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J Oral Pathol Med

doi: 10.1111/jop.12463 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

wileyonlinelibrary.com/journal/jop

Evaluation of efficacy of aloe vera in the treatment of oral


submucous fibrosis a clinical study
Ardra Anuradha, Bharati Patil, Venkataswamy Reddy Asha
Department of Oral medicine & radiology, The Oxford College and Hospital, Bangalore, India

BACKGROUND: Oral submucous fibrosis is a chronic


Introduction
disease, treatment of which has largely been symp-
tomatic. Aloe vera has immunomodulatory, anti-inflam- Oral submucous brosis (OSMF) is a well-recognized
matory, wound healing, antioxidant, and antineoplastic potentially malignant disorder of the oral cavity caused by
activities. All such properties of aloe vera suggest the chewing areca nut which is more prevalent in South Asian
possibility of its use in the management of oral submu- countries. The disease is characterized by epithelial atrophy
cous fibrosis. and formation of submucosal brous bands resulting in
METHODS: Seventy-four patients of oral submucous reduced mouth opening (1).
fibrosis were randomly divided into 2 groups. Group A The various treatment protocols that have been tried to
patients were treated with systemic (juice) and topical improve the signs and symptoms of OSMF include
aloe vera (gel) for 3 months. Group B patients were intralesional injections of corticosteroids, placental extracts,
treated with intralesional injection of hydrocortisone and and hyaluronidase alone or in combination, IFN-a, oral
hyaluronidase for 6 weeks with antioxidant supplements administration of peripheral vasodilators, immune milk,
for 3 months. Patients were assessed for reduction in turmeric, lycopene, and micronutrient supplementation.
burning sensation and increase in mouth opening, cheek Various physiotherapeutic modalities have also shown
flexibility, and tongue protrusion at an interval of 1, 2, and favorable results (2). Steroids till date are the most accepted
3 months. modality of treatment for OSMF. The side effects of steroids
RESULTS: Both the groups showed statistically signifi- and the local discomfort caused by the intralesional injection
cant improvements in all the study parameters at the end necessitate the search of a newer treatment regimen for
of study period (P < 0.001). The clinical response to aloe OSMF.
vera was comparable to that of intralesional injections of Aloe vera is considered as an adaptogen. An adaptogen
hydrocortisone and hyaluronidase with antioxidant sup- is a substance that invigorates or strengthens the system.
plementation. Specically, the term applies to herbs that maintain health
CONCLUSION: The study concludes that aloe vera can by increasing the bodys ability to adapt to environmental
be an alternative, safe, and effective treatment regime in and internal stressors (3). Aloe vera contains 75 poten-
the management of oral submucous fibrosis. Long-term tially active constituents: vitamins, enzymes, minerals,
follow-up studies with larger sample size are recom- sugars, lignin, saponins, salicylic acids, and amino acids
mended. (4). The vitamins present are vitamin A (beta-carotene),
C, and E, which are antioxidants and help to neutralize
J Oral Pathol Med (2016) free radicals. Aloe vera contains nine enzymes: aliase,
alkaline phosphatase, amylase, bradykinase, carboxypepti-
Keywords: aloe vera; hyaluronidase; hydrocortisone; OSMF dase, catalase, cellulase, lipase, and peroxidase. Bradyk-
inase helps to reduce excessive inammation when
applied to the skin or mucosa topically. The polysaccha-
rides contained in the gel of the leaves have wound
healing, anti-inammatory, anticancer, immunomodula-
tory, and gastro-protective properties (4). All such prop-
erties of aloe vera suggest the possibility of its use in the
Correspondence: Ardra Anuradha, Department of Oral Medicine and management of OSMF.
Radiology, The Oxford Dental College and Hospital, Bangalore, Karnataka, Hence, this study was designed to evaluate the efcacy of
India. Tel: +91 7406146411, Fax: 080 202573204656, systemic and topical aloe vera in the treatment of OSMF. It
E-mail: dr_ardra@yahoo.co.in
Ethical committee: Institutional Review Board of the Oxford Dental
also compared the efcacy of aloe vera with intralesional
College and Hospital. injections of hydrocortisone, hyaluronidase with antioxidant
Accepted for publication April 27, 2016 supplements.
Aloe vera for the treatment of OSMF
Anuradha et al.

2
time intervals was made using repeated measures of ANOVA.
Material and methods
Comparison of various study parameters between the two
This study was conducted in the Department of Oral study groups was made using Students unpaired t-test at
Medicine and Radiology at the Oxford Dental College and different visits.
Hospital, Bangalore, India, between November 2013 and
August 2015. Approval from the institutional ethical
Results
committee was obtained for the study. Patients with OSMF
(Stage 2 according to Pindborg) (5) were enrolled in the The study comprised of 63 male and 11 female subjects.
study. Pregnant women, lactating mothers, patients with The mean age of study population was 32.7  10.3 years.
known history of hypersensitivity to aloe vera, and those Gutkha chewing was the most prevalent habit noted
who had received prior treatment for OSMF were excluded. (41.9%). 8.1% of subjects had habit of chewing gutkha,
Seventy-four patients who were ready to quit the habit and areca nut, and smoking. 2.7% of the subjects reported to
accept regular follow-up treatment protocol were included have only areca nut chewing habit. Another 2.7% of
in the study. An informed consent was obtained from all the subjects had habit of gutkha chewing, smoking, and alcohol.
patients after the nature of the study, and its procedures were 1.4% patients did not have any habits. 48.6% of subjects
explained. A thorough clinical examination was carried out, had habit of <5 years, followed by 35.2% with 510 years
and the following parameters were measured and recorded of habit and 16.2% with >10 years of habit.
by an independent examiner. Of the 74 study subjects, 23 were lost to follow-up at
different time intervals. Comparison of different study
1 The intensity of burning sensation was recorded using parameters at baseline between study groups revealed no
a Numerical Rating Visual Analogue Scale. signicant difference for burning sensation and interincisal
2 The interincisal mouth opening was measured using mouth opening, but a signicant difference was observed
a metal scale and divider from the mesioincisal for cheek exibility and tongue protrusion. (Table 1)
angle of upper central incisor to the mesioincisal Patients in Group A, at baseline, had mean VAS score of
angle of lower central incisor and recorded in 7.40  1.35 for burning sensation. At the end of 1st month,
millimeters. improvement of 3.52  1.12 (52.5%) was noticed. At the
3 Cheek exibility (CF) was measured according to the end of 2nd and 3rd month, the improvement in VAS score
method described by Bailoor and Nagesh (6). Two was 1.80  0.65 (46.7%) and 1.48  0.51 (13.3%),
points were marked, one on each side of the face at 1/ respectively. In Group B, the improvement in VAS score
3rd the distance from angle of the mouth on a line for burning sensation at different intervals from baseline to
joining the tragus of the ear and the angle of the mouth. end of 3rd month was 7.58  1.24, 5.27  1.04 (31.7%),
The distance measured between these two points was 3.42  1.10 (35.5%) and 1.85  1.05 (47.5%), respec-
V2. The subject was asked to blow his cheek fully, and tively. Both the groups showed a statistically signicant
the distance measured between the same two points (P < 0.001) reduction in burning sensation at the end of the
was V1. CF = V2 V1. study period. (Table 1, Fig. 1)
4 Tongue protrusion was assessed from normal mesioin- Mean interincisal mouth opening recorded for Group A
cisal angle of upper central incisor to the tip of the subjects at baseline was 2.90  0.57 cm. Patients showed an
tongue when maximally extended with mouth wide increase in mouth opening with mean of 3.20  0.57 cm
open. (10.7%) after 1 month. Mean scores of 3.34  0.53 cm
(4.7%) and 3.42  0.50 cm (4.9%) were noticed at the end of
The patients were randomly divided into 2 groups 2nd and 3rd month, respectively. In group B,
(Group A & Group B). Group A patients were given pure 2.57  0.63 cm was the mean score for mouth opening
aloe vera gel and pure aloe vera juice (Processed and recorded at baseline. Patients in this group showed an increase
manufactured by Hemant Sai, Sun Vision Company, Neel in mouth opening with mean value of 2.77  0.61 cm
RLI Pvt Ltd). They were instructed to drink 30 ml of aloe (8.4%), 2.95  0.59 cm (7.2%), and 3.11  0.56 cm
vera juice twice daily before food and to apply 5 mg (5.0%) after 1st, 2nd, and 3rd month, respectively. This
(apprx 1 scoop) of aloe vera gel over the lesion 3 times per increase in mean values for mouth opening at the end of 3rd
day for 3 months. Group B patients were given intrale- month for both the groups was statistically signicant
sional injections of hydrocortisone acetate 25 mg/ml and (P < 0.001). (Table 1, Fig. 2)
hyaluronidase (1500 IU) weekly for 6 weeks. They were At baseline, Group A patients had a mean score of
also prescribed Cap SM Fibro twice daily for 3 months. 0.16  0.08 cm for cheek exibility. Patients showed an
Same baseline parameters were measured and recorded at increase in cheek exibility after 1 month with mean value of
an interval of 1, 2, and 3 months by the same examiner 0.31  0.06 cm (138.3%). After 2nd and 3rd month, mean
who measured the baseline values and was unaware of the values were 0.38  0.05 cm (26.7%) and 0.43  0.05 cm
treatment received by the study subjects. (13.7%), respectively. The results were statistically signi-
cant (P < 0.001) at the end of 3rd month for this group. Group
Statistical analysis B patients had noticeable change from baseline to the end of
Statistical analysis was carried out using SPSS software 1st month with increase in mean value from 0.29  0.07 cm
version 22 (IBM corp). Intragroup comparison for the study to 0.41  0.09 cm (46.5%). A gradual increase was seen
parameters such as burning sensation, interincisal mouth after 2nd and 3rd month with mean scores of 0.47  0.10 cm
opening, cheek exibility, and tongue protrusion at different (17.7%) and 0.53  0.10 cm (12.3%), respectively. Group B

J Oral Pathol Med


Aloe vera for the treatment of OSMF
Anuradha et al.

<0.001*
0.002*
P-Value
0.12
0.31
1.05
0.56

0.61
After 3rd month

0.1
Group-B




1.85
3.11
0.53
3.21
0.51
0.50
0.05
0.61
Group-A




1.48
3.42
0.43
3.77
Figure 1 Mean percentage reduction in VAS scores for burning sensa-
<0.001*

<0.001*
<0.001*
P-Value

tion.
0.01*
1.85
0.59

0.59
After 2nd month

0.1
Group-B




3.42
2.95
0.47
3.09
0.65
0.53
0.05
0.65
Group-A




3.34
0.38
3.65
1.8
<0.001*

0.004*
P-Value

0.01*
0.06

Figure 2 Mean percentage increase in interincisal mouth opening.


Table 1 Comparison of mean values of study parameters between study groups at different time intervals

1.04
0.61
0.09
0.62
After 1st month
Group-B




5.27
2.77
0.41
2.95
1.12
0.57
0.06
0.62
Group-A




3.52
3.20
0.31
3.47
P-Value

0.004*
0.02*
0.60
0.10
1.24
0.63
0.07
0.64
Group-B
At Baseline





7.58
2.57
0.29
2.79

Figure 3 Mean percentage increase in cheek exibility.


1.35
0.57
0.08
0.67
Group-A





also showed statistically signicant (P < 0.001) increase in


7.40
2.9
0.16
3.22

cheek exibility. (Table 1, Fig. 3)


Statistically signicant (P < 0.001) results were also seen
InterIncisal Mouth Opening

for both the groups for tongue protrusion. In Group A, the


mean values for tongue protrusion were 3.22  0.67 cm,
*Statistically signicant.

3.47  0.62 cm, 3.65  0.65 cm, and 3.77  0.61 cm,
Tongue Protrusion
Burning Sensation

respectively, where as in Group B, the mean scores were


Cheek Flexibility

2.79  0.64 cm, 2.95  0.63 cm, 3.09  0.59 cm, and
3.21  0.61 cm, respectively. Overall mean percentage of
Variables

improvement was 18.5% in Group A and 16.4% in Group


B. (Table 1, Fig. 4)

J Oral Pathol Med


Aloe vera for the treatment of OSMF
Anuradha et al.

4
The reduction in burning sensation can be attributed to
the anti-inammatory properties of aloe vera. The prob-
able mechanisms for the anti-inammatory action of aloe
vera as discussed in the published literature are as
follows:
1 Carboxypeptidases in aloe inactivate bradykinin
which is a principle participant of inammation (16)
2 Magnesium lactate present in aloe vera inhibits
histidine decarboxylase, thereby preventing the forma-
tion of histamine from histidine in mast cells (17)
3 Salicylates are by-products of amodin, aloe-emodin,
and aloin (18)
Figure 4 Mean percentage increase in tongue protrusion.
4 Peptidase bradykinin isolated from aloe vera breaks
down bradykinin, an inammatory substance that
Comparison of different study parameters at different induces pain (19)
intervals between groups revealed a remarkable decrease 5 Reduction in leukocyte adhesion and TNF-a level
(P < 0.001) in burning sensation in Group A in comparison result in inhibition of inammatory process (20)
with Group B at the end of 1st month. Interincisal mouth The most pathognomonic feature of OSMF is the reduced
opening did not differ signicantly (P = 0.06) between the 2 mouth opening, which is attributed to increased collagen
groups at the end of 1st month. Increase in cheek exibility production and decreased breakdown of collagen. Increased
and tongue protrusion was signicantly (P = 0.004 & 0.01, brosis is due to increased cross-linking of collagen through
respectively) higher in Group A subjects than in Group B at up-regulation of lysyl oxidase activity.
the end of 1st month. At the end of 2nd month, all the Till date, no treatment protocol for OSMF has restored
parameters showed a statistically signicant (P < 0.001) the mouth opening to normal; however, an improvement of
improvement in Group A compared with the subjects of few millimeters has been observed. A statistically signicant
Group B. At the end of 3rd month, the decrease in burning improvement in interincisal mouth opening was observed
sensation and increase in mouth opening did not differ for both the groups in the present study. The mean
signicantly (P = 0.12, 0.31) between both the groups. The percentage increase was 19.1% and 23.1% improvement,
improvement in cheek exibility and tongue protrusion respectively, in Group A and Group B at the end of the
differed signicantly (P < 0.001) between Group A and study. The difference in mouth opening between the groups
Group B. (Table 1) was not statistically signicant at the end of 1st and 3rd
month. Group B showed a statistically signicant improve-
Discussion ment in comparison to Group A at the end of the 2nd month.
Group A and Group B showed statistically signicant
It is a known fact that once oral submucous brosis has increase in cheek exibility at the end of the study. The
developed, there is neither regression nor any effective overall mean percentage of improvement was higher in
treatment till date (1). Cochrane review (2008) on treatment Group A (229%) than in Group B (90.7%).
of OSMF stated that the paucity of data and poor In the present study, increase in tongue protrusion in
methodological quality of studies indicate a lack of reliable Group A and Group B was statistically signicant. A
evidence for the effectiveness of any specic intervention gradual increase was noted in both the groups at each visit.
for the management of this disease (7). Aloe vera has many constituents which have varied
Aloe vera is widely used for its medicinal properties. It has actions, the mechanisms that can substantiate the improve-
been studied for the treatment of oral mucosal conditions ment of mouth opening, cheek exibility and tongue
such as mRAS (8), lichen planus (9), burning mouth protrusion are as follows:
syndrome (10), and OSMF (1115). In all these studies,
aloe vera has been used in gel form for topical application. To 1 An increased synthesis of hyaluronic acid and der-
our knowledge, till now there is no published data regarding matan sulfate in the granulation tissue of a healing
the use of aloe vera systemically in the management of wound (21)
OSMF. The present study is the rst study to evaluate the 2 Aloe vera stimulates the broblasts which produce the
efcacy of aloe vera used both topically and systemically for collagen and elastin bers that make the skin more
the treatment of OSMF. elastic (22)
Burning sensation is often the common complaint of However, there are other studies that show an increase in
patients with OSMF and is caused by epithelial atrophy broblast activities resulting in increased collagen content.
preceded by juxtaepithelial inammation. In the present
study, both Group A and Group B subjects showed a 1 Topical application of aloe vera derivative, allantoin
statistically signicant reduction in burning sensation. Mean gel stimulates broblast activity, and collagen prolif-
percentage reduction in VAS score for Group A and Group eration (23)
B was 79.5% and 75%, respectively. The reduction in 2 Mannose-6-phosphate component of the gel has been
burning sensation was rapid in Group A, whereas the credited with a wound healing effect. Fibroblast
reduction obtained in Group B subjects was more gradual. proliferation was also observed in vitro and in vivo

J Oral Pathol Med


Aloe vera for the treatment of OSMF
Anuradha et al.

5
following treatment with carrisyn, a component of aloe
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J Oral Pathol Med