|Year : 2014 | Volume
| Issue : 2 | Page : 94-98
Efficacy of pentoxifylline in the management of oral submucous fibrosis
Santosh Patil1, Sneha Maheshwari2
1 Department of Oral Medicine and Radiology, Chattisgarh Dental College Research Institute, Rajnanadgaon, Chattisgarh, India
2 Dental Practitioner, Jodhpur, Rajasthan, India
|Date of Web Publication||16-Oct-2014|
Department of Oral Medicine and Radiology, Chattisgarh Dental College Research Institute, Rajnanadgaon - 491 441, Chattisgarh
Source of Support: None, Conflict of Interest: None
Aim: Oral submucous fibrosis (OSMF) is a high risk premalignant condition predominantly seen in the Indian subcontinent. The aim of the present study was to evaluate the efficacy of newer drug pentoxifylline in the management of OSMF. Materials and Methods: A total of 106 subjects with clinic-pathologically diagnosed OSMF were included in the study and divided equally in two groups, Group A (pentoxifylline group) and Group B (placebo group). Group A was administered 400 mg pentoxifylline twice daily and Group B was given multivitamins for 3 months. Evaluation for different clinical parameters was done at regular intervals and data were analyzed using the Chi-square test. P < 0.05 was considered to be statistically significant. Results: The patients in Group A showed significant improvement (P < 0.05) in all the parameters measured, mouth opening, tongue protrusion, pain associated with the condition, burning sensation and difficulty in speech and swallowing. However, few patients from Group A complained of bloating, nausea, anxiety and dyspepsia. Conclusion: Pentoxifylline can bring about significant clinical improvements in the symptoms like mouth opening and tongue protrusion, thereby improving the quality of life of the affected individuals.
Keywords: Oral submucous fibrosis, pentoxifylline, treatment
|How to cite this article:|
Patil S, Maheshwari S. Efficacy of pentoxifylline in the management of oral submucous fibrosis
. J Orofac Sci 2014;6:94-8
|How to cite this URL:|
Patil S, Maheshwari S. Efficacy of pentoxifylline in the management of oral submucous fibrosis
. J Orofac Sci [serial online] 2014 [cited 2020 Feb 26];6:94-8. Available from: http://www.jofs.in/text.asp?2014/6/2/94/143048
| Introduction|| |
Oral submucous fibrosis (OSMF) is a potentially malignant disorder of the oral cavity, pharynx and upper digestive tract, characterized by progressive inability to open the mouth and by inflammation and progressive fibrosis of the submucosal tissues.  Pindborg and his associates defined the condition as "an insidious chronic disease affecting any part of the oral cavity and sometimes pharynx. Although occasionally preceded by and/or associated with vesicle formation, it is always associated with juxta-epithelial inflammatory reaction followed by fibroelastic changes in the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa causing trismus and difficulty in eating."  Susrutha in ancient medicine described a condition similar to OSMF as "vidari," under the umbrella of mouth and throat diseases.  In 1952, Schwartz described a condition of the oral mucosa as "atrophia idiopathica mucosa oris," with the term OSMF coined by Joshi in 1953. , The pathogenesis of the disease is not well known, but the etiology is believed to be multifactorial. The condition is particularly associated with areca nut chewing, which is the main component of betel quid.  The ingredients of arecanut induce excessive reactive oxygen species leading to damage of the cell structures. This is accompanied with vitamin deficiency, iron deficiency anemia, and poor nutrition, which can disturb the repair of the inflamed oral mucosa, resulting in poor healing. This in turn leads to atrophic oral mucosa, which becomes more susceptible to the effects of areca nut. The antioxidant vitamins are thus employed to stabilize and deactivate the free radicals before they attack cells. 
Treatment modalities for relieving the symptoms have been advocated, but have not been successful so far. The discontinuation of habit is the first step of preventive measure, which can be encouraged through education, counseling and advocacy and to maintain proper oral hygiene. The symptomatic improvements such as improved mouth opening can be achieved by medical treatment, which specifically includes administration of steroids, placental extracts, interferon (IFN)-γ, pentoxifylline, lycopene, surgical excision, etc. , However, each treatment has its own limitations.
Pentoxifylline is a methylxanthine derivative with vasodilating, antiinflammatory and immune modulatory properties. It has been found to be effective in the management of OSMF in a few pilot studies. , The present study was carried out to evaluate the efficacy of this newer drug in the management of OSMF.
| Materials and methods|| |
The present prospective study included 106 subjects with clinically and histopathologically diagnosed OSMF reporting to the Department of Oral Medicine and Radiology. Patients of either sex with OSMF were included in the study. Those with any evidence of severe psychiatric, cardiac, gastro-intestinal or metabolic disorders and pregnancy and lactation were excluded from the study. Ethical clearance was obtained from the Institutional Ethical Committee. A written informed consent was obtained from the patients prior to the inclusion in the study. Detailed family and medical history with a history of associated habits and the course of the disease was recorded. A thorough clinical examination was carried out, and relevant findings were recorded. The subjects were randomly divided equally in two groups, Group A (pentoxifylline group) and Group B (placebo group). Group A was administered 400 mg pentoxifylline twice daily, and Group B was given multivitamins for 3 months. Mouth opening was measured by measuring the distance between the center of incisal edges of maxillary central incisors and mandibular central incisor at maximum opened mouth. In edentulous patients, the inter ridge (alveolar) distance along the midline was measured.  3 measurements were recorded consecutively, and the average value was calculated and recorded. Tongue protrusion was measured as the distance between mesial contact area of lower central incisor and tip of the tongue on protrusion with a metal grade scale.  Evaluation for the presence, absence or reduction of other clinical parameters such as burning sensation, pain associated with the lesion, difficulty in swallowing and speech and variation in the size of the lesion was done at regular intervals of 1-month, 2 months and 3 months. The clinical parameters such as burning sensation, pain associated with the lesion, difficulty in swallowing and speech were evaluated by using a visual analog scale. The score of 0-1 was considered as absent, score in the range of 1-6 was considered as reduced and a score of 7-10 was evaluated as present. The subjects were also advised and encouraged to quit the associated habit during the study period. The data were entered using computer software SPSS 12.0 (SPSS Inc., Chicago, USA) and analyzed using the Student's paired t-test and Chi-square test. P < 0.05 was considered as statistically significant.
| Results|| |
There were 59 males and 47 females with a mean age of 31.9 ± 12.1 years. 58% of the patients had habit of betel nut chewing, while 23% of the patients had tobacco chewing habit. 42% of the patients consumed spicy foods, which were among the main causative factors for OSMF in the study population. Clinical improvements in mouth opening, tongue protrusion, difficulty in speech and swallowing, pain associated with the lesion and burning sensation were significant in the Group A (P < 0.05) [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]. Eight patients in the Group A experienced nausea, bloating of the stomach, dyspepsia and anxiety. The symptoms were mild in nature and resolved within a few days, without the need for cessation of the drug. None of the patients withdrew from the study due to any reason. The patients were followed-up for a period of 2 months during which 6 patients from Group A and 4 patients from Group B presented with pain and burning sensation.
|Table 1: Effect of pentoxifylline and placebo in improving mouth opening (mean values in mm)|
Click here to view
|Table 2: Effect of pentoxifylline in improving tongue protrusion (mean values in mm)|
Click here to view
| Discussion|| |
Oral submucous fibrosis is a premalignant condition of the oral cavity and oropharynx seen predominantly in the Indian subcontinent and Southeast Asian countries. The pathophysiology of this condition is complex, and various factors such as, ingestion of spicy food, genetic susceptibility, nutritional deficiencies, altered salivary constituents, autoimmunity and collagen disorders are thought to be involved in the pathogenesis.  The fibrotic potential of arecanut alkaloids and tannin have been proved to have an effect in the etiology of this chronic inflammatory mucosal disease.  However, the contribution of other mentioned factors cannot be overlooked. The condition is preceded by burning sensation of the oral cavity, ulceration/vesicles and pain. It is characterized by blanching and depigmentation of the oral mucosa, reduced movement and depopulation of tongue and progressive reduction of mouth opening. , Nasal twang due to fibrosis of nasopharynx and hearing impairment due to stenosis of Eustachian tube may be observed in advanced stages of the condition.
Majority of OSMF patients present with irreversible moderate-to-severe condition. The changes are limited to oral tissues and similar to those observed in scleroderma. OSMF may be associated with oral leukoplakia and other potentially malignant disorders or with squamous cell carcinoma. The precancerous nature of this debilitating condition has been proved by, higher occurrence of OSMF in oral squamous cell carcinoma patients, histopathological diagnosis of cancer without any clinical suspicion in OSMF, high frequency of epithelial dysplasia and higher prevalence of leukoplakia among OSMF patients. However, its role in the initiation of malignancy due to epithelium or due to connective tissue is still unanswered. , Although, it has been suggested that the pathology develops in the epithelium itself due to intraoral trauma and various other irritating factors. 
The overall prevalence rate in India is believed to be about 0.2-0.5% and the prevalence by gender varies from 0.2-2.3% in males to 1.2-4.5% in females. , It is considered to have a high degree of malignant potential, which ranges between 2.3% and 7.6%.  The treatment of the condition still remains a challenge. Many therapeutic and surgical treatment modalities have been advocated to relieve the patients of the symptoms, but no definitive and widely accepted treatment is available till date. It is said that when a disease has developed, there is no regression and no effective treatment, and this holds true for OSMF. The first step of preventive measure should be in advising the patient to discontinue the habit, through education, counseling and advocacy. Medical treatment includes steroids, placental extracts, IFN-γ, lycopene, pentoxifylline, surgical excision, laser removal, etc. These have proved to be symptomatic and are predominantly aimed at improving mouth movements. However, each treatment has its own limitations. According to Caniif et al. the medical management of OSMF is both empirical and unsatisfactory.  According to Maher et al. multiple minerals and micronutrients showed significant improvement in mouth opening of 41% of the patients.  Whereas, Borle and Borle showed improvement in symptoms of OSMF but insignificant improvement in mouth opening with Vitamin A.  , The control group in the present study, also showed improvement in mouth opening, tongue protrusion, and other subjective symptoms, but these were also not significant. Singh et al. have shown significant improvement in mouth opening, hyperkeratosis, pain in mouth and size of the lesion with oxitard capsules.  Sudarshan et al. have shown significant improvement in the mouth opening with aloe vera.  Lycopene has also showed significant improvement in mouth opening in the study by Karemore and Motwani  Singh et al. showed an improvement in the sign score of the OSMF patients when they were administered a combination of triamcinolone acetonide and hyaluronidase at 15 days interval for 22 weeks.  Rajendran et al. and Mehrotra et al. have shown the efficacy of newer drug pentoxifylline in the improvement of symptoms of OSMF. , The present study evaluated the efficacy of the newer drug, pentoxifylline in the improvement of various clinical parameters such as, mouth opening, tongue protrusion, pain associated with the lesion, burning sensation and difficulty in speech and swallowing in a larger sample than the previously conducted studies.
Pentoxifylline is a tri-substituted methylxanthine derivative, with numerous biologic activities. It is termed as a "rheologic modifier." It improves microcirculation and decreases aggregation of platelet as well as granulocyte adhesion. It increases leukocyte deformability as well as inhibits neutrophil adhesion and activation. It increases production of prostaglandin E2 and prostaglandin I2 by vascular epithelium and maintain cellular integrity and homeostasis after acute injury. In addition, it causes degranulation of neutrophils, promotes natural killer cell activity and inhibits T-cell and B-cell activation.  Pentoxifylline has also shown a direct effect on inhibiting burn scar fibroblasts.  Haddad et al. treated 34 radiation-induced superficial fibrotic lesions of the skin with pentoxifylline and Vitamin E for 3 months and reported a significant effect in the improvement of radiation-induced fibrosis.  It has been postulated that pentoxifylline may be a valuable drug for reducing burn scar contractures. It has been shown to be effective in various medical disorders such as stroke, aphthous stomatitis, peripheral arterial occlusion, cerebrovascular insufficiency and pretibial myxedema.  In the light of these findings, the drug has been also used to relieve the symptoms in patients with OSMF. It was administered for 3 months, which showed statistically significant results in the present study. Rajendran et al. found significant results with mouth opening and burning sensation similar to the present study, although results with tongue protrusion were not significant.  All patients in this study also received local heat therapy and underwent forceful mouth stretching exercises. It has been found by Fedorowicz et al. who reviewed the trial, that since the patients also received local heat therapy and underwent forceful mouth stretching exercises, it could not be deciphered if the improvement was due to the drug or to associated heat therapy and stretching exercises.  Mehrotra et al. showed 49.2% improvement in total score (i.e., symptom + sign) in pentoxifylline administered patients, opposed to only 25% improvement in the placebo group.
The present study showed a significant (P < 0.05) improvement in mouth opening, tongue protrusion, difficulty in speech and swallowing, pain associated with the lesion and burning sensation. Most side effects with pentoxifylline involve the central nervous system and the gastro-intestinal tract. The most common gastro-intestinal problems include dyspepsis, nausea and/or vomiting. A few may also report bloating, flatus and bleeding. The side effects related to the central nervous system include dizziness, headache, tremor, anxiety and confusion.  8 patients in the Group A experienced nausea, bloating of the stomach, dyspepsia and anxiety. The symptoms were mild in nature and resolved within a few days, without the need for cessation of the drug. This was similar to the findings of Rajendran et al. and Mehrotra et al. , The side effects are said to be dose related and can be minimized with reduction of dose.
The results of the present study show a statistically significant improvement in the Group A, and it can be concluded that pentoxifylline can be used as a routine treatment modality in OSMF. Further studies with an even larger sample size, with a longer period of treatment follow-up, and a multi-institutional double-blind prospective study for assessment of effects of pentoxifylline treatment is recommended to draw further conclusion on its utility in the treatment of OSMF.
| Conclusion|| |
Treatment of OSMF has been a challenge ever since its discovery. Newer drugs have been constantly evolving for the management of this complex disease. The preliminary study of primary therapy with pentoxifylline has been suggested for a number of disorders, but its use has not been recommended. The results of the present study showed that pentoxifylline was found to be effective in the management of OSMF. However, it has shown few side effects in the patients who were administered the drug, but showed better patient outcomes. Intervention studies and public health campaigns at the community level may be the best way of controlling OSMF by making the people quit the habit.
| References|| |
Cox SC, Walker DM. Oral submucous fibrosis. A review. Aust Dent J 1996;41:294-9.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.
Gupta SC, Yadav YC. "Misi" an aetiological factor in oral submucosal fibrosis. Indian J Otolaryngol 1978;30:5-6.
Schwartz J. Atrophia Idiopathica Mucosa Oris. Demonstrated at the 11 th
International Dental Congress: London; 1952.
Joshi SG. Fibrosis of the e palate and pillars. Indian J Otolaryngol 1953;4:1.
Chole RH, Gondivkar SM, Gadbail AR, Balsaraf S, Chaudhary S, Dhore SV, et al.
Review of drug treatment of oral submucous fibrosis. Oral Oncol 2012;48:393-8.
Singh BP, Mittal N, Sharma V, Palani. Evaluation of role of oxitard capsules in the treatment of oral submucous fibrosis. Antiseptic 2009;106:103-7.
Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy: A new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res 2006;17:190-8.
Mehrotra R, Singh HP, Gupta SC, Singh M, Jain S. Pentoxifylline therapy in the management of oral submucous fibrosis. Asian Pac J Cancer Prev 2011;12:971-4.
Gupta J, Srinivasan SV, Daniel MJ. Efficacy of betamethasone, placental extract and hyaluronidase in the treatment of OSMF. EJ Dent 2012;2:132-5.
Khan S, Chatra L, Prashanth SK, Veena KM, Rao PK. Pathogenesis of oral submucous fibrosis. J Cancer Res Ther 2012;8:199-203.
More CB, Das S, Patel H, Adalja C, Kamatchi V, Venkatesh R. Proposed clinical classification for oral submucous fibrosis. Oral Oncol 2012;48:200-2.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.
Yoithapprabhunath TR, Maheswaran T, Dineshshankar J, Anusushanth A, Sindhuja P, Sitra G. Pathogenesis and therapeutic intervention of oral submucous fibrosis. J Pharm Bioallied Sci 2013;5:S85-8.
Pindborg JJ. Is submucous fibrosis a precancerous condition in the oral cavity? Int Dent J 1972;22:474-80.
Dayal Reddy R, Anuradha Bhat K. Malignant potential of oral submucous fibrosis due to intraoral trauma. Indian J Med Sci 2000;54:182-7.
Canniff JP, Harvey W. The aetiology of oral submucous fibrosis: The stimulation of collagen synthesis by extracts of areca nut. Int J Oral Surg 1981;10:163-7.
Maher R, Aga P, Johnson NW, Sankaranarayanan R, Warnakulasuriya S. Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan. Nutr Cancer 1997;27:41-7.
Borle RM, Borle SR. Management of oral submucous fibrosis: A conservative approach. J Oral Maxillofac Surg 1991;49:788-91.
Sudarshan R, Annigeri RG, Sree Vijayabala G. Aloe vera in the treatment for oral submucous fibrosis - a preliminary study. J Oral Pathol Med 2012;41:755-61.
Karemore TV, Motwani M. Evaluation of the effect of newer antioxidant lycopene in the treatment of oral submucous fibrosis. Indian J Dent Res 2012;23:524-8.
Singh M, Niranjan HS, Mehrotra R, Sharma D, Gupta SC. Efficacy of hydrocortisone acetate/hyaluronidase vs triamcinolone acetonide/hyaluronidase in the treatment of oral submucous fibrosis. Indian J Med Res 2010;131:665-9.
Rawlins JM, Lam WL, Karoo RO, Naylor IL, Sharpe DT. Pentoxifylline inhibits mature burn scar fibroblasts in culture. Burns 2006;32:42-5.
Haddad P, Kalaghchi B, Amouzegar-Hashemi F. Pentoxifylline and vitamin E combination for superficial radiation-induced fibrosis: A phase II clinical trial. Radiother Oncol 2005;77:324-6.
Pineda AM, Tianco EA, Tan JB, Casintahan FA, Beloso MB. Oral pentoxifylline and topical clobetasol propionate ointment in the treatment of pretibial myxoedema, with concomitant improvement of Graves' ophthalmopathy. J Eur Acad Dermatol Venereol 2007;21:1441-3.
Fedorowicz Z, Chan Shih-Yen E, Dorri M, Nasser M, Newton T, Shi L. Interventions for the management of oral submucous fibrosis. Cochrane Database Syst Rev 2008;4:CD007156.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
|This article has been cited by|
||Effectiveness of Pentoxifylline in the treatment of oral submucous fibrosis patients: a case-control study
| ||Annette M. Bhambal,Ajay Bhambal,U. S. Shukla,Aashna Dhingra |
| ||Applied Cancer Research. 2019; 39(1) |
|[Pubmed] | [DOI]|
||Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview
| ||Wei Xiong Wen,Siang Yin Lee,Rafaella Siang,Rhun Yian Koh |
| ||Advances in Therapy. 2017; 34(6): 1245 |
|[Pubmed] | [DOI]|
||Evaluating the efficacy of pentoxifylline in the treatment of oral submucous fibrosis: A meta-analysis
| ||J Liu,F Chen,Z Wei,M Qiu,Z Li,H Dan,Q Chen,L Jiang |
| ||Oral Diseases. 2017; |
|[Pubmed] | [DOI]|