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| Year : 2012 | Volume
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| Issue : 4 | Page : 524-528 |
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| Evaluation of the effect of newer antioxidant lycopene in the treatment of oral submucous fibrosis |
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Tapasya Vaibhav Karemore, Mukta Motwani
Department of Oral Med. and Radio, V.S.P.M. Dental College, Hingna, Nagpur, Sharad Pawar Dental College, Wardha, Maharashtra, India
Click here for correspondence address and email
| Date of Web Publication | 20-Dec-2012 |
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 Abstract | | |
Background and Objective: Oral submucous fibrosis (OSMF) is a well-known premalignant condition encountered in Indian population. Although the disease is advancing rapidly, its reliable treatment modality for its various stages has not yet evolved.
The aim of the present study is to compare the effect of newer antioxidant lycopene with a placebo in conjunction with the cessation of causative habit in the treatment of OSMF.
Materials and Methods: The study group included 92 patients with OSMF. The OSMF diagnosis was established through a composite of accepted clinical and histopathological characteristics. Out of 92, 46 patients were given lycopene and remaining 46 were on placebo drug. Lycopene group patients received 8 mg Lycored TM per day in two divided doses of 4 mg each, while placebo group patients received placebo tablet twice a day. Patients were examined for changes in mouth opening and other clinical symptoms of OSMF during three months and were followed up for next two months.
Results: Lycopene was found to be significantly efficacious in the amelioration of signs and symptoms of OSMF. It was effective in reducing the objective signs of OSMF as demonstrated by the improved maximal mouth opening, percentage of which was 69.56%(P<0.05).
Interpretation and Conclusion: Reactive oxygen compounds or free radicals have been implicated as one of the major harmful factors for premalignant and malignant conditions. Present study concludes that lycopene, a newer antioxidant, appears to be a very promising drug in the management of OSMF. Keywords: Lycopene, OSMF, oral precancer
How to cite this article:
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 |
How to cite this URL:
Karemore TV, Motwani M. Evaluation of the effect of newer antioxidant lycopene in the treatment of oral submucous fibrosis. Indian J Dent Res [serial online] 2012 [cited 2023 Mar 30];23:524-8. Available from: https://www.ijdr.in/text.asp?2012/23/4/524/104964 |
Oral submucous fibrosis is a chronic debilitating potentially malignant disease of the oral cavity associated with betel nut chewing.
The pathogenesis and management of oral submucous fibrosis has been the subject of controversy ever since Schwartz first described the condition in 1952. [1] Various types of treatment modalities which can be categorized as invasive and conservative have been tried to improve signs and symptoms of oral submucous fibrosis. Invasive methods of treatment which include intralesional injection of steroids, placentrex, fibrinolytic agents and surgical elimination of the fibrotic bands are traumatic and gave variable and unsatisfactory results. [2] Conservative treatment using vitamins - acting as antioxidants, and iron supplements are proven to be easily acceptable, give promising results and are safe and painless.
Oral submucous fibrosis is widely prevalent in all age groups and across all socioeconomic strata in India. It has a high rate of morbidity because of the progressive inability to open the mouth, resulting in difficulty in eating and nutritional deficiencies.
A low intake of fruits and vegetables is associated with an increased risk for oral and other cancers. [3] Further several epidemiological studies have suggested substantial decrease in cancerous and precancerous lesions with increasing levels of antioxidants. [4]
Lycopene, an effective antioxidant from tomato extract, has been proved to be the most potent radical scavenger in various in vivo as well as in vitro studies. Tomatoes are predominant source of carotenoid lycopene, which is a non provitamin A carotenoid. It has got various properties like, most potent singlet oxygen quencher, [5] inhibiting proliferation of several types of cancer cells, including those of breast, lung, and endometrium, [6] and inhibiting malignant transformation [4],[7] of brain cells in rats.
Lycopene was successfully tried in leukoplakia, a precancerous lesion, where it has given excellent and favorable results. [8] A. Kumar et al, [9] tried lycopene in OSMF with a daily dose of 16 mg and the drug has given promising results in reducing signs and symptoms in the initial stages of the disease. The optimum dosage for lycopene has not been established, but the amount found helpful in studies generally fell in the range of 4 to 8 mg daily.
This study makes an attempt to try this potential antioxidant in the treatment of the most prevalent and challenging disease of the Indian subcontinent i.e.oral submucous fibrosis .
| Materials and Methods | |  |
Interventional single blind study was carried out in 92 randomly selected patients of OSMF whose age range was 17-57 years out of which 80 were males and 12 were females during the period of 2004-2006 in the Department of Oral Diagnosis, Medicine and Radiology of Sharad Pawar Dental College and Hospital, Wardha, MS, India. Ethical approval was obtained from relevant ethical committee prior to study commencement.
A complete personal history was recorded in a predetermined format. Special reference was given to frequency and duration of habits of betel nut, betel quid, tobacco and pan/pan masala chewing and smoking. Clinical diagnosis of oral submucous fibrosis was made when patients presented with characteristic features of OSMF like vesicles, ulceration, and intolerance to spicy foods, pallor and stiffness of oral mucosa, fibrous bands in buccal or labial mucosa including other sites and progressive inability to open the mouth. The maximum unaided mouth opening was recorded using a graduated vernier caliper by measuring the distance between the upper and lower incisal edge in millimeters.
According to Khanna and Andrade staging, patients in both lycopene and placebo group were staged as follows;
Lycopene group: Group I - 6, Group II - 10, Group III - 28, Group IVA-2
Placebo group: Group I - 8, Group II - 14, Group III - 22, Group IVA- 2
After complete clinical examination, routine hemograms were ordered to rule out any associated systemic disease.
After an informed consent and explaining need of biopsy and treatment plan to the patient, a biopsy, using 6-mm diameter disposable punch biopsy tool, with a judgment of sufficient connective tissue sample is obtained at the beginning and the end of three months treatment period.
The patients were divided into two groups viz. lycopene group and placebo group irrespective of age, sex, and severity of the disease [Graph 1]. Lycopene group patients received 8 mg softgel Lycored TM orally per day in two divided doses of 4 mg each for a period of three months, while placebo group patients received softgel placebo twice a day orally which bore structural resemblance to softgel Lycored.(both drugs were sponsored and manufactured by Jagsonpal Pharmaceuticals, New Delhi)
Patients were evaluated every 15 days during the treatment period of three months and were further followed up for two months.
During each visit, the patients were examined for;
- Presence or absence of erythematous areas/ulceration/erosions
- Burning sensation and intolerance to spices whether present, absent or reduced, and
- Any changes in mouth opening.
After a three-month treatment period, post treatment biopsy was done to evaluate histopathological changes if any. Histopathological changes were observed in terms of degree of epithelial thickness, keratosis, dysplasia, loss of rete ridges, juxta-epithelial collagen deposition, and chronic inflammatory infiltrate.
| Results and Statistical Analysis | | |
Ninety-two subjects were recruited to the study with 46 in each group. The results and observations of the effect of drug were measured and interpreted by examining the following:
1) Maximum mouth opening (MMO), 2) Intolerance to spices and burning sensation of oral cavity, 3) Presence/absence of erythematous areas/ulcerations/erosions, both at baseline and at the end of treatment period.
For the criteria of mouth opening; if maximum mouth opening at exit (at the end of three month drug regimen) was <3 mm of baseline, then it was considered as deteriorated., 37 if >2 mm of baseline then it was considered as stable. [10] and if it was >3 mm of baseline then was considered as improved. [10] (mouth opening measured by Vernier Gauge had an accuracy of ±1.) [Table 1] and [Table 2]. | Table 2: Z-test for comparing the significance of difference between two means of mouth opening (post-treatment) for lycopene and placebo group
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There was significant (P<0.05) difference of maximum mouth opening between study and placebo group with Z calculated value of 5.65 mm at exit in maximum mouth opening.
Burning sensation and intolerance to spices [10] were graded from 0 to 3 as 0 - absent, 1 - mild, 2 - moderate, 3 - severe. Any change from higher readings to lower readings was considered as reduced and vice versa as increased.
When readings decreased to zero, then were considered as absent and same readings at exit were considered as no change. [Table 3] and [Table 4]. | Table 3: Burning sensation and/or intolerance to spices Lycopene group Placebo group
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 | Table 4: Chi-square test for comparing burning sensation and/or intolerance to spices at baseline and at exit in both the groups
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For erythematous areas/ulcerations/ erosions; present indicates the presence of erythematous areas/ulcerations/erosions present at baseline or within period of three months of drug regimen or at exit, even if reduced in size or frequency or change in site of occurrence while absent indicates absence of erythematous areas/ulcerations/erosions at exit. [Table 5] and [Table 6]. | Table 5: Erythematous areas/ulcerations/erosions at baseline and exit Lycopene group Placebo group
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 | Table 6: Chi-square test for comparing erythematous areas/ ulcerations/erosions at exit of lycopene and placebo group
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There were no reported instances of side effects or intolerance to lycopene when used with other antioxidant supplements. The clinical history of examination revealed no significant illness contraindicating the treatment.
For lycopene group, during follow up period, changes were similar as at the end of treatment except for one case which showed ulceration and burning sensation of oral cavity for a period of one week. In placebo group, 14 patients reported with intermittent ulceration of oral cavity and burning sensation during the follow up.
Considering the criteria of histopathologic examination pre and post treatment biopsies were obtained. Statistical comparisons were carried out for both the groups.
Chi-square test was used for comparing histological findings at baseline and exit of both groups wherein lycopene group showed significant decrease in post-treatment juxta-epithelial collagen deposition and chronic inflammatory infiltrate, whereas placebo group at exit showed significant decrease in chronic inflammatory infiltrate.
| Discussion | | |
All patients in the present study gave a positive history of areca nut chewing in the raw form, as a quid or in a commercial preparation such as gutkha or pan masala which has proven to be a major causative agent for oral submucous fibrosis in the literature. [11],[12],[13],[14],[15] Other associated habits such as tobacco, cigarette smoking and alcohol though present in some subjects were not associated with causation or severity of the disease. This is in lieu of earlier studies on the said premalignant condition.
Epidemiologic studies have established the protective role of diets rich in fruits and vegetables with high intake of carotenoids in oral precancerous and cancerous conditions and reduced risk of same. [12] Very few studies although with variable results have tried vitamin A, vitamin B and other micronutrients as a conservative mode of treatment in oral submucous fibrosis. [13],[14]
According to J P Caniff, medical management of oral submucous fibrosis is both empirical and unsatisfactory, while treatment with vitamins was ineffective in improving trismus as stated by Lai DR et al. According to Rehana Maher et al, multiple micronutrients and minerals showed significant improvement in symptoms with 41% cases showing some improvement in mouth opening, contrary to which RM Borle and SR Borle showed improvement in symptoms of oral submucous fibrosis with vitamin A but not in mouth opening. Considering existing data, a newer antioxidant like lycopene with more potent properties is tried in the present study.
Lycopene is a powerful antioxidant obtained from tomatoes. It has been shown to inhibit various types of cancers and have potent benefits in oral pre malignant lesion where it has been shown to modulate dysplastic changes. [8] The interest in the various mechanisms of action of this particular carotenoid is relatively recent and has the highest singlet oxygen quenching capacity with high capability of quenching other free radicals
in vitro. The inverse relationship between lycopene intake or serum values and cancer risk has been observed in particular for cancers of prostrate, pancreas, bladder, cervix and oral leukoplakias. [8] Additionally, laboratory findings demonstrate that lycopene inhibits cancer cell growth in vivo and in vitro. New evidence has provided other explanations for the anticancer activity of lycopene by the upregulation of connexin 43 and stimulation of gap junctional communication that does not involve its role as an antioxidant. [7]
The present study is designed to observe the effect of lycopene on oral submucous fibrosis in general. Patients were categorized into lycopene or placebo group irrespective of the severity of OSMF on the basis of clinical parameters. Present study showed significant improvement in symptoms of oral submucous fibrosis in placebo group with cessation of habit only, which reinforces the literature published about stoppage of habit as the first line of treatment. [15] Significant improvements were observed in the form of better tolerance to spices and burning sensation and absence of erythematous areas or ulceration or erosions. In addition, significant increase in maximum mouth opening in OSMF patients was observed after three months treatment with lycopene as compared with OSMF patients in placebo group.
When difference between two means of mouth opening at exit among both groups was calculated by Z test, value of significance (5.65mm/ P<0.05) was obtained.
The mean ± SD of significant increase in maximum mouth opening in OSMF patients in the study group was 4.48 ± 3.65 mm while in placebo group it was 1.13±1.6 mm. The average of increase in MMO in placebo group was 1.11 mm while in lycopene group it was 4.39 mm, which indicates that this increase in MMO is not due to oral habit intervention only. Although the mechanisms leading to trismus in OSMF patients are still unclear, the primary cause may be fibrosis and fibrous band formation in the oral mucosa. [16]
Percentage of improved mouth opening with lycopene group was 69.56%, which is higher than the study by Rehena Maher and et al (41%) using multiple micronutrients.
Patients who had shorter history of OSMF had a greater improvement in mouth opening than patients who had long-term disease. In the present study, some patients who complained of decreased mouth opening had stopped chewing betel nut three-four years back. These individuals when treated with lycopene could not show observable improvement in mouth opening compared to those who stopped their habit recently or just before the trial, thus suggesting that there may be a synergistic effect of lycopene and stoppage of the habit in bringing about the improvement in mouth opening.
A significant symptomatic improvement of tolerance to spices and burning sensation was reported by patients at exit in lycopene and placebo group. [Table 3] and [Table 4] Out of 46, 31 subjects in lycopene group were relieved of intolerance to spices and burning sensation and 28 subjects had no erythmatous areas or ulcerations or erosions at exit. Relief from burning sensation and intolerance to spices was found in 67.39% along with significant improvement in erythematous areas / ulcerations / erosions.
While out of 46, only 7 subjects in placebo group were relieved of intolerance to spices and burning sensation and only 19 subjects had no erythematous areas or ulcerations or erosions at exit.
Only one patient in lycopene group reported with palatal blood filled vesicles, which resolved at exit.
Evaluation of drug response in recall visits was subjective and highly individual on clinical basis but might have not compromised the accuracy for result regarding the symptoms of the disease.
Follow up for treatment was found to be poor in placebo group patients. This could be due to the lack of perceptible improvement in the condition of these patients. Self perceived improvement was found to be an important factor in the motivation of the patient toward treatment.Study could have been carried out for longer follow up period and with large sample size to get more accuracy in the management of OSMF. Also the third group with routine treatment modality i.e. topical corticosteroid along with antioxidants could have been made for comparison.
As mentioned, there were no clinical side effects of the drug but serological tests to correlate those findings might have been more helpful in proving the efficacy of the drug. Above said facts can be considered as the shortcomings of the study.
Histopathologically, each case was assessed by taking pretreatment and post-treatment biopsy. Lycopene group showed significant decrease in post-treatment juxta-epithelial collagen deposition and chronic inflammatory infiltrate. These histological findings help to co-relate improvement in signs and symptoms of OSMF in study group. Out of 46 cases of lycopene group, pretreatment atrophic epithelium was present in 37 cases. When histologic changes were compared with post treatment clinical findings, increase in epithelial thickness was observed in 7 cases that clinically showed loss of burning sensation while decrease in juxta-epithelial collagen deposition was observed in 16 cases that clinically showed improvement in mouth opening.
While the study by Mohitpal singh et al showed significant reversal of dysplasia in leukoplakia when treated with lycopene, in the present study percentage of dysplasia was found to be 12, including both the groups while only one patient showed absence of dysplasia at the end of treatment in lycopene group. Patients who showed dysplasia were kept on follow up further.
| Conclusion | | |
Lycopene was seen to be a more efficacious drug in the management of oral submucous fibrosis proving more safe and reliable treatment. In contrast to other management modalities for submucous fibrosis, it offers a non invasive option that yields significant improvements in the symptoms as well as objective signs of the condition, which may be due to its anti-poliferative, anti-inflammatory and anti-oxidant, [5] activity, [4],[6],[7] It could therefore be used as a first line drug that will play a substantial role in successful management or control of progression of this debilitating condition.
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Correspondence Address:
Tapasya Vaibhav Karemore
Department of Oral Med. and Radio, V.S.P.M. Dental College, Hingna, Nagpur, Sharad Pawar Dental College, Wardha, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0970-9290.104964
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6] |
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