J Oral Pathol Med
doi: 10.1111/jop.12463
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
disease, treatment of which has largely been symp-
tomatic. Aloe vera has immunomodulatory, anti-inflam-
matory, wound healing, antioxidant, and antineoplastic
activities. All such properties of aloe vera suggest the
possibility of its use in the management of oral submu-
cous fibrosis.
METHODS: Seventy-four patients of oral submucous
fibrosis were randomly divided into 2 groups. Group A
patients were treated with systemic (juice) and topical
aloe vera (gel) for 3 months. Group B patients were
treated with intralesional injection of hydrocortisone and
hyaluronidase for 6 weeks with antioxidant supplements
for 3 months. Patients were assessed for reduction in
burning sensation and increase in mouth opening, cheek
flexibility, and tongue protrusion at an interval of 1, 2, and
3 months.
RESULTS: Both the groups showed statistically signifi-
cant improvements in all the study parameters at the end
of study period (P < 0.001). The clinical response to aloe
vera was comparable to that of intralesional injections of
hydrocortisone and hyaluronidase with antioxidant sup-
plementation.
CONCLUSION: The study concludes that aloe vera can
be an alternative, safe, and effective treatment regime in
the management of oral submucous fibrosis. Long-term
follow-up studies with larger sample size are recom-
mended.
J Oral Pathol Med (2016)
Keywords: aloe vera; hyaluronidase; hydrocortisone; OSMF
Correspondence: Ardra Anuradha, Department of Oral Medicine and
Radiology, The Oxford Dental College and Hospital, Bangalore, Karnataka,
India. Tel: +91 7406146411, Fax: 080 202573204656,
E-mail: dr_ardra@yahoo.co.in
Ethical committee: Institutional Review Board of the Oxford Dental
College and Hospital.
Accepted for publication April 27, 2016
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop
Introduction
Oral submucous brosis (OSMF) is a well-recognized
potentially malignant disorder of the oral cavity caused by
chewing areca nut which is more prevalent in South Asian
countries. The disease is characterized by epithelial atrophy
and formation of submucosal brous bands resulting in
reduced mouth opening (1).
The various treatment protocols that have been tried to
improve the signs and symptoms of OSMF include
intralesional injections of corticosteroids, placental extracts,
and hyaluronidase alone or in combination, IFN-a, oral
administration of peripheral vasodilators, immune milk,
turmeric, lycopene, and micronutrient supplementation.
Various physiotherapeutic modalities have also shown
favorable results (2). Steroids till date are the most accepted
modality of treatment for OSMF. The side effects of steroids
and the local discomfort caused by the intralesional injection
necessitate the search of a newer treatment regimen for
OSMF.
Aloe vera is considered as an adaptogen. An adaptogen
is a substance that invigorates or strengthens the system.
Specically, the term applies to herbs that maintain health
by increasing the bodys ability to adapt to environmental
and internal stressors (3). Aloe vera contains 75 poten-
tially active constituents: vitamins, enzymes, minerals,
sugars, lignin, saponins, salicylic acids, and amino acids
(4). The vitamins present are vitamin A (beta-carotene),
C, and E, which are antioxidants and help to neutralize
free radicals. Aloe vera contains nine enzymes: aliase,
alkaline phosphatase, amylase, bradykinase, carboxypepti-
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
management of OSMF.
Hence, this study was designed to evaluate the efcacy of
systemic and topical aloe vera in the treatment of OSMF. It
also compared the efcacy of aloe vera with intralesional
injections of hydrocortisone, hyaluronidase with antioxidant
supplements.
 Aloe vera for the treatment of OSMF
Anuradha et al.
2
Material and methods
This study was conducted in the Department of Oral
Medicine and Radiology at the Oxford Dental College and
Hospital, Bangalore, India, between November 2013 and
August 2015. Approval from the institutional ethical
committee was obtained for the study. Patients with OSMF
(Stage 2 according to Pindborg) (5) were enrolled in the
study. Pregnant women, lactating mothers, patients with
known history of hypersensitivity to aloe vera, and those
who had received prior treatment for OSMF were excluded.
Seventy-four patients who were ready to quit the habit and
accept regular follow-up treatment protocol were included
in the study. An informed consent was obtained from all the
patients after the nature of the study, and its procedures were
explained. A thorough clinical examination was carried out,
and the following parameters were measured and recorded
by an independent examiner.
1 The intensity of burning sensation was recorded using
a Numerical Rating Visual Analogue Scale.
2 The interincisal mouth opening was measured using
a metal scale and divider from the mesioincisal
angle of upper central incisor to the mesioincisal
angle of lower central incisor and recorded in
millimeters.
3 Cheek exibility (CF) was measured according to the
method described by Bailoor and Nagesh (6). Two
points were marked, one on each side of the face at 1/
3rd the distance from angle of the mouth on a line
joining the tragus of the ear and the angle of the mouth.
The distance measured between these two points was
V2. The subject was asked to blow his cheek fully, and
the distance measured between the same two points
was V1. CF = V2 V1.
4 Tongue protrusion was assessed from normal mesioin-
cisal angle of upper central incisor to the tip of the
tongue when maximally extended with mouth wide
open.
The patients were randomly divided into 2 groups
(Group A & Group B). Group A patients were given pure
aloe vera gel and pure aloe vera juice (Processed and
manufactured by Hemant Sai, Sun Vision Company, Neel
RLI Pvt Ltd). They were instructed to drink 30 ml of aloe
vera juice twice daily before food and to apply 5 mg
(apprx 1 scoop) of aloe vera gel over the lesion 3 times per
day for 3 months. Group B patients were given intrale-
sional injections of hydrocortisone acetate 25 mg/ml and
hyaluronidase (1500 IU) weekly for 6 weeks. They were
also prescribed Cap SM Fibro twice daily for 3 months.
Same baseline parameters were measured and recorded at
an interval of 1, 2, and 3 months by the same examiner
who measured the baseline values and was unaware of the
treatment received by the study subjects.
Statistical analysis
Statistical analysis was carried out using SPSS software
version 22 (IBM corp). Intragroup comparison for the study
parameters such as burning sensation, interincisal mouth
opening, cheek exibility, and tongue protrusion at different
J Oral Pathol Med
time intervals was made using repeated measures of ANOVA.
Comparison of various study parameters between the two
study groups was made using Students unpaired t-test at
different visits.
Results
The study comprised of 63 male and 11 female subjects.
The mean age of study population was 32.7  10.3 years.
Gutkha chewing was the most prevalent habit noted
(41.9%). 8.1% of subjects had habit of chewing gutkha,
areca nut, and smoking. 2.7% of the subjects reported to
have only areca nut chewing habit. Another 2.7% of
subjects had habit of gutkha chewing, smoking, and alcohol.
1.4% patients did not have any habits. 48.6% of subjects
had habit of <5 years, followed by 35.2% with 510 years
of habit and 16.2% with >10 years of habit.
Of the 74 study subjects, 23 were lost to follow-up at
different time intervals. Comparison of different study
parameters at baseline between study groups revealed no
signicant difference for burning sensation and interincisal
mouth opening, but a signicant difference was observed
for cheek exibility and tongue protrusion. (Table 1)
Patients in Group A, at baseline, had mean VAS score of
7.40  1.35 for burning sensation. At the end of 1st month,
improvement of 3.52  1.12 (52.5%) was noticed. At the
end of 2nd and 3rd month, the improvement in VAS score
was 1.80  0.65 (46.7%) and 1.48  0.51 (13.3%),
respectively. In Group B, the improvement in VAS score
for burning sensation at different intervals from baseline to
end of 3rd month was 7.58  1.24, 5.27  1.04 (31.7%),
3.42  1.10 (35.5%) and 1.85  1.05 (47.5%), respec-
tively. Both the groups showed a statistically signicant
(P < 0.001) reduction in burning sensation at the end of the
study period. (Table 1, Fig. 1)
Mean interincisal mouth opening recorded for Group A
subjects at baseline was 2.90  0.57 cm. Patients showed an
increase in mouth opening with mean of 3.20  0.57 cm
(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
2nd and 3rd month, respectively. In group B,
2.57  0.63 cm was the mean score for mouth opening
recorded at baseline. Patients in this group showed an increase
in mouth opening with mean value of 2.77  0.61 cm
(8.4%), 2.95  0.59 cm (7.2%), and 3.11  0.56 cm
(5.0%) after 1st, 2nd, and 3rd month, respectively. This
increase in mean values for mouth opening at the end of 3rd
month for both the groups was statistically signicant
(P < 0.001). (Table 1, Fig. 2)
At baseline, Group A patients had a mean score of
0.16  0.08 cm for cheek exibility. Patients showed an
increase in cheek exibility after 1 month with mean value of
0.31  0.06 cm (138.3%). After 2nd and 3rd month, mean
values were 0.38  0.05 cm (26.7%) and 0.43  0.05 cm
(13.7%), respectively. The results were statistically signi-
cant (P < 0.001) at the end of 3rd month for this group. Group
B patients had noticeable change from baseline to the end of
1st month with increase in mean value from 0.29  0.07 cm
to 0.41  0.09 cm (46.5%). A gradual increase was seen
after 2nd and 3rd month with mean scores of 0.47  0.10 cm
(17.7%) and 0.53  0.10 cm (12.3%), respectively. Group B
 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
Figure 4 Mean percentage increase in tongue protrusion.
Comparison of different study parameters at different
intervals between groups revealed a remarkable decrease
(P < 0.001) in burning sensation in Group A in comparison
with Group B at the end of 1st month. Interincisal mouth
opening did not differ signicantly (P = 0.06) between the 2
groups at the end of 1st month. Increase in cheek exibility
and tongue protrusion was signicantly (P = 0.004 & 0.01,
respectively) higher in Group A subjects than in Group B at
the end of 1st month. At the end of 2nd month, all the
parameters showed a statistically signicant (P < 0.001)
improvement in Group A compared with the subjects of
Group B. At the end of 3rd month, the decrease in burning
sensation and increase in mouth opening did not differ
signicantly (P = 0.12, 0.31) between both the groups. The
improvement in cheek exibility and tongue protrusion
differed signicantly (P < 0.001) between Group A and
Group B. (Table 1)
Discussion
It is a known fact that once oral submucous brosis has
developed, there is neither regression nor any effective
treatment till date (1). Cochrane review (2008) on treatment
of OSMF stated that the paucity of data and poor
methodological quality of studies indicate a lack of reliable
evidence for the effectiveness of any specic intervention
for the management of this disease (7).
Aloe vera is widely used for its medicinal properties. It has
been studied for the treatment of oral mucosal conditions
such as mRAS (8), lichen planus (9), burning mouth
syndrome (10), and OSMF (1115). In all these studies,
aloe vera has been used in gel form for topical application. To
our knowledge, till now there is no published data regarding
the use of aloe vera systemically in the management of
OSMF. The present study is the rst study to evaluate the
efcacy of aloe vera used both topically and systemically for
the treatment of OSMF.
Burning sensation is often the common complaint of
patients with OSMF and is caused by epithelial atrophy
preceded by juxtaepithelial inammation. In the present
study, both Group A and Group B subjects showed a
statistically signicant reduction in burning sensation. Mean
percentage reduction in VAS score for Group A and Group
B was 79.5% and 75%, respectively. The reduction in
burning sensation was rapid in Group A, whereas the
reduction obtained in Group B subjects was more gradual.
J Oral Pathol Med
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)
4 Peptidase bradykinin isolated from aloe vera breaks
down bradykinin, an inammatory substance that
induces pain (19)
5 Reduction in leukocyte adhesion and TNF-a level
result in inhibition of inammatory process (20)
The most pathognomonic feature of OSMF is the reduced
mouth opening, which is attributed to increased collagen
production and decreased breakdown of collagen. Increased
brosis is due to increased cross-linking of collagen through
up-regulation of lysyl oxidase activity.
Till date, no treatment protocol for OSMF has restored
the mouth opening to normal; however, an improvement of
few millimeters has been observed. A statistically signicant
improvement in interincisal mouth opening was observed
for both the groups in the present study. The mean
percentage increase was 19.1% and 23.1% improvement,
respectively, in Group A and Group B at the end of the
study. The difference in mouth opening between the groups
was not statistically signicant at the end of 1st and 3rd
month. Group B showed a statistically signicant improve-
ment in comparison to Group A at the end of the 2nd month.
Group A and Group B showed statistically signicant
increase in cheek exibility at the end of the study. The
overall mean percentage of improvement was higher in
Group A (229%) than in Group B (90.7%).
In the present study, increase in tongue protrusion in
Group A and Group B was statistically signicant. A
gradual increase was noted in both the groups at each visit.
Aloe vera has many constituents which have varied
actions, the mechanisms that can substantiate the improve-
ment of mouth opening, cheek exibility and tongue
protrusion are as follows:
1 An increased synthesis of hyaluronic acid and der-
matan sulfate in the granulation tissue of a healing
wound (21)
2 Aloe vera stimulates the broblasts which produce the
collagen and elastin bers that make the skin more
elastic (22)
However, there are other studies that show an increase in
broblast activities resulting in increased collagen content.
1 Topical application of aloe vera derivative, allantoin
gel stimulates broblast activity, and collagen prolif-
eration (23)
2 Mannose-6-phosphate component of the gel has been
credited with a wound healing effect. Fibroblast
proliferation was also observed in vitro and in vivo

following treatment with carrisyn, a component of aloe
vera (24)
3 Aloe vera not only increases collagen content of a
wound but also changes collagen composition and
increases the degree of collagen cross-linking (25)
These observations suggest a further need of in vitro
studies on the effect of aloe vera on broblasts of OSMF
patients.
The results of the present study can be compared with
the preliminary study carried out by Sudarsan et al. in
2012. They have reported an improvement in various
parameters such as burning sensation, mouth opening,
cheek exibility, and tongue protrusion using aloe vera on
OSMF patients. Reduction in VAS score for burning
sensation was 58%, and improvement in mouth opening,
cheek exibility, and tongue protrusion was 5.1%, 0.06%
and 3.1%, respectively, in this preliminary study, where as
in the present study, the mean percentages were 79.5%,
19.1%, 229%, and 18.5%, respectively. Alam et al. in
2013 used aloe vera as an adjunct with dexamethasone,
hyaluronidase, and showed statistically signicant
improvement in various parameters in OSMF patients.
They also reported aloe vera to be useful in the prevention
of relapse of the improved mouth opening achieved after
surgery. The results of the above-mentioned studies are in
accordance with our study, whereas different studies by
Patil S et al. in 2014 and 2015 have reported better results
in various parameters for OSMF patients with the use of
oxitard, lycopene, and spirulina when compared with aloe
vera.
The improvement recorded for all the parameters was
high in the present study in comparison with the other
studies on aloe vera for treatment of OSMF. The present
study used both topical and systemic aloe vera, which could
have been the reason for the better treatment response that
was observed. No serious side effects were reported in
patients receiving aloe vera. Only one patient complained of
an increase in appetite. The study subjects of the intrale-
sional injection group experienced local pain and soreness.
Increased patient compliance for Group A was another
signicant observation in the study.
Conclusion
In the present study, aloe vera showed comparable clinical
response to that of combination of intralesional injections of
hydrocortisone, hyaluronidase, and antioxidant supple-
ments. No serious side effects were reported. Ease of
availability, safety of use, cost-effectiveness, and non-
invasiveness attributes of aloe vera make it an alternative,
effective choice of treatment regime in the management of
OSMF. Further studies involving a larger sample size with
longer period of treatment follow-up are recommended.
Financial support
None.
Conflict of interest
None.
Aloe vera for the treatment of OSMF
Anuradha et al.
5
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J Oral Pathol Med