protrusion 24.2 ± 5.83 mm to 27.53 ± 2.81 cm
Ardra. et al. (2016)	RCT	37	drink 30 ml of aloe vera juice twice daily before food and apply 5 mg (apprx 1 scoop) of aloe vera gel over the lesion 3 times per day	3	Burning sensation − 13.3% Mouth opening − 4.9% Cheek flexibility − 13.7%	High
		37	intralesional injections of hydrocortisone acetate 25 mg/ml and hyaluronidase (1500 IU) weekly	3	Burning sensation − 47.5% Mouth opening − 5.0% Cheek flexibility − 12.3%
Bohra, A. et al. (2021)	Clinical trials	21	Kali Haldi (2mg), Aloe vera gel (2 mg), measuring scoop of 1mg in a ratio of 2:2, over the lesion 3 times a day	3	Burning sensation − 75.9% Mouth opening − 4.9cm Cheek flexibility − 92.6% Tongue Protrusion − 2.4%	Moderate
		21	injections of hydrocortisone acetate 25 mg/ml and hyaluronidase (1500 IU) weekly along with turbocort twice daily	3	Burning sensation − 57.2% Mouth opening − 4.5cm Cheek flexibility − 82% Tongue Protrusion − 1.7%
Nerkar Rajbhoj. et al. (2021)	RCT	30	5 mg of curcumin gel at respective site for 3–4 times a day	-	Burning sensation − 3.06 ± 0.944 Mouth opening − 1.733 ± 1.048	High
		30	Aloe V era gel (aloe gel 100%)	-	Burning sensation − 4.500 ± 1.106 Mouth opening − 1.367 ± 1.129
Singh. et al. (2016)	RCT	19	Aloe vera gel on each side of the oral mucosa three times daily	3	Burning sensation − 93.8% Mouth opening − 9.1% Tongue Protrusion − 3.9%	High
		18	antioxidant capsules twice daily	3	Burning sensation − 71.2% Mouth opening − 5.3% Tongue Protrusion − 2.2%
Sudarshan. et al. (2012)	RCT	10	5 mg of Aloe vera gel on each side of the buccal mucosa three times daily	3	Burning sensation − 58.0 ± 18.7 Mouth opening − 5.1 ± 2.5 Cheek flexibility − 0.06 ± 0.05 Tongue Protrusion − 3.1 ± 2.2	High
		10	antioxidant capsules twice daily	3	Burning sensation − 36.5 ± 12.9 Mouth opening − 2.5 ± 1.9 Cheek flexibility − 0.00 ± 0.06 Tongue Protrusion − 1 .7 ± 1.0
Jiang. et al. (2015)	RCT	24	intralesional injection of triamcinolone acetonide (2 mg)	4	Mouth opening − 2.27 ± 0.84 mm Burning sensation − 2.79 ± 0.87	High
		24	intralesional injection of allicin (1 mg)	4	Mouth opening − 5.16 ± 1.04 mm Burning sensation − 4.33 ± 1.04
Krishnamoorthy. et al. (2013)	RCT	25	colchicine 0.5 mg twice daily + injection of Hyaluronidase 1,500 IU was mixed in 1 ml of lignocaine. 0.5 ml	3	33% in group 1 got relief in the second the week itself as against 21% in group 2	High
		25	intralesional injection of Hyaluronidase 1,500 IU and 0.5 ml of injection Hydrocortisone acetate 25 mg/ml in each buccal mucosa once a week	3
Raizada. et al. (2022)	RCT	24	biweekly intralesional injections of dexamethasone 1.5 ml and hyaluronidase 1500 IU mixed with lignocaine for 6 weeks and the placebo for 3 months	3	Mouth opening grade II − 3.91 ± 0.903mm grade III − 3.66 ± 1.15 mm Tongue Protrusion grade II − 2.33 ± 1.49mm grade III − 1.41 ± 1.5 mm Cheek flexibility grade II − 2.58 ± 1.54 mm grade III − 1.58 ± 1.37 mm Burning sensation grade II -5.41 ± 1.44 mm grade III − 6.5 ± 1.0 mm	High
		24	biweekly intralesional injections of dexamethasone 1.5 ml and hyaluronidase 1500 IU mixed with lignocaine along with 3 gm of omega 3 per day.	3	Mouth opening grade II − 7.13 ± 1.06 mm grade III − 5.66 ± 1.0 mm Tongue Protrusion grade II -4.93 ± 1.83 mm grade III − 4.11 ± 1.69 mm Cheek flexibility grade II − 3.8 ± 2.14mm grade III − 3.11 ± 1.5 mm Burning sensation grade II − 8.06 ± 1.66 mm grade III − 9.22 ± 0.83mm
Santosh P. et al. (2015)	RCT	60	2 oxitard capsules twice daily	3	Mouth opening Baseline 19.1 ± 2.4 After 3 months 31.5 ± 2.9 Tongue Protrusion Baseline 10.1 ± 1.4 After 3 months 24.5 ± 2.5 Burning sensation Baseline 60 After 3 months 3	High
		60	placebo tablets twice daily	3	Mouth opening Baseline 20.1 ± 2.1 After 3 months 23.1 ± 1.9 Tongue Protrusion Baseline 9.3 ± 2.2 After 3 months 22.1 ± 1.8 Burning sensation Baseline 60 After 3 months 24

The treatment of OSF is difficult, and the current treatment methods are mainly aimed at relieving the signs and symptoms of the disease. Usually, OSF is treated with drugs in the early stages, followed by physical therapy in severe cases and surgery in the late or advanced stages. Many studies have shown that a combination of drugs, including steroids, enzymes, antioxidants, multivitamins, and minerals, can alleviate the signs and symptoms of OSF; however, these studies lacked solid evidence or the sample size was too small to be representative, and related drug therapy trials have been disappointing. Therefore, it is fairly challenging to compare or even combine their effects in a scientifically meaningful manner. Therefore, our article reviewed RCTs, clinical trials and meta-analyses for a better assessment of the available evidence.

Steroids

Owing to their immunosuppressive and anti-inflammatory properties, steroids are widely used to treat OSF. In terms of immunosuppression, steroids can activate sensitized lymphocytes against specific antigens to release soluble factors. In terms of their anti-inflammatory effects, steroids can inhibit the proliferation of inflammatory factors and increase the apoptosis of inflammatory cells. Several glucocorticoids, such as short-acting (hydrocortisone), medium-acting (triamcinolone), and long-acting (dexamethasone and betamethasone), have been used for the treatment of OSF[11]. In the early stage, steroids can effectively improve mouth opening and burning sensation; however, they do not improve the abnormal accumulation of fibrotic tissue[12]. Therefore, steroids alone cannot completely improve the quality of life of patients with OSF. A meta-analysis by Guo et al.[13] concluded that in combination with steroids, salvia miltiorrhiza B (SMI) can effectively improve the subjective symptoms of mouth opening and burning sensation in patients with OSF and reduce the area of oral mucosal lesions without causing adverse reactions. Compared with control drugs (such as lycopene, aloe vera, and pentoxifylline), hyaluronic acid combined with steroids was equally effective in relieving burning and improving mouth opening in patients with OSF but superior to placebo. At the same time, owing to their side effects, systemic corticosteroids are rarely used in the treatment of OSF and usually administered as intrafocal injections or mouthwashes[14]. Overall, steroids can alleviate the signs and symptoms of OSF and can be used in combination with other medications as adjunctive therapy.

Enzymes

A significant feature of OSF is the massive abnormal deposition of collagen fibers and reduced fibrinolysis[15]. Therefore, exogenous enzymes can alleviate or cure OSF through the breakdown of abnormal fibrotic tissues. Enzymes used in the treatment of OSF include hyaluronidase, collagenase, and chymotrypsin[16]. Hyaluronidase was originally found in bacteria and widely distributed in nature. It can break down hyaluronic acid (an important component of the extracellular matrix), which reduces the viscosity of intracellular cement and collagen formation. Hyaluronidase has been used to treat lymphedema and scarring and as an adjunct to improve the bioavailability of other drugs in the clinical setting. Studies included in this review showed that hyaluronidase could effectively improve mouth opening and reduce mucosal tightness, compensating for the lack of effect of steroids in improving the abnormal accumulation of fibrotic tissue; therefore, the two drugs are often used in combination[17]. A meta-analysis by Guo et al.[18] showed that hyaluronidase combined with steroids showed a significantly better effect than placebo in alleviating the burning sensation and improving the mouth opening in OSF and was as effective as control drugs (such as aloe vera, pentoxifylline, and lycopene).

Peripheral vasodilators

A potential cause of OSF is the progressive loss of diseased mucosal blood vessels, which can lead to epithelial atrophy[19]. Therefore, vasodilators are considered effective for the treatment of OSF. Pentoxifylline (PTX), a trisubstituted methylxanthine derivative, is used as a vasodilator and is effective in the treatment of diseases caused by chronic peripheral arterial occlusion[20]. As mucosal ischemia and the resulting epithelial atrophy may be factors in the pathogenesis of OSF, PTX can be therapeutic owing to its ability to relax and dilate blood vessels, ensuring increased blood supply to the ischemic tissue and enabling nutritional and therapeutic drugs to reach the affected tissue[21]. Isoxsuprine is a phenylalanine derivative of epinephrine and a β-adrenoreceptor agonist that causes an overall increase in the cytosolic calcium concentration, stimulating the production and release of several endothelium-derived vasodilators[22]. In a clinical trial, isoxsuprine and dexamethasone with hyaluronidase injection combined with physiotherapy reported a significantly better outcome in reducing burning sensation and improving mouth opening compared with physiotherapy alone. How systemic side effects (nausea, stomach bloating, dyspepsia, and anxiety). Studies with a longer follow-up period are needed to determine the duration of symptom relief and impact of varying severity on disease progression[23]. A meta-analysis by Liu J et al.[24] showed that PTX is an effective treatment as it can not only increase the maximum mouth opening (MMO) of patients with OSF but also relieve burning sensation in the mouth. Thus, 400 mg twice daily PTX is well tolerated and is expected to become more effective over time.

Antioxidants

One of the pathogenic mechanisms of betel nut is the production of reactive oxygen species, free radicals, and peroxidase to destroy the cellular structure. Based on this hypothesis, several studies have tested various natural or synthetic antioxidants and reported that using them can improve the condition of betel nut damage to the mouth. Natural antioxidants include lycopene, aloe vera, curcumin, and spirulina.

Lycopene

Lycopene is a carotenoid with strong antioxidant properties because of its high singlet oxygen quenching ability and the ability to quench other free radicals in vitro; it also has antioxidant properties[25]. In a study by Piyush et al.[26], lycopene showed superior therapeutic effects in terms of mouth opening, burning sensation, cheek flexibility, and tongue protrusion in 90 patients. In addition, a meta-analysis by Guo et al.[27] showed that lycopene was more effective than placebo in improving the MMO of patients with OSF. Compared with control patients who received drugs such as aloe vera gel, curcumin, spirulina, and betamethasone, patients with OSF showed significantly improved MMO after 1, 2, and 3 months of lycopene treatment, with no significant effect on burning sensation, tongue process, or lesion-related pain. Therefore, lycopene is a promising antioxidant for the treatment of patients with OSF, especially for improving MMO.

Spirulina

Spirulina is a blue-green alga with abundant vitamins (A and B12), minerals, carotenoids, and phycocyanin. It imparts the antioxidant effect by increasing IL-2 concentration and decreasing IL-6 concentration[28]. Prathima et al.[29] reported that spirulina can effectively improve mouth opening and burning sensation in patients with OSF. Studies by Mulk et al. and Patil et al.[30] showed that spirulina was more effective in improving mouth opening than pentoxifylline and vera gel.

Aloe vera

Aloe vera is a rich source of vitamins, enzymes, minerals, and sugars. Vitamins A, C, and E are antioxidants that help neutralize free radicals[28]. Enzymes in aloe vera help reduce inflammation, and polysaccharides promote wound healing and exhibit anti-inflammatory, anticancer, immunomodulatory, and gastric protective properties that explain their role in treating OSF. Rajbhoj et al.[31] reported that compared with hydrocortisone acetate and hyaluronidase, aloe vera effectively improved burning sensation and cheek flexibility. Two other trials showed that aloe vera improved symptoms better than other antioxidant drugs. A meta-analysis conducted by Al-Maweri et al.[32] showed that compared with other drugs, aloe vera was well tolerated, had few side effects, and was significantly better in reducing burning sensation in the short-term treatment; however, differences in its long-term treatment effects and improvements in mouth opening, tongue protrusion, and cheek flexibility were not significant. Thus, short-term treatment with aloe vera can effectively improve the oral burning sensation in patients with OSF.

Curcumin

Curcumin is a polyphenolic compound extracted from the rhizome of curcuma longa and tuber tubers of Zingiberaceae, it is widely used as an antioxidant in many diseases. It interacts with thioredoxin reductase to induce reactive oxygen species (ROS) and inhibit the action of nicotinamide adenine dinucleotide phosphate oxidase, which is responsible for the generation of ROS, thus playing an antioxidant role[33]. In this review, seven trials investigated the efficacy of curcumin and reported its effectiveness in improving mouth opening, burning sensation, and cheek flexibility. In addition, Lanjekar et al.[34] evaluated the efficacy of curcumin in patients with OSF and found that curcumin showed better improvement in mouth opening, whereas patients who received intralesional dexamethasone and hyaluronidase showed better improvement in burning sensation. Therefore, a combination of curcumin, triamcinolone acetonide, and hyaluronidase is recommended as hyaluronidase facilitates deeper administration of curcumin and triamcinolone acetonide, which have synergistic effects between each other. A meta-analysis by Guo et al.[35] showed that compared with placebo, oral curcumin significantly improved the symptoms of MMO and burning sensation. Compared with lycopene and other drugs, curcumin was less effective in improving mouth opening after 1 month of treatment, and the improvement of burning sensation after 3 months of treatment was better than that in the control group. Therefore, curcumin can be used as an effective treatment for OSF; however, it can cause indigestion, abdominal pain, abdominal distension, dizziness, and other minor adverse reactions. Therefore, more attention should be paid to its adverse reactions to ensure that curcumin is effective and safe for the treatment of OSF.

Other drugs

In addition to the abovementioned drugs, allicin, colchicine, omega 3, and oxitard have a certain effect on the treatment of OSF. There is evidence showing that allicin has important anti-inflammatory effects. Studies have shown that TNF-α is associated with the severity of OSF. First, allicin can reduce TNF-α protein and mRNA levels[36]. Second, allicin has antioxidant activity, which can reduce lipid peroxidation and scour hydroxyl radicals[37]. Finally, allicin can increase the expression of vascular endothelial growth factor and angiopoietin and decrease the expression of angiostatin, thereby promoting angiogenesis and accelerating self-repair[38]. Therefore, we attributed the possible therapeutic mechanism of allicin to its anti-inflammatory and antioxidant effects and the angiogenic ability of its breakdown products. One study showed that intralesional injection of allicin (1 mg) for 16 weeks can significantly improve mouth opening and burning sensation compared with the control group[39]. Colchicine reduces collagen synthesis by disrupting microtubule formation and preventing the extrusion of collagen from fibroblasts[40]. Krishnamoorthy et al.[41] studied the effects of oral administration of 500 mg colchicine and intralesional injection of 0.5 ml hyaluronidase 1,500 IU in the management of OSF and found superior results with colchicine in ameliorating the symptoms of OSF. Omega 3 fatty acids are polyunsaturated essential fatty acids that humans cannot synthesize and must rely on dietary sources. They competitively inhibit the production of arachidonic acid metabolites through the cyclooxygenase and lipoxygenase pathways, thereby limiting tissue damage[42]. Studies have confirmed the inhibitory effect of omega 3 on the secretion of pro-fibrotic TGFβ1 and MMP-9[43]. It can improve endogenous fibrinolysis and microcirculation by improving vasomotor function. Thus, it enhances vasodilatation and ameliorates the mucosal vessels that are significantly damaged by fibrosis in OSF. In their study, Raizada et al.[44] reported that omega 3 can be used as an adjunctive treatment option in patients with OSF to reduce subjective symptoms, and when combined with dexamethasone and hyaluronidase, omega 3 improved mouth opening, burning sensation, and cheek flexibility more effectively. Oxitard capsules are formulated using extracts of mango, morelle, carrot, licorice, grape, triglyceride powder, and wheat oil. These components have the effects of regulating immunity, antiinflammation, convergence and inhibition of burning sensation, antioxidation, and wound healing, as well as certain curative effects on OSF for various reasons[45]. Santosh et al.[45] showed that oxitard capsules significantly improve mouth opening, tongue protrusion, burning sensation, pain associated with the lesion, and difficulty in swallowing and speech, with very few side effects.

In a network meta-analysis comparing the efficacy of different treatment interventions for OSF[46], most interventions were found to be superior to placebo in improving clinical symptoms, such as mouth opening and burning sensation. Oxitard is superior to other interventions in improving mouth opening, aloe vera is superior in relieving burning sensation, and lycopene has the lowest propensity for side effects and can be considered the best safety agent.

GRADE system was used to evaluate the evidence quality, and it was found that drugs with evidence high quality were SMI combined with triamcinolone acetonide, lycopene, pentoxifylline, curcumin, it is a good choice for the treatment of OSF.

This review had a few limitations, the first of which was the small sample size; only one clinical trial involved more than 150 people. Second, patients could only be verbally advised not to chew betel nuts during the trial. However, there was no effective means to monitor and confirm that all patients have eliminated the harmful habits and thus the results might be biased to some extent.

In conclusion, our findings found that steroids, hyaluronidase, pentoxifylline, antioxidants, omega 3, colicine, and allicin can alleviate the symptoms of OSF, for long-term treatment, lycopene is effective and has few side effects. Aloe vera is the most effective for relieving the symptoms of severe burning. Regardless of the number of treatment options available, abstaining from betel nut chewing is the best strategy to prevent OSF. Our review is intended only as a reference for clinical medication management, we hope that more high-quality meta-analyses, systematic reviews and multicenter RCTs with larger samples will provide more reference suggestions for the treatment of OSF in the future.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

Natural Science Foundation of Hunan Province (No. 2021JJ70062); The Scientific Research Project of Hunan Health Commission (No.D202313048136); Chinese medicine research Project of Hunan Province(No.B2023048); Joint Fund Project of Hunan University of Chinese Medicine (No.2022XYLH120 and 2022XYLH134).

Author Contribution

Xueru Chen contributed to the data acquisition, interpretation and analysis, and manuscript writing; Jincai Guo contributed to the data acquisition and interpretation, data analysis, and critical revision of the manuscript; Hui Xie contributed to the critical revision and approval of the manuscript.

Acknowledgment

The authors gratefully acknowledge the financial supports by Natural Science Foundation of Hunan Province (No. 2021JJ70062); The Scientific Research Project of Hunan Health Commission (No. D202313048136); Chinese medicine research Project of Hunan Province (No. B2023048); Joint Fund Project of Hunan University of Chinese Medicine (No.2022XYLH120 and 2022XYLH134).

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Drug treatment for oral submucous fibrosis: a systematic review

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