Ravi Mehrotra, HP singh, SC gupta, M singh, S jain; Department of pathology and E.N.T. & Head & neck

surgery, M.L.N. Medical college & S.R.N. Hospital, Allahabad, India

2011 Asian Pacific J cancer prev, 12, 971-974

PENTOXIFYLLINE THERAPY IN THE MANAGEMENT OF ORAL SUBMUCOUS

FIBROSIS

INTRODUCTION

Oral submucous fibrosis is a common premalignant condition in the Indian subcontinent.

It is caused by chewing areca nut and other irritants in various forms. It is characterized by the progressive build up of constricting bands of

collagen in the cheeks and adjacent structures of the mouth which can severely restrict mouth opening and tongue movement.

It also cause problems with speech and swallowing.

Its medical treatment is not yet fully standardized. In this study we compared the efficacy of Pentoxifylline to placebo.

Aziz SR (2009). Lack of reliable evidence for oral submucous fibrosis treatments. Evid Based Dent, 10, 8-9.Fedorowicz Z, Chan Shih-Yen E, et al (2008). Interventions for the anagement of oral submucous fibrosis. Cochrane Database Syst Rev, 4, CD007156.

Oral submucous fibrosis (OSF) is a chronic and potentially malignant condition of the oral cavity. It is characterized by a juxtraepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria and associated epithelial atrophy. The disease affects most part of the oral cavity as well as the upper third of the esophagus.

Areca nut, incriminated in the causation of OSF is often wrapped in the leaf of a tropical creeper, Piper betle L. commonly known as the betel leaf or paan The usage of paan is widespread in the Indian subcontinent, mostly in the Hindi speaking heartland of North and Central India.

Tilakratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol. 2005;30:30–32.

Jayavelu P., Medical Treatment Modalities of Oral Submucous Fibrosis,NJIRM,2012,VOL 3(1)147-151

Clinical Grading: Grade I: Presence of only blanching of oral mucosa without symptoms.

Grade II: Presence of blanching and burning sensation, dryness of the mouth, Vesicles or ulcers in the mouth.

Grade III: Presence of blanching and burning sensation, dryness of the mouth, vesicles or ulcers in the mouth with restriction of mouth opening and palpable bands all over the mouth without tongue involvement.

Grade IV: Presence of blanching and burning sensation, dryness, of the mouth, vesicles or ulcers in the mouth with restriction of mouth opening and palpable bands all over the mouth with tongue involvement.

Grade V: Presence of all features of grade IV associated with chronic Ulcer and histopathological proven carcinoma.

The assessment of blanching based on colour of mucosa: Score

(0): Normal Pink colour Score (1): Red or deep Pink colour Score (2): Pale white colour Score (3): Blanched white colour

The assessment of presence and absence of burning sensation: Score (0): No burning sensation Score (1): Mild burning sensation Score (2): Moderate Burning sensation Score (3): Severe burning sensation. The assessment of inter incisal distance (Mouth opening) grades: Grade I : Mouth opening 36 mm (or) above Grade II : Mouth opening 26 mm to 35 mm Grade III: Mouth opening 16 mm to 25 mm Grade IV: Mouth opening 6 mm to 15 mm The assessment of tongue protrusion was based on the following grades: Grade I : Beyond the border of Lower Lip. Grade II : Within the Vermilion border of Lower Lip. Grade III: Up to the incisal third of lower mandibular anteriors. Grade IV: Cannot protrude, tongue within the floor of mouth

Treatment options include iron and multivitamin supplements including lycopene - an extract of tomato,

and a range of medicines

e.g. intralesional injection of steroids,

hyaluronidase,

human placenta extracts,

chemotrypsin,

Pentoxifylline and collagenase.

Laser ablation and surgery, including cutting of the fibrous bands of the jaw muscles and temporomandibular joint, has been used for more extreme cases.Mehrotra R, Chaudhary A, Pandya S, et al (2010). Correlation of

addictive factors, human papilloma virus infection and histopathology of oral submucous fibrosis. J Oral Pathol Med, 39, 460-464

Treatment

Contd…

Pentoxyphylline/oxypentifylline

Pentoxifylline is a tri-substituted methylxanthine derivative, the biologic activities of which are numerous.

It is termed as a “Rheologic modifier.”

It improves microcirculation and decreases platelet aggregation as well as granulocyte adhesion.

It increases leukocyte deformability as well as inhibits neutrophil adhesion and activation.

The medication also has antithrombin, antiplasmin activities and fibrinolytic activity.

In addition, it causes degranulation of neutrophils, promotes natural killer cell activity and inhibits T-cell and B-cell activation.

Samlaska CP, Winfield EA (1994). Pentoxifylline. J Am Acad Dermatol, 30, 603-21

Pentoxyphylline/oxypentifylline

An analogue to theophylline and a phosphodiesterase inhibitor, It increases blood flow in ischaemic areas by reducing whole blood viscocity

and by increasing flexibility of RBCs Well tolerated Other indications- stroke, non-cerebrovascular insufficiency, transient

ischaemic attack, trophic leg ulcers, gangrene, non haemorrhagic stroke

Side effects – nausea, vomitting, dyspepsia, bloating

Dose- 400mg BD-TDS, TRENTAL-400, FLEXITAL-400mg SR tab, 300 mg/15 ml for slow i.v. inj

KD Tripathi Medical Pharmacology, 4th edi.- 537

Adverse effects

Adverse effects by frequency:[1][2][3][5][6]

Common (1-10% frequency):DizzinessHeadacheNauseaVomitingIndigestionFlushingUncommon (0.1-1% frequency):Angina

PalpitationsRare (<0.1% frequency):HypersensitivityItchinessRashHivesBleedingHallucinationsArrhythmiasAseptic meningitis

"Trental, Pentoxil (pentoxifylline) dosing, indications, interactions, adverse effects, and more". Medscape Ref. WebMD.February 2014.

Placebo/dummy medication

Latin word-’I SHALL PLEASE’This is an innert substance which is given in the garb of medicine.Limited role in practical therapeutics. It works by psychological rather than pharmacological means and often

produces responses equivalent to the active drug.Placebo reactors-individual easily responding to placeboUsed as a control device in clinical trials of drugsTo treat a patient who does not require active drug. It induces physiologic responses like they can release endorphins in brain

causing analgesia.

Common placebo- lactose tablets Distilled water inj.

KD Tripathi Medical Pharmacology, 4th edi.- 63-64

Pure- phrmacologically inert like lactose tab.Impure- pharmacologic activity Effective in treating the subjective responses[pain of angina, cancer,headache and surgical wounds]Therapeutic responses to placebo and to active drugs

may resemble to each other in magnitude and duration.eg-pain relief and cough suppression afforded by a placebo may parallel that of codeine

Side effects-nausia, drowsiness, sweating, xerostomia1/3rd patient reacts to placeboJohn A,,Enid A,pharmacology and therapeutics for Dentistry4th edi.46- 47

There are few controlled clinical trials in this area.

A comparative study was planned to assess the usefulness of

Pentoxifylline versus placebo in the treatment of OSMF.

Rajendran R, Rani V, Shaikh S (2006). Pentoxifylline therapy: A new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res, 17, 190-98

Patients, 18 years of age and older, were enrolled in the study and written consent was obtained.

Patients who had difficulty in chewing, had restricted mouth opening with the presence of fibrous bands and had a histopatho-logically confirmed diagnosis of OSMF were included.

Patients who refused scalpel biopsy as well as those with medical problems or dental appliances such as orthodontic or other fixed prostheses that could potentially interfere with the examination were not included in the study.

75 patients were enrolled in the study and out of these 62 patients came for regular followup and took regular treatment, thus 13 patients were excluded.

All patients were examined with a conventional overhead examination light and then divided randomly into the drug or placebo groups.

The demographic information of each patient,including age, gender and history of tobacco use was obtained.

Detailed clinical examination was performed on each patient to assess the site/size of the oral mucosal lesions and this was recorded on a standard form.

All routine investigations including pre-treatment biopsy for confirmation of histological diagnosis were done.

Biopsy samples, obtained under local anesthesia using the standard scalpel technique, were analyzed by two pathologists who were blinded to the clinical data.

Clinical assessment of maximal jaw opening was carried out monthly and outcomes were expressed by measured change in the inter-incisor distance.

Group A (n=30) patients were given placebo (multivitamin) therapy. Group B (n=32) patients were given Tab. Pentoxifylline 400 mg for a period of

7 mnths. The drug Pentoxifylline was administered as an inductive regime for the initial

30 days at a reduced dosage of 2 tablets daily and then the dose was hiked to 3 tablets daily for 6 more months as per previous studies

Primary outcomes included:(1) Resumption of normal eating, chewing and speech.(2) Change or improvement in maximal jaw opening, measured

by the interincisal distance.

Secondary outcomes included(1) Discomfort or pain as a result of the intervention: patient-

assessment using a validated pain scale.(2) Hospital admission: length of stay.(3) Quality of life and patient satisfaction as assessed by a

validated questionnaire.

.

Subjective improvement in symptoms: 1) Burning sensation in mouth;2) Repeated vesiculation/ ulceration in oral mucosa; 3) Resumption of normal eating, chewing and speech.

Objective improvement in signs: 1) Trismus;2) Ankyloglossia; 3) Vesicles/ Ulcers; 4) Fibrosis

Clinical follow-up of all the patients was carried out for 18 months and the findings were compared pre and post-treatment.

Side effects of treatment, if any, were also investigated.

Results

37% of the patients - third decade 22%- second decade 20%-fourth decade of life. The youngest patient seen was 16 years and the oldest was 70 years old. The mean age of presentation was 35.1 years. Male to female ratio was 4.29: 1. Males - age group of 21 – 30 years, Females - 41-50 years. 64% - habit of using panmasala or dohra (mixture of tobacco and slaked lime

– sold locally), 20% patients used pan masala or dohra with betel quid, 7% patients used betel quid with tobacco 6% - smokers.

Those who chewed areca nut in any form were habituated to 1 to 20 chews per day, (median 6.0) for a period of 1 to 25 years (median 6 years).

Fibrosis was present in all patients.The soft palate was involved in 100% of patients buccal mucosa in 90%- unilateral-10%, bilateral-80%,Retromolar trigone in 90% -unilateral-28%, bilateral-62%, anterior faucial pillar in 80%- unilateral-16%, bilateral-62%, Floor of mouth in 24 %, and tongue in 20% of patientsThe participants did not complain of any discomfort or pain due to

therapy, nor were any of them admitted to the hospital.The participants’ compliance was 62/75 (82%) for drug treatment.

Symptoms Group A Group B

1.Burning sensation2.Vesicle/ulcer formation improvement3.Total sign score4.Mean improvement in trismus5.Total symptom score6.Mouth opening7.Ankyloglossia 8.Fibrotic bands9. Total Sign+symptom score

39.4%35.5%19.9%15.4%38.2%6mm22.6%19.5%25%

86.6%84.1%38.5%35.7%85.8%10mm39.3%32.9%49.2%

The difference between the group A and group B proved to be statistically significant (p< 0.05) in total (i.e. symptom +sign) score.

16/32 patients in the treatment group came for long term (18months) follow-up and revealed stable progress with none of them going back to chewing habits.These symptoms were relatively mild in nature, lasted for 1-2 weeks and settled on their own without cessation of drug or requiring medication.

Side effects Group A Group B

1.Dyspepsia & nausia

2.Bloating & flatus

3.Headache, vomitting, anxiety,remors

No side effects

24%

18%

2%

Discussion

Treatment for OSMF remains a challenge. It is said that once the disease has developed, there is neither regression nor any effective treatment. Consequently, improved oral opening and relief of symptoms form the main objectives of treatment.

In general, the management modalities can be categorized into conservative and surgical.

Aziz SR (2009). Lack of reliable evidence for oral submucous fibrosis treatments. Evid Based Dent, 10, 8-9.Jiang X, Hu J (2009). Drug treatment of oral submucous fibrosis: a review of the literature. J Oral Maxillofac Surg, 67, 1510-1515

A recent study from the author’s group recommended the use of combination of triamcinolone acetonide (10 mg/ ml)/ hyaluronidase (1500 IU) at 15 days interval for 22 weeks.

This was more convenient to the patients because it required only weekly injections, less daily dosing, better patients compliance, and improvement in the sign score. (trismus, ankyloglossia, vesicle formation and fibrosis)

Singh M, Niranjan HS, Mehrotra R, et al (2010). Efficacy of hydrocortisone acetate/ hyaluronidase versus triamcinolone acetonide/ hyaluronidase in the treatment of oral submucous fibrosis. Indian J Med Res, 131, 659-669.

On the other hand, an earlier cochrane review on this subject concluded that the paucity of data and poor methodological quality of studies indicated a lack of reliable evidence for the effectiveness of any specific interventions for the management of this disease

Fedorowicz Z, Chan Shih-Yen E, et al (2008). Interventions for the management of oral submucous fibrosis. Cochrane Database Syst Rev, 4, CD007156.

REVIEW OF THE LITERATURE

Fedorowicz Z, Chan Shih-Yen E, et al (2008). Interventions for the management of oral submucous fibrosis. Cochrane Database Syst Rev, 4, CD007156

This article provides a basic review of OSF and focuses on nonsurgical management.

OSF is an insidious disease affecting the oral cavity, pharynx and upper digestive tract.

Its aetiology is directly linked to betel nut usage, which is common to the Indian subcontinent, Far East and Pacific Rim. Betel nut usage is thought to be the primary cause of the condition.

OSF's morbidity and mortality is associated with significant masticatory dysfunction (trismus) and an increased risk of developing squamous cell carcinoma, with a malignant transformation rate of 7–30%.

Indian studies indicate that over 5 million people in India suffer from OSF (0.5% of the population of India).

It is estimated that, in addition, up to 20% of the world's population use

betel nut is some form, so the incidence of OSF is probably higher than figures in the published literature suggest.

Currently, OSF is considered a public health issue in the Indian subcontinent, UK and South Africa.

With the migration of peoples of the Indian subcontinent to all corners of the world, the general practitioner will certainly encounter this disorder at some point of their career.

In this review, Fedorowicz and colleagues did not identify any randomised controlled trials of surgical procedures.

Only two studies examining nonsurgical treatment of OSF. One study used lycopene in conjunction with intralesional injections of a steroid, and the other pentoxifylline in combination with mouth-stretching exercises and heat, and the review authors note that both trials provided unreliable results.

The lack of good quality trials of medical and surgical procedures for OSF is disappointing but unsurprising given that the largest burden of this disease is found in under-resourced countries

Pandya S, Chaudhary AK, M Singh, et al (2009). Correlation of histo pathological diagnosis with habits and clinical findings in oral sub-mucous fibrosis. Head Neck Oncol, 1, 10.

Two hundred and thirty nine patients were studied, yielding a male to female ratio of 6.8:1. Maximum patients were in the 21–30 years age group with a marked male predominance.

Of these, 197 (82.4%) patients chewed areca nut/dohra, 14 (5.8%) were smokers and 2 (0.8%) patients were habituated to alcohol.

89(37.2%) patients reported difficulty in opening of the mouth (trismus). 51 (57.4%) patients were found to have stage II (2–3 cm) trismus while rest had stage I and III.

The buccal mucosa was found to be the most commonly involved site. On the basis of histopathological examination, 52(21.7%) were classified as OSF grade I, 75(31.3%) patients as grade II and 112(46.8%) had grade III disease.

The widespread habit of chewing dohra/paan masala is a major risk factor of OSF, especially in the younger age group.

In this study, an increase in histopathological grading was found with severity and duration of addiction habit. However no significant correlation was found between clinical staging and histopathological grading.

Jiang X, Hu J (2009). Drug treatment of oral submucous fibrosis: a review of the literature. J Oral Maxillofac Surg, 67, 1510-1515

Buccal mucosa was found the most commonly involved site in 66(20.8%) patients followed by palate 37(17.7%) and the retromolar area 22(14.7%). Previous reports also corroborated these findings. In this study, none of the patients were reported with involvement of the larynx, pharynx or the esophagus.

Clinically, trismus is an important symptom of OSF. In this study, 89 (37.2%) patients were found to have trismus of which, 16

(17.9%) had stage I, 51(57.3%) patients had stage II trismus followed by 22 (24.7%) of stage III.

He also reported that 75% males and 80% females with OSF patients had stage II disease and suggested that this could be due to the fact that the majority of the patients reported for treatment only after the onset of restriction in their ability to open their mouths.

Rajendran R, Rani V, Shaikh S (2006). Pentoxifylline therapy: A new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res, 17, 190-98

Rajendren et al reported that Pentoxifylline as an adjunct in OSMF treatment and after 7 months trial and 6-12 months follow-up, the patients showed improvement in signs and symptoms as compared to controls.

They reported significant improvement in patients in the experimental group as compared to patients in the control group.

There was improvement in objective criteria of mouth opening, tongue protrusion, and relief from perioral fibrotic bands and subjective symptoms of intolerance to spices, burning sensation of mouth, tinnitus, difficulty in swallowing and difficulty in speech with Pentoxifylline as compared to placebo.

All patients also received local heat therapy and underwentforceful mouth stretching exercises