A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available

Abstract

The word “Aphthous” originated from the Greek word “aphtha”, the meaning of which is ulcer Aphthous Stomatitis
is one of most common ulcerative disease associated mainly with the oral mucosa characterized by the extremely
painful, recurring solitary, multiple ulcers in the upper throat and oral cavity. The disease is known by lay public and
professionals by several other names such as cold sores, canker sores, recurrent aphthous stomatitis (RAS) and
recurrent aphthous ulcers (RAU). These are quite painful; may lead to difficulty in eating, speaking and swallowing
thus may negatively affects the life standard of patient’s. Aphthous stomatitis is divided into three varieties: minor
aphthae, major aphthae and herpetiform. The precise etiopathogenesis of aphthous stomatitis is not entirely
disclosed. The factors responsible for aphthous ulcers are genetic predisposition, mechanical injury, microelement
and vitamin B12 deficiencies, increased oxidative stress, food allergies, microbial factors, anxiety, hormonal defects,
and systemic diseases. In spite of much clinical and research observation, the root causes continue to exist was
imperfectly understood. The ulcers are unavoidable, and therapy is symptomatic. The goals of therapy are 3-fold: (a)
control the ulcer pain, (b) stimulate healing of ulcer and (c) prevent recurrence. There are several treatment options
both local and systemic for management of aphthous stomatitis. No single treatment has been found to be
consistently effectual in all patients with RAU, it may be necessary to try several types of medications for optimum
response and prevention of recurrence. The present review article aims to summarize the type etiopathogenesis,
management and treatment options for RAS.

Full text

A Comprehensive Review on Aphthous Stomatitis, its Types, Management
and Treatment Available
Sharma D1,2* and Garg R3
1Ph.D. Research Scholar, I K Gujral Punjab Technical University, Jalandhar, Punjab, India
2Assistant Professor, Department of Pharmaceutics, Rayat Bahra Institute of Pharmacy, Hoshiarpur, Punjab, India
3Associate Professor, Department of Pharmaceutics, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab, India
*Corresponding author: Deepak Sharma, Ph.D. Research Scholar, IKG Punjab Technical University, Jalandhar, Punjab, India, Tel: 919988907446; E-mail:
deepakpharmacist89@yahoo.com
Rec date: August 27, 2018; Acc date: September 24, 2018; Pub date: October 01, 2018
Copyright: © 2018 Sharma D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The word “Aphthous” originated from the Greek word “aphtha”, the meaning of which is ulcer Aphthous Stomatitis
is one of most common ulcerative disease associated mainly with the oral mucosa characterized by the extremely
painful, recurring solitary, multiple ulcers in the upper throat and oral cavity. The disease is known by lay public and
professionals by several other names such as cold sores, canker sores, recurrent aphthous stomatitis (RAS) and
recurrent aphthous ulcers (RAU). These are quite painful; may lead to difficulty in eating, speaking and swallowing
thus may negatively affects the life standard of patient’s. Aphthous stomatitis is divided into three varieties: minor
aphthae, major aphthae and herpetiform. The precise etiopathogenesis of aphthous stomatitis is not entirely
disclosed. The factors responsible for aphthous ulcers are genetic predisposition, mechanical injury, microelement
and vitamin B12 deficiencies, increased oxidative stress, food allergies, microbial factors, anxiety, hormonal defects,
and systemic diseases. In spite of much clinical and research observation, the root causes continue to exist was
imperfectly understood. The ulcers are unavoidable, and therapy is symptomatic. The goals of therapy are 3-fold: (a)
control the ulcer pain, (b) stimulate healing of ulcer and (c) prevent recurrence. There are several treatment options
both local and systemic for management of aphthous stomatitis. No single treatment has been found to be
consistently effectual in all patients with RAU, it may be necessary to try several types of medications for optimum
response and prevention of recurrence. The present review article aims to summarize the type etiopathogenesis,
management and treatment options for RAS.
Keywords: Aphthous stomatitis; Etiopathogenesis; Topical and
systemic therapy; Symptomatic treatment
Introduction
e word “Aphthous” originated from the Greek word “aphtha”, the
meaning of which is ulcer. Aphthous stomatitis is one of most common
ulcerative disease associated mainly with the oral mucosa
characterized by the extremely painful, recurring solitary, multiple
ulcers in the upper throat and oral cavity. ese types of ulcers are
usually small, multiple, ovoid or round with circumscribed margins
which are having gray or yellow oors and are encompassed by
erythematous haloe [1,2]. It was delineated in 400 B.C by Hippocrates;
the disease is known by lay public and professionals by several other
names such as cold sores, canker sores, recurrent aphthous stomatitis
(RAS), and recurrent aphthous ulcers (RAU). is is the most
prevailing oral ulcerative disorder aecting up to 10-20% of our
inhabitants and recurrence rate of 3 months in 50% of population [3].
ese are quite painful that leads to diculty in eating, speaking and
swallowing that’s why it negatively aects the patient’s quality of life
[4]. Aphthous stomatitis is divided into three varieties: minor aphthae,
major aphthae and herpetiform. Minor aphthae also called as Miculiz’s
aphthae, is one of the most common variant that constitute 75-85% of
all RAS cases. ese types of ulcers have size usually less than 1 cm (10
mm) and heal without leaving scarring within 10 to 14 days. is type
is commonly found in the non-keratinized mucosal surfaces like
buccal mucosa, labial mucosa, and mouth oor as shown in Figure 1.
Major aphthae also called as Sutton’s disease; usually exceeds 1 cm (10
mm) cause deeper ulceration thus leave scar. It constitutes only 10-15%
of RAS cases. ese ulcers may remain about 10-20 days and may take
months also. e usual sites are throat, lips and so palate as shown in
Figure 2. e Herpetiform is least common variant of RAS that
constitutes only 07-10% of RAS cases. Ulcer size is very small
measuring 2-3 mm in diameter; numerous in numbers (around 100
ulcers at once) can fuse together producing large irregular lesions that
last for 7-10 days without leaving scars as shown in Figure 3 [5-7].
Figure 1: Minor Aphthous stomatitis.
J
o
u
r
n
a
l
o
f
D
e
v
e
l
o
p
i
n
g
D
r
u
g
s
ISSN: 2329-6631
Journal of Developing Drugs
Sharma and Garg, J Develop Drugs 2018, 7:2
DOI: 10.4172/2329-6631.1000189
Review Article Open Access
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

Figure 2: Major Aphthous stomatitis.
Figure 3: Herpetiform Aphthous stomatitis.
Etiopathogenesis
e precise etiopathogenesis of aphthous stomatitis is not fully
disclosed. e potential factors responsible for aphthous ulcers are
genetic predisposition, mechanical injury, microelement and vitamin
B12 deciencies, increased oxidative stress, food allergies, microbial
factors, anxiety, hormonal defects, systemic diseases (e.g., ulcerative
colitis, celiac disease, AIDS, Crohn’s disease) [8]. Each of them was
described below:
Genetic predisposition: For the development of aphthous stomatitis
genetic predisposition is responsible for about 40% of patients that
have family history and these persons develop ulcers in earlier age
which are of severe in nature [9].
Mechanical injury: Mechanical injury because of local anesthetic
injections, dental treatments, sharp tooth and injury due to tooth
brush may susceptible to the occurrence of recurrent aphthous
ulceration [10]. Lack of adequate saliva to lubricate and protect the
oral mucosa from injury and antigenic exposure may rise to the
development of RAS [11].
Microelement and vitamin B12 deciencies: Deciencies of vitamin
B12, folic acid, and iron may contribute to development of RAS. Lack
of these microelements is two times more usual in these persons as
compared to controls. Contradictory detections in dierent
investigations linking the relationship of hematinic deciency and RAS
have been elaborated because of alter genetic backgrounds and dietary
habits of the study population [12].
Stress: Stress and psychological imbalance have been linked with
recurrent aphthous ulcers. Patient oen manifest increased stress with
inception of aphthous ulcers and several studies have reported higher
occurrence. Fergusson et al. suggested that antidepressant therapy
reduces the incidence of ulcers. Several mechanisms can be postulated
for a cause and eect relationship between trait anxiety and recurrent
aphthous stomatitis. ere could be an as yet unknown biochemical
eect or trait anxiety that could lead to parafunctional habits including
lip and cheek biting and physical trauma which might initiate the
ulcerative process in susceptible individual [13,14].
Food allergies: Food such as chocolate, coee, almonds, cereals,
peanuts, strawberries, tomatoes, cheese and wheat our containing
gluten may be responsible for aphthous ulcers [15].
Microbial factors: ere is limited consistent conrmation to assist
the presumption that RAS constitutes an infectious disease. In
particular from investigations to examine whether there might be an
association between previously suspect L-forms of streptococci and
RAS or the adenoviruses, herpes simplex virus (HSV), varicella- zoster
virus or cytomegalovirus and RAS, the accessible proof indicates that
none of these micro-organisms appears to be directly responsible for
RAS in spite of continued speculation about their feasible role. One
should record that an antiviral agent, acyclovir provide no valuable
outcome in preventing or reducing episodic outburst of the condition,
which set out to weaken logic in favor of a possible viral causation for
RAS. From irregular unscientic cases in which patients outline a
noticeable reconcilable time related association between their
aphthous outbursts and an immediately antecedent reactivated
(recurrent) HSV infection, it is tempting to postulate that in a narrow
subset of individuals who get RAS, the herpes virus may serve as an
antigenic ‘trigger’ that initiates the cascade of immunologic events that
result in ulceration. In a limited subset of RAS patients, it is possible
that this is actually the case. Presumably, such patients would benet
from appropriate therapeutic and prophylactic antiviral therapy,
coupled with treatments specically aimed at lessening the severity and
frequency of the RAS episodes by modulating their supposedly
heightened immune responses to the viral ‘trigger’. Such therapeutic
strategies probably would be best carried out in consultation with an
infectious disease specialist. It must be emphasized, however, that
regarding most aphthous patients, any suggestion of a causative nexus
between RAS and HSV seems to represent unsubstantiated conjecture
rather than proven fact [16].
Tobacco smoking: Nonsmokers persons usually are more prone to
RAS and there is a lower occurrence and extremity of RAS among
heavy smokers as compared to moderate smokers. Few patients report
an onset of RAS aer cessation of smoking, while others report control
on smoking re-initiation. e usage of smokeless tobacco is linked with
a remarkably lower universality of RAS. e tables containing Nicotine
also seems to manage the frequency of RAS [17].
Immunopathogenesis: RAS with primary immunologic
abnormalities result into altered immunoregulatory balances. For
example, there are rise in antibody dependent cell cytotoxicity and
higher levels of serum immunoglobulins in patients with RAS
Lymphocytes from patients with serious RAS demonstrate growing
numbers of T-helper/inducer cells, decreased numbers of T-
suppressor/inducer cells, and depressed responses to mitogens.
Activated T-lymphocytes aggregate in the periphery of RAS lesions
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 2 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

conrming the hypothesis that RAS represents an activated cell
mediated immune response. Immunohistochemical studies of
lymphocyte subsets in aphthous ulcers of HIV-seronegative patients
and HIV-seropositive patients have yielded similar ndings, which
strongly indicate that these ulcers represent a cell-mediated
immunologic dysfunction in which inltrating T-lymphocytes play a
primary role. It seems likely that in genetically predisposed persons,
antibody-dependent cellular cytotoxicity mad local immune complex-
related reactions are involved in the immunopathogenesis of RAS, but
the precipitating factors are unknown. Unfortunately, to date no
consistent theory of immunopathogenesis has been accepted. is
information will be useful in the future so that more eective
treatment and preventive modalities can be identied [18].
Hormonal defects: It appears from dierent and sometimes
conicting studies that a minor subset of women with RAU have
cyclical oral ulceration related to the onset of menstruation or the
luteal phase of the menstrual cycle. Complete remission during
pregnancy has been reported with exacerbation occurring in the
puerperium. Although 10% of women have been reported to have had
their rst episode of RAU between the ages of 50-59 and more recent
work has not uncovered an association between RAU and the
menopause [19].
Drugs: Drugs such as non-steroidal anti-inammatory drugs
(NSAIDs e.g., Diclofeanac phenylacetic acid and proprionic acid) can
cause oral ulcers identical to those of RAU, accompanied with genital
ulceration or only oral ulcers in the case of piroxicam. A relationship
between beta-blockers and aphthous ulcers was also proposed. ese
types of ulcers commonly occur as an adverse side eect and fade away
when the usage of drug is discontinued [19].
Systemic diseases: Behcet’s disease (BD) is a multisystemic, chronic,
relapsing vasculitis that aects nearly all organs and systems. It is
associated with multiple oral, genital ulcers, arthritis, hematemesis,
melena and epigastric pain as predominant manifestations. Seung-Ho
described that RAS and BD had similar presenting symptoms like oral
lesions and abdominal pain. ere were no clinical, endoscopical,
histopathological or serological dierence between patients with
intestinal BD, RAS and healthy volunteers in anti-neutrophil
cytoplasmic antibodies [20]. Celiac disease (CD) is caused by gluten
sensitivity of the small intestines. According to Selim the CD
prevalence (40%) in patients with RAS is higher than in the normal
population. It is also described that RAS may be the presenting sign of
the disease and may be used as a marker for the CD [21]. e intraoral
involvement in Crohn’s disease is observed in approximately 9% of
cases and oral inammation precedes intestinal symptoms in about
60% of these patients. Hence it is important to consider the dierential
diagnosis of Crohn’s disease in subjects with intestinal symptoms and
RAS [22].
Management and treatment of aphthous stomatitis
In spite of much clinical and research observation, the root causes
continue to exist was imperfectly understood. e ulcers are
unavoidable and therapy is symptomatic. Various local and systemic
factors are correlated with these conditions and there is evidence that a
genetic and immunopathogenic form a basis for recurrent aphthous
ulceration. ere is no specic treatment for RAS, and management
strategies depend on the symptoms, duration, and severity [18]. ere
is abundance of therapies for recurrent aphthous ulcers. e goals of
therapy are 3-fold: (a) control the ulcer pain, (b) stimulate healing of
ulcer and (c) prevent recurrence. For the determination of appropriate
treatment, the medical history of patient, pain severity, outburst/
frequency and medication tolerance ability of patient is some of factors
have to be considered to start the treatment. It is very important that
all the susceptible factors should be treated or ruled out before starting
specic treatment for RAS. As there is no single treatment is available
which is uniformly eective in RAS, it is important to explore a
spectrum of therapies to validate a denitive treatment strategy [23].
e First choice for aphthous stomatitis treatment is the topical agents
because they are cheap, eective and safe. e problem with topical
agents is obtaining eective drug delivery, because substances applied
to mucosal surfaces are inevitably rubbed or rinsed away. Topical
management of aphthous stomatitis may not be enough for the
constantly recurring and severe ulcerations. In those cases, systemic
medications are employed. e rst line therapy options consists of
antiseptics and anti-inammatory drugs/analgesics and second line
therapy options include systemic immunomodulator, systemic
antibiotic and systemic corticosteroids as shown in Table 1[24, 25].
First Line Therapy
Topical Antiseptic Chlorhexidine Gluconate, Triclosan
Topical/ Systemic Anti-inflammatory/ Analgesic Benzydamine Hydrochloride, Diclofenac
Topical Anesthetic Lidocaine, Benzocaine
Topical antibiotic Chlortetracycline, Doxycycline
Topical corticosteroids Hydrocortisone hemisuccinate, Triamcinolone acetonide, Betamethasone valerate, Beclometasone dipropionate,
Budesonide, Clobetasol
Second Line Therapy
Systemic Immunomodulator Levamisole, Colchicine, Hydrocortisone and Triamcinolone, Thalidomide, Dapsone, Pentoxphylline, 5-Amino salicylic
acid, Azathioprine, Prostaglandin E2
Systemic Antibiotic Penicillin G Potassium
Systemic Corticosteroids Prednisone
Table 1: erapeutic Options for Aphthous stomatitis.
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 3 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

First Line erapy
Topical therapy
When there is recurrent incidence of aphthous ulcers are occurred
in limited number that are either minor or major, closely opposed to
one another and scattered on readily available oral surfaces such as the
labial or vestibular mucosa or the anterior portion of the tongue, rst-
line therapeutic management based on conservative topical therapy
should be involve [26].
Topical gels, creams and pastes: Dierent gels and pastes can be
employed to cover the ulcer surface to form a defensive obstacle
against secondary infection and further mechanical irritation. e rst
option of the treatment of RAS is the topical agents. A little amount of
cream or gel should be applied by patient aer rinsing and stay away
from drinking or eating for 30 min. It should be followed by 3 to 4
times a day [27]. It is good to employ various types of adhesive bases in
association with drug that prevents the topical medications to wash
away from the target region. e inammatory process that occurred
with the development of aphthae may limit by topical corticosteroids.
Al-Namah et al. have concluded that the novel dexamucobase was
found to be equally effective in treating oral aphthous ulceration, with
some advantages, as the widely used preparation Kenalog in Orabase
[28]. Meng et al. have indicated that amlexanox oral adhesive pellicles
are as effective and safe as amlexanox oral adhesive tablets in the
treatment of minor RAS for this Chinese cohort. However, pellicles
seem to be more comfortable to use when compared with the dosage
form of tablets. erefore in clinical practice, amlexanox oral adhesive
pellicles may be a better choice for RAS patients [29].
Topical anesthetic: Lidocaine in 2% is found to be benecial in
alleviate pain related with recurrent aphthous ulcer (RAS), but mixture
of adrenaline (1:8000) further enhances the pain relief period that
permit the patient more time to take the meals. Patient is directed to
apply 2 to 3 drops of it onto the surface of ulcer and ask to keep open
the mouth [30].
Topical antimicrobials: In the RAS management, the aqueous mouth
rinse containing Chlorhexidine gluconate provides some benecial
eects. Investigations reect that it decreases the ulcers duration but
the recurrence of ulcers cannot prevent by it. It is generally used as
0.2% w/w (weight for weight) mouth rinse but the 0.1% w/w
mouthwash or 1% gel can also be benecial [31].
Topical antibiotics: e antibacterial effect of tetracycline is also
known to decrease the breakdown of collagen. is can be employed in
mouth rinse form prepared by dissolving the capsule of 250 mg into
180 ml of water and direct the patient to swish and spit four times a
day for 4 to 5 days. Tetracycline is considered inferior to minocycline
due to additional immunomodulatory effects of minocycline. It can be
used by dissolving the 100 mg tablets in 180 ml of water and direct the
patient to rinse two times daily for 4 to 5 days. In both cases patient
should be directed to stay away from food or drink for at least 30
minutes [32].
Topical corticosteroids: ese are the backbone for the treatment of
RAS. Dierent types of topical corticosteroids are employed that
alleviate the symptoms of RAS with no suppression of adrenal. Some of
currently available agents are designed in new drug delivery system in
form of protective lm that is designed to attach rmly to the wet
moving mucous there by forming a protective lm over the ulcer area
leads to rapid healing and faster relief of pain. It has applied in paste
form 2-3 times in a day. ese steroids may develop local candidiasis
on long term use. Other topical corticosteroids include: Clobetasol
Propionate 0.05%, Triamcinolone acetonide, Fluocinionide 0.05%
[33,34].
Topical anti-inammatory agents: 5% Amlexanonx in paste form
possesses anti-inammatory and anti-allergic property has been found
to be ecient and clinically safe in many clinical investigations for
RAS management [35]. In the treatment of RAS ulcerations, topical
sucralfate when given at 5 ml, 4 times in a day found to be very
eective. It forms a protective barrier on the aected area by adhering
to mucous membrane tissues, there by exerts a soothing effect on the
lesions. It is commonly employed for treatment of peptic ulcers [36].
Topical analgesic/anti-inammatory spray and rinses: Topical
analgesic sprays or rinses such as Benzydamine hydrochloride can be
utilized to alleviate discomfort in aphthous stomatitis due to its
analgesic, anti-inammatory, antimicrobial and anesthetic activity
[37].
Topical hyaluronic acid: Topical application of Hyaluronic acid in
form of 0.2% gel is found to be benecial in RAS treatment. e main
function of hyaluronic acid is activation and moderation of
angiogenesis, promoting re-epithelization via proliferation of basal
keratinocytes and reducing collagen disposition and scarring [38].
Second Line erapy
Systemic therapy
e outbreaks of RAS are normally resolved with topical treatments,
though in some cases these measures prove insucient because of the
severity of the lesions or for unknown reasons. is is when second
line therapy with systemic drug substances are utilized as given
following:
Levamisole: Due to its vast immumostimulatory eects, it was
recommended as a possible treatment for RAS. By giving a dose of
10-15 mg/day for a period of 2-3 months helps in alleviate the pain,
frequency, number and duration of ulcer. Due to its hazardous eects
like dyspepsia, nausea, agranulocytosis and hyperemia, the use of this
drug is limited [39].
alidomide: is is one of the few drugs that are extensively
ecacious in the management of RAS. It retards the synthesis of tumor
necrosis factor alpha and neutrophil function and also aids in the
healing of aphthae, disappearance of pain and delay or disappearance
of recurrence. When it is given in standard dosing levels of 100-300
mg/day or 50 mg/day, a dose dependent eect originates in 7-10 weeks
following the treatment. Due to its widely known adverse reaction like
teratogenicity and irreversible polyneuropathy, the therapy should be
given only in case of severe ulceration and conned to patient with
ulceration relating to HIV [40].
Pentoxifylline: Pentoxifylline is a drug that retards the synthesis of
tumor necrosis factor alpha, chemotaxis and neutrophil function.
When administered at a dosage of 400 mg three times a day, it alleviate
the level of pain, reduce the ulcer size and number during episodes of
RAS. Due to its lesser adverse eects and escalating results it is
regarded as primary systemic medication for RAS treatment [41].
Colchicine: Colchicine with anti-inammatory activity may be of
clinical benet in severe cases of RAS and Behcet's disease. erefore, a
therapeutic trial at least over 4 to 6 weeks in a dose of 1 to 2 mg/day
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 4 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

orally is recommended, which is followed by long-term therapy
according to tolerability and clinical response [42].
Zinc sulphate: Systemic zinc treatment causes an improvement or
remission in patients with RAS. It is given systemically, a total of 660
mg of zinc sulphate per day in divided doses [43].
Azathioprine: Azathioprine has been eective in decrease the
incidence, severity and frequency of severe oral and genital aphthae
when it is administered alone or in combination with other
immunosuppressants in a dosage of 1 to 2 mg/kg/day (50-150 mg/day)
[34].
Methotrexate: Methotrexate, an a analogue of folic acid found to be
very benecial in severe oro-genital aphthosis when administered in a
dosage of 3-6 mg/kg or 7.5 to 20 mg weekly. Aer intake of
methotrexate the intermittent administration of folic acid should be
given [34].
Prednisone: It can be utilized in association with topical mouth
rinses and gels. Systemic treatment of prednisone should be started at
dose of 1.0 mg/kg a day as a single dose in the patients with severe
RAU and it should be reduce aer 1 to 2 weeks because on long term
exposure drug carries the risk of several adverse eects such as
hyperglycemia, moon faces, depression, lipodystrophy and
hypothalamic-pituitary-adrenal axis suppression. at’s why it should
be used for a shorter period of time. In order to provide the eective
treatment, it can be given along with other immunosuppressive agent,
azathioprine to reduce the dosage of prednisone [19].
Vitamin B12: When researchers treated the patients suering from
RAS with a dosage of 1000 μg of vitamin B12, they concluded aer 5 to
6 months of treatment that number of ulcers, duration of outbreaks
and level of pain were remarkably reduced. During the treatment of
around six months, “no aphthous ulcers status” was obtained by 74.1%
of 31 interventional group participants concluded that treatment of
RAS with vitamin B12 seems to be eective, cheap and lower risk in
treating patients with RAS irrespective of their initial level of serum
vitamin B12 [44].
Dapsone: It is an extensively employed drug for the treatment of
leprosy in long term and some dermatologic conditions have been
tried with limited success in the management of major aphthae. It is
administered orally in a dosage of 100 mg in divided doses and it can
also be increased at the rate of 50 mg/day per week to a maximum of
300 mg/day. Due to its toxic nature it can precipitate hemolytic
anemia, therefore strict patient monitoring for methemoglobinemia,
hemolysis, agranulocytosis and anemia is required [45].
Rebamipide: It is the rst antiulcer drug that is found to enhance the
endogenous prostaglandins in mucosa and retards the production of
oxygen derived free radical. Investigations revealed that when the drug
administered in a dose of 100 mg (tablet) three times a day for seven
days decreases the pain and number of aphthae with excellent recovery
by seventh day [46].
Irsogladin: When the drug is administered orally 2 to 4 mg/day
which is used for treatment of peptic ulcer and gastritis, found to be
decreasing the ulcer counts and on regularly taken it also prevent the
recurrence of aphthous stomatitis [47].
Cyclosporine A: At a dosage of 3-6 mg/kg, was found to be
ecacious in about 50% of patients suered from aphthosis. However,
abrupt withdrawal of therapy may lead to a rebound phenomenon.
Due to the potential for severe side-eects from therapy, clinical and
serologic vigilance must be observed [25].
Adalimumab: Adalimumab is an anti-TNF- monoclonal antibody
that has been used to treat severe, recalcitrant, RAS, but in view of the
risk of serious adverse eects, it should be used with extreme caution
[48].
Acyclovir: Acyclovir (400 mg twice a day for 1 year) was used in a
double-blind study in 25 patients with RAS without any benet in the
prevention of ulcers. 64 Alternatively, higher dosages (800 mg twice a
day for 8 weeks) of acyclovir were used in one study of eight patients
with recurrent RAS, and six patients experienced either total regression
of existing ulcers or relief of symptoms within 2 days of therapy [49].
Montelukast: In a study carried out by Femiano, in which 20
participants received a daily oral dosage of 10 mg montelukast for 1
month followed by alternate days for the second month. It was
concluded that the time in days to resolution of rst ulcer was shorter,
accompanied with a remarkable reduction in the total count of new
lesions over the treatment period of 2-months [50].
Iniximab: Recently, it has been shown by LP Robertson that
iniximab (Remicade), a chimeric anti-TNF antibody, is very eective
in the management of refractory and recurrent oral and genital ulcers.
It is usually given in a dose of 5 mg/kg body weight intravenously in
dierent schemes (e.g., 2, 6 and 32 weeks aer the rst injection) [34].
Etanercept: Etanercept (Enbrel) is a recombinant TNF-soluble
receptor can be used cases of recalcitrant, recurrent ulceration in a
dose of 25 mg subcutaneously twice a week. e only adverse eect
reported is mild erythema, induration and tenderness at injection site
[51].
Clofazimine: It is an antimicrobial used for the treatment of leprosy
is combination with other drugs such as rifampicin and dapsone. In
application to severe RAS, and when administered at a dose of 100
mg/day during 6 months, the emergence of new lesions was found to
be inhibited by drug during the prescribed period of treatment [52].
Penicillin G potassium: Penicillin G potassium in 50 mg tablets
administered four times a day during four days reduces the size of the
ulcers and lessen the pain [53].
Research work done on aphthous stomatitis (Mouth ulcers)
A very few research work has been done on aphthous stomatitis
which makes it challenging for scientists as well as for the researchers.
Some of works done reported are given as follows:
In 2018, Zhang developed and evaluate
in-vitro in-vivo
the
bilayered mucoadhesive buccal lm containing ornidazole (OD) and
dexamethasone sodium phosphate (DEX) in combined form
employing solvent casting technique for the treatment of oral ulcers.
e prepared lms were evaluated systemically for
in-vitro
in order to
nd the optimized formulation. e rabbit oral ulcer model was
investigated to study the therapeutic eectiveness of these lms and
the
in-vivo
release of OD and DEX in the human oral cavity was also
evaluated. It was concluded that the developed lm become a local
drug delivery device for the treatment of oral ulcers [54].
In 2017, Heng-zhong developed and evaluate the fast disintegrating
lms containing Lignocaine as a model drug to treat the mouth ulcers.
For the evaluation of local anesthetic activity of developed lm, tail
ick test in rat model was performed. 32 full factorial design was
applied to develop oral fast disintegrating lms by solvent casting
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 5 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

evaporation technique. Chitosan, Croscarmellose Sodium (CCS) and
Dibutyl Phthalate (DBT) were used as polymer, superdisintegrant and
plasticizer respectively. e developed lms were evaluated for physical
appearance, thickness, weight variation, folding endurance,
disintegration time, drug content uniformity and
in-vitro
drug release.
It was concluded that oral fast disintegrating lms of Lignocaine serves
as potential drug delivery systems for mouth ulcer management [55].
In 2017, Joshi developed a herbal oral dissolving lm for mouth
ulcer and throat infection treatment contained herbal plants extract
and powders of
Ocimum tenuiorum
(Tulsi),
Glycyrrhiza glabra
(yastimadhu),
Curcuma longa
(turmeric). ese plants have
antimicrobial, astringent, antiulcer and anti-inammatory activity.
HPMC was selected as polymer and plasticizer for the lm
formulation. e lms were subjected to physicochemical
examinations such as weight uniformity, folding endurance, surface
pH disintegration time, % moisture absorption, % moisture loss,
surface pH, swelling index etc. e obtained results for prepared herbal
lms disintegrate within 1 minute. ese lms are economic,
convenient and do not show any side eect [56].
In 2016, Aslani developed an oral gel from
Punica granatum
(Pomegranate) ower extract for the treatment of recurrent aphthous
stomatitis. Dierent formulations were prepared using dierent
amounts of hydroxypropyl methylcellulose K4M, sodium
carboxymethylcellulose (SCMC) and carbomer 934. Aer this, the
condensed extract was uniformly dispersed in polyethylene glycol
(PEG) 400 and added to gel bases. Form the results it was found that
mucoadhesion of gel enhanced as the polymer amount in gel increases
that lead to longer durability in mouth. erefore, the formulation F4
having highest mucoadhesion and viscosity due to its higher polymer
content which is able to remain for a longer period of time to release its
active ingredient. Hence due to proper appearance, stability,
uniformity, acceptable mucoadhesion and viscosity the F4 formulation
was selected as best nal formulation [57].
In 2016, Li W developed a lm for the mouth ulcer treatment
containing compound calculus bovis sativus (CBS) and ornidazole by
employing three polymers (hydroxypropyl methyl cellulose, chitosan,
poly(vinyl alcohol) (PVA)). e lm was developed with the lm-
forming suspension, using casting-solvent evaporation technique. e
prepared lms were evaluated for drug content, swelling index, release
behavior and mucoadhesive properties. e prepared lms displayed
desirable swelling properties and
in-vitro
drug release behaviors. It was
concluded that prepared lm was able to remarkably relieve the
mucosal wounds in animals [58].
In 2015, orat developed thermoreversible mucoadhesive gel
(TMG) containing curcumin for treatment of mouth ulcer. e
formulations were developed by employing Xanthan gum and
carbomers as bioadhesive material along with thermoreversible agent
such as Pluronic F68 and Pluronic F127. e developed preparations
were evaluated for pH, gel strength, spreadability, gelation
temperature,
in-vitro
mucoadhesion and
in-vitro
drug release. From
the results it was concluded that a sustain drug release pattern was
obtained along with enhanced residence time as well as the contact
area of curcumin at the site of ulcer thus making the curcumin
thermoreversible gel a suitable candidate for the treatment of mouth
ulcer [59].
In 2014, Ambikar developed a herbal oral dissolving lm containing
herbal plants extract and powders of
Ocimum tenuiorum
(tulasi),
Azadiracta indica
(neem),
Syzygium aromaticum
(lavanga),
Boerhaavia diusa
(punarnava),
Glycyrrhiza glabra
(yastimadhu),
Jasminum grandiorum
(jasmine), (triphala) for treatment of mouth
ulcer. ese plants exhibit antiulcer, astringent, antimicrobial and anti-
inammatory activity. HPMC and ethyl cellulose were selected as
polymer for lm formation. e lms were subjected to
physicochemical examinations such as weight uniformity, folding
endurance, surface pH disintegration time, % moisture absorption, %
moisture loss, surface pH, swelling index etc [60].
In 2014, Bhutkar developed a mucoadhesive herbal buccal patch
of Psidium Guava L. for the treatment of oral ulcers by employing
HPMC K15 and Carbopol 940 as a rate controlling and mucoadhesive
polymer. It was concluded that the patch containing polymer HPMC
K15 and Carbopol 940 successfully delivered the herbal constituent
quercetin isolated from
Psidium Guava L
[61].
In 2013, Alsadat developed a mucoadhesive paste of chlorhexidine
and Betamethasone to study the eect on the process of oral ulcer
recovery in rats. From the results obtained it was concluded that the
best wound healing processes from clinical and histological aspects
were achieved in the betamethasone (B) and betamethasone-
chlorhexidine (BC) groups. Also, use of chlorhexidine alone had no
signicant eect on wound healing and other criteria; theefore, the
authors concluded it is not eective, when it is used alone [62].
Conclusion
Aphthous stomatitis is the most common inammatory ulcerative
condition of the oral mucosa, it occur as painful ulcers and recur from
time to time. e etiopathogenesis of this disease is unclear. Much
research has been done to nd treatments to reduce pain related to,
duration of and frequency of ulcer outbreaks. ere are several
treatment options, both local and systemic, that could be helpful for
management of aphthae in the primary care setting. No single
treatment has been found to be uniformly eective in all patients with
RAU, it may be necessary to try several types of medications for
optimum response and prevention of recurrence. Treatment strategies
must be directed toward providing symptomatic relief by reducing
pain, increasing the duration of ulcer-free periods, and accelerating
ulcer healing. Future research should focus on identifying RAS
etiology, developing standardized diagnostic criteria for RAS, and
improving the design and reporting of clinical trials.
Acknowledgements
e authors are grateful to Central Library Department of I.K.
Gujral Punjab Technical University, Jalandhar and Rayat Bahra
Institute of Pharmacy, Hoshiarpur, Punjab for the providing us the
literature search facilities for accomplishing this review work.
Conicts of Interest
e authors declare no conict of interest regarding the publication
of this review article.
References
1. Preeti L, Magesh K, Rajkumar K, Karthik R (2011) Recurrent aphthous
stomatitis. J Oral Maxillofac Pathol 15: 252-256.
2. Pongissawaranun W, Laohapand PP (1991) Epidemologic study on
recurrent aphthous stomatitis in a thai dental patient population.
Community Dent Oral Epidemiol 19: 52-53.
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 6 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

3. Shashy RG, Ridley MB (2000) Aphthous Ulcers: A dicult clinical entity.
Amer J Otolaryngol 21: 389-393.
4. Wadhawan R, Sharma S, Solanki G, Vaishnav R (2014) Alternative
medicine for aphthous stomatitis: A Review. Int J Adv Case Rep 1: 5-10.
5. Munoz-Corcuera M, Esparza-Gomez G, Gonzalez-Moles MA, Bascones-
Martinez A (2009) Oral ulcers: clinical aspects. A tool for dermatologists,
Part I, Acute ulcers. Clin Exp Dermatol 34: 289-294.
6. Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N (2015)
Guideline for the diagnosis and treatment of recurrent aphthous
stomatitis for dental practitioners. J Int Oral Health 7: 74-78.
7. Swain N, Pathak J, Poonja LS, Penkar Y (2012) Etiological factors of
recurrent aphthous stomatitis: A common perplexity. J Contemp Dent 2:
96-100.
8. Slebioda Z, Szponar E, Kowalska A (2014) Etiopathogenesis of recurrent
aphthous stomatitis and the role of immunologic aspects: Literature
review. Arch Immunol er Exp 62: 205-215.
9. Scully C, Porter S (2008) Oral mucosal disease: Recurrent aphthous
stomatitis. Br J Oral Maxillofac Surg 46: 198-206.
10. Jurge S, Kuer R, Scully C, Porter SR (2006) Recurrent aphthous
stomatitis. Oral Dis 12: 1-21.
11. Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M (2001) Recurrent
aphthous stomatitis. Quintessence Int 31: 95-112.
12. Edgar NR, Saleh D, Miller RA (2017) Recurrent Aphthous Stomatitis: A
Review. J Clin Aesth Dermatol 10: 26-36.
13. Akintoye SO, Greenberg MS (2005) Recurrent aphthous stomatitis. Dent
Clin North Amer 49: 31-47.
14. Shastri A, Srivastava R (2015) Etiopathogenesis, Diagnosis and Recent
Treatment Modalities for Recurrent Aphthous Stomatitis: A Review. Int J
Contemp Med Res 2: 1-5.
15. Scully C, Nur FL (2003) Diagnosis and management of recurrent
Aphthous stomatitis. e J Amer Dent Assoc 134: 200-207.
16. Swain N, Pathak J, Poonja LS, Penkar Y (2012) Etiological Factors of
Recurrent Aphthous Stomatitis: A Common Perplexity. J Contemp Dent
2: 96-100.
17. Arun Kumar M, Ananthakrishnan V, Goturu J (2014) Etiology and
pathophysiology of recurrent aphthous stomatitis: A review. Int J Cur Res
Rev 6: 16-22.
18. Ship JA, Arbor A, Mich (1996) Recurrent aphthous stomatitis: An update.
Oral Surg Oral Med Oral Patho 81: 141-147.
19. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, et al.
(2004) Recurrent aphthous ulcers today: a review of the growing
knowledge. Int J Oral Maxillofac Surg 33: 221-234.
20. Rhee SH, Kim YB, Lee ES (2005) Comparison of Behcet’s disease and
recurrent aphthous ulcer according to characteristics of gastrointestinal
symptoms. J Korean Med Sci 20: 971-976.
21. Aydemir S, Tekin NS, Aktunç E, Numanoglu G, Ustundag Y (2004) Celiac
disease in patients having recurrent aphthous Stomatitis. Turk J
Gastroenterol 15: 192-195.
22. Rogers RS (1997) Recurrent aphthous stomatitis: Clinical characteristics
and associated systemic disorders. Seminars in Cutaneous Medicine and
Surgery 16: 278-283.
23. Vivek V, Bindu JN (2011) Recurrent aphthous stomatitis: Current
concepts in diagnosis and management. J Ind Acad Oral Med Radiol 23:
232-236.
24. Guallar IB, Soriano YJ, Lozano AC (2014) Treatment of recurrent
aphthous stomatitis. A literature review. J Clin Exp Dent 6: 168-174.
25. Pramod GV (2013) Management strategies for recurrent oral aphthous
ulcers. e-J Dent 3: 352-360.
26. Eisenberg E (2003) Diagnosis and treatment of recurrent aphthous
stomatitis. Oral Maxillofacial Surg Clin N Am 15: 111-122.
27. Casiglia JM (2002) Recurrent aphthous stomatitis: Etiology, diagnosis,
and treatment. Gen Dent 50: 157-166.
28. Al-Namah ZM, Carson R, anoon IA (2009) Dexamucobase: A novel
treatment for oral aphthous ulceration. Quintessence Int 40: 399-404.
29. Meng W, Dong Y, Liu J, Wang Z, Zhong X, et al. (2009) A clinical
evaluation of amlexanox oral adhesive pellicles in the treatment of
recurrent aphthous stomatitis and comparison with amlexanox oral
tablets: A randomized, placebo controlled, blinded, multicenter clinical
trial. Trials 10: 30.
30. Aljbab AA, Almuhaiza M, Patil SR, Alanezi K (2015) Management of
recurrent aphthous ulcers: An Update. Int J Dent Oral Health 2: 1-4
31. Piccione N (1979) Use of chlorhexidine in the therapy of some
stomatological diseases. Minerva Stomatol 28: 209-214.
32. Graykowski EA, Kingman A (1978) Double-blind trial of tetracycline in
recurrent aphthous ulceration. J Oral Pathol 7: 376-382.
33. Pimlott SJ, Walker DM (1983) A controlled clinical trial of the ecacy of
topically applied fluocinonide in the treatment of recurrent aphthous
ulceration. Br Dent J 154: 174-177.
34. Altenburg A, Zouboulis CC (2008) Current concepts in the treatment of
recurrent aphthous stomatitis. Skin erapy Lett 13: 1-10.
35. Khandwala A, Van Inwegen RG, Alfano MC (1997) 5% Amlexanox oral
paste, a new treatement for recurrent minor apthous stomatitis. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 83: 222-230.
36. Ricer RE (1989) Sucralfate vs. placebo for the treatment of aphthous
ulcers: a double-blinded prospective clinical trial. Fam Pract Res J 9:
33-41.
37. Qnane PA, Graham GG, Ziegler JB (1998) Pharmacology of
Benzydamine. Inammopharmacology 6: 95-107.
38. Nolan A, Baillie C, Badminton J, Rudralingham M, Seymour RA (2006)
e ecacy of topical hyaluronic acid in the management of recurrent
aphthous ulceration. J Oral Pathol Med 35: 461-465.
39. Scheinfeld N, Rosenberg JD, Weinberg JM (2004) Levamisole in
dermatology: a review. Am J Clin Dermatol 5: 97-104.
40. Genvo MF, Faure M, ivolet J (1984) Treatment of aphthosis with
thalidomide and with colchicine. Dermatologica 168: 182-188.
41. Pizarro A, Navarro A, Fonseca E, Vidaurrazaga C, Herranz P (1995)
Treatment of recurrent aphthous stomatitis with pentoxifylline. Br J
Dermatol 133: 659-660.
42. Puri N, Gill JK, Kaur H, Kaur N, Kaur J (2015) Recurrent aphthous
stomatitis: erapeutic management from topicals to systemics. J Adv
Med Dent Sc Res 3: 165-170.
43. Bor NM, Karabiyikoglu A, Karabiyikoglu T (1990) Treatment of
recurrent aphthous stomatitis with systemic zinc sulphate. J Islam Acad
Sci 3: 343-347.
44. Cui RZ, Bruce AJ, Rogers RS (2016) Recurrent aphthous stomatitis. Clin
Dermatol 34: 475 481.
45. Sarmadi M, Ship JA (2004) Refractory major aphthous stomatitis
managed with systemic immunosuppressants: A case report.
Quintessence Int 35: 39-48.
46. Kudur MH, Hulmani M (2013) Rebamipide: A novel agent in the
treatment of recurrent aphthous ulcer and Behcet’s Syndrome. Indian J
Dermatol 58: 352-354.
47. Nanke Y, Kamatani N, Okamoto T, Ogiuchi H, Kotake S (2008)
Irsogladine is eective for recurrent oral ulcers in patients with Behçet’s
disease : an open-label, single-centre study. Drugs R D 9: 455-459.
48. Vujevich J, Zirwas M (2005) Treatment of severe, recalcitrant, major
aphthous stomatitis with adalimumab. Cutis 76: 129-132.
49. Pedersen A (1992) Acyclovir in the prevention of severe aphthous ulcers.
Arch Dermatol 128: 119-120.
50. Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N (2010) Pilot study
on recurrent aphthous stomatitis (RAS): a randomized placebo-
controlled trial for the comparative therapeutic eects of systemic
prednisone and systemic montelukast in subjects unresponsive to topical
therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:
402-407.
51. Robinson ND (2003) Recalcitrant, recurrent aphthous stomatitis treated
with etanercept. Arch Dermatol 139: 1259-1262.
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 7 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189

52. De Abreu MA, Hirata CH, Pimentel DR, Weckx LL (2009) Treatment of
recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 108: 714-721.
53. Zhou Y, Chen Q, Meng W, Jiang L, Wang Z et al. (2010) Evaluation of
penicillin G potassium troches in the treatment of minor recurrent
aphthous ulceration in a chinese cohort: a randomized, double-blinded,
placebo and no-treatment-controlled, multicenter clinical trial. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 109: 561-566.
54. Zhang C, Liu Y, Li W, Gao P, Xiang D et al. (2018) Mucoadhesive buccal
lm containing ornidazole and dexamethasone for oral ulcers: in vitro
and in vivo studies. Pharm Dev Technol 25: 1-9.
55. Heng-Zhong X, Jing L, Xiao-xiu F (2017) Pharmacological evaluation of
oral fast disintegrating lms containing local anaesthetic agent
Lignocaine. Biomed Res 28: 1135-1141.
56. Joshi P, Waghamare N, Karande M (2017) Herbal oral disintegrating lm.
Sci J 1: 1-4.
57. Aslani A, Zolfaghari B, Davoodvandi F (2016) Design, formulation and
evaluation of an oral gel from Punica Granatum Flower extract for the
treatment of recurrent aphthous stomatitis. Adv Pharm Bull 63: 391-398.
58. Li W, He WX, Gao P, Zhang C, Cai H et al. (2016) Preparation in vitro
and in vivo evaluations of compound calculus bovis sativus and
ornidazole lm. Biol Pharm Bull 39: 1588-1595.
59. orat S, Sarvagod AM, Kulkarni SV, Hosmani AH (2015) Treatment of
mouth ulcer by curcumin loaded thermoreversible mucoadhesive gel: A
technical note. Int J Pharm Pharm Sci 7: 399-402.
60. Ambikar RB, Phadtare GA, Powar PV, Sharma PH (2014) Formulation
and evaluation of the herbal oral dissolving lm for treatment of
recurrent aphthous stomatitis. Int J Phytother Res 4: 11-18.
61. Bhutkar KG (2014) Formulation and evaluation of mucoadhesive herbal
buccal patch of psidium Guava L. J Cur Pharm Res 5: 1372-1377.
62. Alsadat Hashemipour M, Borna R, Gandjaliphan Nassab A (2013) Eects
of Mucoadhessive Paste of Chlorhexidine and Betamethasone on Oral
Ulcer Recovery Process in Rats. Wounds 25: 104-112.
Citation: Sharma D, Garg R (2018) A Comprehensive Review on Aphthous Stomatitis, its Types, Management and Treatment Available. J
Develop Drugs 7: 189. doi:10.4172/2329-6631.1000189
Page 8 of 8
J Develop Drugs, an open access journal
ISSN: 2329-6631
Volume 7 • Issue 2 • 1000189