The Best Treatment For Aphthous Ulcers

The Best Treatment For Aphthous Ulcers
An evidence-based study of the literature
R. Fernandes, T. Tuckey, P. Lam, S. Allidina, S. Sharifi and D. Nia
Abstract
This evidence-based study of the literature set out to examine the various treatment options for recurrent aphthous stomatitis
(RAS) and identify the best therapeutic choice for managing the condition. Currently, treatment options include symptomatic
relief of the canker sore using topical agents or antibiotics, or non-intervention treatment wherein the ulcer heals on its own. The
review is based on literature from a search of several electronic databases including references from the potential articles
obtained, as well as information obtained from dental textbooks and an oral pathologist. A total of 69 randomized control trials
(RCTs) were deemed relevant and were critically appraised according to an “efficacy checklist”. Six studies met the criteria of
scoring >13/15 on the checklist with statistically significant results and potential applications in clinical treatment. The therapeutic
options investigated included 5% amlexanox, penicillin G, silver-nitrate cautery and doxymycine. Benefits versus risk for each
treatment option were examined, and the best form of therapy was based on an agent that would encompass reduction in pain
and healing time and prevent further recurrences. Based on these criteria, 5% amlexanox was determined to be the most
effective form of treatment for RAS.
MeSH Key Words: Aphthous stomatides; Aphthous stomatitis; Recurrent Aphthous Stomatitis; Stomatides,
Aphthous; Aphthae; Ulcer, Aphthous; Aphthous ulcer; Aphthous ulcers; Aphthous; Ulcers, Aphthous; Canker sore;
Canker sores; Sore, Canker; Sores, Canker; Periadenitis mucosa necrotica recurrence
Aphthous ulcers or recurrent aphthous
stomatitis (RAS), commonly referred to as canker
sores, are inflammatory lesions of the mucous
lining of the mouth which may involve the cheeks,
gums, tongue, lips, and roof or floor of the mouth.
It is usually painful and associated with redness,
swelling, and occasional bleeding from the
affected area(s). Manifestation of the disease can
range from mild to severe and, in extreme cases,
even hinder a person’s ability to ingest foods,
thereby making the person susceptible to
malnutrition.1
The cause of RAS is unknown, although
several factors are suspected including genetics,
stress, nutritional deficiencies, diet, hormonal
changes, and immunological disorders. 1,2,5 Due to
the indeterminate etiology of the disease, it is
difficult to find a definitive cure and current
treatments are aimed towards ameliorating the
symptoms.
There are 3 clinical presentations of RAS:
aphthous minor, aphthous major and herpetiform
ulcers. Aphthous minor are the most common
and account for 80-95% of all RAS lesions. They
are white ulcerative lesions that may be single or
multiple and round or oval.2,3 Two to eight crops
of lesions occur per year, lasting 7 to 14 days and
then heal without scars.4 Aphthous major,
accounts for 10-15% of RAS cases and is
characterized by larger lesions with 1-2 lesions
occurring at a time. These are more common in
the immunodeficient population, and are
associated with severe pain, lasting 6 or more
weeks.1 Herpetiform ulcers are the least common
variety and account for only 5-10% of cases.2,3
They appear on both non-keratinized and
keratinized mucosa unlike aphthae minor and
major which are limited to non-keratinized
mucosa.3
Aphthous minor is amongst the most
common form of oral ulcerative diseases and
affects an estimated 15-20% of the population
worldwide. In some populations, the prevalence
has been documented as being as high as 50-66%5
and it is especially common in North America.3
These aphthae can also occur as widespread
lesions in association with systemic diseases
including Behcet’s syndrome, and gastrointestinal
malabsorption disorders like Crohn's and Celiac
diseases. 1,3,6 It is unclear whether these
presentations are manifestations of the underlying
disease or represent a separate oral disorder.3
Treatment for RAS is symptomatic; the
goals being to decrease pain, healing time, number
and size of the ulcer, and to increase disease-free
periods. Current treatment options include topical
agents,
systemic
and
topical
steroids,
corticosteroids, cauterization, antibiotics, mouth
rinses containing active enzymes, laser treatments
and combination therapy. Given the prevalence of
RAS, primary care physicians and dentists should
become familiar with its presentation and
management and be able to offer therapeutic
options that meet their patients’ needs. The report
serves as an educational medium for health
professionals, so that they may become equipped
1
with the knowledge to manage patients who
present with RAS. Since aphthous minor is the
most prevalent form of RAS, this report focuses
specifically on its treatment options. The findings
of this report may not be generalizable to patients
with major or herpetic aphthae or those with
forms of RAS that are manifestations of systemic
disorders. For other forms of RAS, therapy should
be individually tailored to the patient depending
on the severity of the ulcer and the patient’s health.
Methods
A systematic literature search was employed to
identify, select, critically appraise and utilize
relevant studies.
Search Strategy
MeSH was initially used to expand on the
vocabulary, so as to conduct a more extensive
search on the topic. The following terms were
used in the searches: Aphthous stomatides;
Recurrent aphthous stomatitis; Aphthous
stomatides; Aphthae; Aphthous ulcer; Aphthous
ulcers; Aphthous; Canker Sore; Canker Sores;
Apthous ulcer; treatment/therapy for Aphthous
ulcer(s) and management of/managing aphthous
ulcers. To locate relevant articles, several
electronic databases were used: Pubmed (1966 –
present), Ovid Medline (1966 – present) and
Cochrane, which yielded 2546, 505 and 12 articles
respectively. The next stage was to limit the search
to studies published in English that dealt with
human subjects of all ages and this decreased the
number of potentially relevant articles to 1466 in
Pubmed while the others remained unchanged. In
addition to using online databases, textbooks in
oral pathology were consulted, as was the expert
opinion of an oral pathologist.
Determination of Relevance using Validity
Instruments
In the abstract stage, queries were limited
to Randomized Controlled Trials and this process
yielded 69 articles in Pubmed, 17 in Ovid Medline
and none in Cochrane. Following the elimination
of duplicate articles (overlapping articles within
the electronic databases), a total of 69 articles
remained. A search of the references within these
articles was also conducted, on the basis of titles,
but no articles were retrieved in this manner.
Of these 69 articles, 40 were eliminated
based on titles – these articles either dealt with
non-healthy populations (i.e. people with AIDS)
or RAS as a manifestation of a systemic disorder.
The remaining 29 articles were retrieved and
analyzed for relevance. Articles were considered
relevant if they met the following criteria: 1)
primary research; 2) the best evidence as set by the
classification system of the Canadian Task Force
on the Periodic Health Examination (CFTPHE)7;
and 3) a score of >13/15 on the checklist to
assess the efficacy of a therapy or intervention
(Table 1)8. Articles with inconclusive or
conflicting evidence were disregarded, as were
articles with poor design or those using an
alternate therapy as a control (Appendix 1). A
total of 6 RCTs met all criteria and were further
analyzed. From the 6 relevant studies 3
investigated 5% Amlexanox (Aphtheal), 1
investigated penicillin G, 1 investigated silver
nitrate cautery and the last investigated
Doxymycine (Table 2).
Table 1: Checklist to Assess Evidence of Efficacy of Therapy or Prevention8
Was the study ethical? (1 point)
Was a strong design used asess efficacy? (1)
Were outcomes (benefits and harms) validly and reliably measured? (1)
What were the results?
•
Was the treatment effect large enough to be clinically important? (1)
•
Was the estimate of the treatment effect beyond chance and relatively precise? (1)
•
If the findings were “no difference” was the power of the study 80% or better? (1)
Are the results of the study valid?
•
Was the assignment of patients to treatments randomized? (1)
•
Were all patients who entered the trial properly accounted for and attributed at its conclusion?
¾ Was loss to follow-up less than 20% and balanced between test and controls?(1/2)
¾ Were patients analyzed in the groups to which they were randomized? (1/2)
•
Was the study of sufficient duration? (1)
•
Were patients, health workers, and study personnel “blind” to treatment? (1)
•
Were groups similar at the start of the trial? (1)
•
Aside from the experimental intervention, were the groups treated equally? (1)
•
Was care received outside the study identified and controlled for? (1)
Will the results help in caring for your patients? (1)
•
Were all clinically important outcomes considered? (1)
•
Are the likely benefits of treatment worth the potential harms and costs? (1)
2
Results
Table 2: Studies investigating treatment of RAS
Study
Subjects
Treatment Method
Date of
[Total (final)]
publication
Binnie and
Adults ≥ 18 (mean 27.5)
Tx: 5% Amlexanox oral paste
others, 1997
48% male, 86%
Control: placebo (vehicle)
Caucasian
Evaluated daily until 1st of
Generally healthy, history ulcers healing or study ending
of minor RAU
[1133(1124)]
Khandwala and
others, 1997
Adults ≥ 18 (mean 28.6)
633 male, 702 female
Generally healthy, history
of minor RAU
[1335 (1295)]
Ylikontiola and
others, 1997
Adults 28-45 (mean 38)
4 men, 27 women
Generally healthy, history
of minor RAU
[31(31)]
Kerr and others,
2003
Adults ≥15
Generally healthy, history
of minor RAU
[110 (100)]
Alidaee and
others, 2005
Adults 16-40 (mean 26)
43 men, 42 women
Generally healthy, history
of painful RAU
[97 (85)]
Murray and
others, 2005
Adults (mean 37)
60% female, 98% white
Generally healthy, history
of RAU & associated
prodromal symptoms
[46 (46)]
Tx: of 5% Amlexanox oral
paste
Control: placebo (vehicle) and
no treatment
“Dab” applied to ulcers 4x/day
until ulcers healed or study
ended
Tx: 150 mg doxymycine + 1ml
of 0.9% NaCl + 1 drop cryo
(n=15)
Control: 150 mg calcii
gluconase, 1ml 0.9% NaCl,
1cryo (n=16)
Mean pain level VAS recorded
by pts for 10 days
Tx: topical 50mg penicillin G
potassium troches (Cankercillin)
applied 4x/day for 4 days
(n=31)
Control: placebo (n=33), no tx
(n=36)
Tx: silver nitrate sticks gently
painted on ulcer = chemical
cauterization (n=47)
Control: placebo (n=38)
Tx: 0.5cm of 5% Amlexanox
paste applied 4x/day beginning:
1. within 12h of onset of
prodromal stage to see if ulcer
could be prevented
2. within 12h of onset of
ulceration to see if healing could
be improved
Control: placebo
Effect(s) observed
-↓ healing time by 1.6 days
-↓ time to pain relief by 1.3 days
-After 3 days, a significant difference in
healing (21% vs. 8%) and complete pain
resolution (44% vs 20%)
-Vehicle may provide some benefit
-No unusual or unexpected adverse reactions
reported
-↓ healing time by 0.8 days compared to
vehicle and 1.6 days compared to no
treatment
-Vehicle may provide some benefit
-↓ mean pain level significantly
-Adhesive: mean duration 3.5 hrs (not a
good adhesive)
-All components non-toxic
-Significant acceleration of healing and pain
relief
-No allergic reactions were observed
-Significant ↓ pain 1 day after procedure
(70% pain reduction compared to 11% in
placebo group)
-No significant difference in time to heal
-No side effects but
-Must be done by trained professional
-By day 3, 35% of prodromal group had an
ulcer present compared with 97% in placebo
group and 66% in treated ulcer group
-Prodromal tx ↓ ulcer size and extent by
84%, pain by 69%, and extent of pain by
85% compared to placebo
-↓ healing time by 4.1 days if used at
prodromal onset and 0.7 days if used at
onset of ulceration
-Tx at onset of prodrome rather than at
ulceration = 71% ↓ in extent of ulceration
and a 35% ↓ in max pain
-Side effects were mild and transient (e.g, dry
mouth and numbness at application site)
-Product considered easy to use
VAS: visual analog scale
Tx: treatment
3
Four studies investigated the drugs’ effects
on pain and healing times. Three of these examined
5% Amlexanox9,10,11 and these studies showed a
significant (p<0.05) reduction in pain and healing
time when Aphtheal was applied to the ulcer 4 times
a day from ulcer onset until healing. It was further
demonstrated that application of 5% Amlexanox
during the prodromal stage significantly reduced ulcer
recurrence11. The fourth study12 examined Penicillin
G and showed a significant decrease in pain and
healing time when it was applied 4 times daily until
complete healing of the ulcer. None of the subjects in
any of these experiments showed any significant side
effects.
Two studies investigated the drug’s effect on
pain only: Ylikontiola and others13 investigated the
effects of Doxymycine and Alidaee and others14
investigated the effects of silver nitrate cauterization.
Both drugs significantly reduced pain without any
significant reduction in healing time. The reduction of
pain seen with silver nitrate is rapid and lasts for the
duration of the lesion; however it was perhaps due to
the destruction of local nerve endings. 14 Furthermore,
adverse effects have been reported with silver nitrate
such as argyria, mucocutaneous reactions15 and
tattooing of the mucosa.16 These side effects make
silver nitrate an unlikely choice of treatment especially
since the healing time is not affected by the
cauterization.
Discussion
According to this literature review, the best
treatment for minor RAS is 5% Amlexanox. It is the
only agent that has a “triple action” in the form of
preventing recurrences, decreasing healing time and
accelerating pain resolution.
Penicillin G only
reduced pain and healing time, while doxymycine and
silver nitrate both only reduced pain.
Amlexanox has only mild and transient side
effects.11 While the results are statistically significant,
they do not necessarily correlate well as being
clinically useful since the prodromal stage (the stage at
which the drug was shown to have the “triple action”
effect) is hard to determine. The prodromal stage is
characterized as a burning or pricking sensation 24 48 hours before the onset of the ulcer but it is not
easily identified by all patients. In Murray’s study,11
the prodromal stage was determined through
subjective measures of sensation to predict the ulcer
as well as the use of a thermographic imager as
confirmation. Thermographically active data meant a
surface temperature difference of 0.05°C between the
symptomatic mucosa and the contralateral
asymptomatic area. In combination with the fact that
most offices and homes do not possess
thermographic imagers, and alongside the compliance
issue of applying the paste 4 times per day, diagnosing
and treating the prodromal ulcer is difficult and the
treatment is unlikely to yield the same results as seen
in the study. Furthermore, the reduction in pain and
healing time is not necessarily clinically significant.
Alidaee and others 14 found healing to take 7-10 days
with pain subsiding after 4-5 days; however, with
Amlexanox treatment, median healing time was only
reduced by 1.6 days and the median time to complete
pain relief was decreased by only 1.3 days – results
which are not necessarily clinically significant.
Further, Murray11 found that 5% Amlexanox lead to
pain resolution in 83% of subjects compared with
73% of those using a vehicle, indicating that simply
covering the lesion provided some benefit to the
patient.
In conclusion, due to the unknown etiology
of RAS most of the treatment is therapeutic.
Literature shows that aphthous ulcers are best treated
with 5% Amlexanox as it decreases healing time and
pain and prevents recurrences if applied in the
prodromal stage. The effectiveness of treatment,
however, is not clinically significant since pain relief
and healing time is accelerated by only 1.3 and 1.6
days respectively and since a vehicle also reduces pain.
The effectiveness of prevention showed statistically
significant results; however, diagnosis of the
prodromal stage is subjective, while the objective
thermographic imaging is impractical and thus not
clinically utilizable. Therefore, based upon the
inherent difficulties associated with treatment of
aphthous ulcers, the clinician should individualize
treatment to each patient by considering a number of
relevant factors, including the potential psychological
benefits of treatment, the degree of patient
discomfort experienced, the probability of patient
compliance with required application procedures and
trade-offs between the enhanced rate of recovery and
the economic burden of purchasing the treatment.
Acknowledgements: The authors wish to thank Dr. Iona
Leong, Department of Oral Pathology and Oral Medicine,
Faculty of Dentistry, University of Toronto for her guidance in
determining which treatments for aphthous ulcers were clinically
useful.
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4
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Appendix 1: List of articles excluded and reasons for exclusion
Articles
Chadwick and others 1991; Drinnan and Fischman 1978; Fridh
and Koch 1999; Garnick and others 1998; Hodosh and others
2004; Matthews and others 1987; Miles and others 1993; Muzio
and others 2001; Olsen and Silverman 1978; Saxen and others
1997
Atik and others 2003; Brice and others 1997; Jacobson and others
1997; Jacobson and others 2001; Jenkins and others 1984; Revuz
and others 1990; Ricer 1989; Taylor and others 1993;
Cree and others 1978
Lu Muzio and others 2001; Saxen and others 1997
Femiano and others 2003
Pedersen and others 1990; Pedersen and others 1990
Rattan and others 1994
Reason for exclusion
Did not score ≥13/15 on efficacy checklist
Inconclusive evidence (statistically insignificant)
Conflicting evidence
Other variables were being compared e.g. use of adhesive /
delivery vehicle
Used an existing therapy as control (rather than placebo or
no treatment)
Did not have washout period to rule out lingering effects of
1st treatment
Poor study design
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2. Brice S. Clinical evaluation of the use of low-intensity ultrasound in the treatment of recurrent aphthous
stomatitis. Oral Surg Oral Med Oral Pathol 1997; 83(1):14-20.
3. Chadwick B, Addy M and Walker DM. Hexetidine mouthrinse in the management of minor aphthous ulceration
and as an adjunct to oral hygiene. Br Dent J 1991; 171:83-7.
4. De Cree J, Verhaegen H, De Cock W, and Verbruggen F. A randomized double-blind trial of levamisole in the
therapy of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1978; 45 (3):378-84.
5. Drinnan AJ and Fischman SL. Randomized, double-blind study of levamisole in recurrent aphthous stomatitis.
J Oral Path 1978; 7(6):414-17.
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study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol 2003;
42(5):394-7.
7. Fridh G and Koch G. Effect of a mouth rinse containing amyloglucosidease and glucose oxidase on recurrent
aphthous ulcers in children and adolescents. Swed Dent J 1999; 23:49-57.
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nitrate/dimethyl isosorbide. Quintessence International 2004; 35 (2):137-144.
10. Jacobson JM, Greenspan JS, Spritzler J, Fox L, Fahey JL, Jackson JB, Chernoff M, Wohl DA, Pulvirenti JJ,
Hooton TM, and Shikuma C. Thalidomide in low intermittent doses does not prevent recurrence of human
immunodeficiency virus-associated aphthous ulcers. J Infect Dis 2001; 183(2):343-6.
11. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail
LA, Vasquez GJ, and Wohl DA. Thalidomide for the treatment of oral aphthous ulcers in patients with human
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6
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