Download Canker Sores (Recurrent Aphthous Stomatitis

Canker Sores (Recurrent Aphthous Stomatitis)
Cause and Control
INTRODUCTION AND BACKGROUND
Recurrent aphthous stomatitis (RAS) is an often studied, but a largely misunderstood phenomena.1
Recurrent aphthous stomatitis or canker sore, has been termed the most common oral mucosal disease
known to human beings.2 This malady can be somewhat benign, but may be quite distressing and
debilitating to the affected individual.3 Incidence rates for RAS vary greatly among different populations
of individuals.3 Rates of RAS occurrence range from 2% in the Swedish population to as high as 66% in
a student population.1 Recurrent aphthous stomatitis is not to be confused with the stomatitis that is caused
by various chemotherapeutic agents, which is beyond the scope of this article.
ETIOLOGY
Most patients with RAS have no major associated medical condition other than their complaint of
RAS.1 Oral ulcerations that resemble RAS; however, are seen in other diseases and syndromes such as
Behçet’s Syndrome, Sweet’s Syndrome, agranulocytosis, periodic fever syndrome and various nutritional
deficiencies and in patients with HIV disease.1 There have been many proposed origins for RAS, but none
has been proven to be the ultimate cause.1,2 Some of the factors which are thought to play a part in the
development of RAS are discussed below.
Local Factors
It has been noted that oral trauma may precipitate the development of RAS in certain susceptible
individuals.1,2,7 Rees noted in a study of 128 RAS patients, that 20 of these patients claimed a traumatic
incident to the oral mucosa was associated with their development of RAS.1 The trauma required to
stimulate RAS lesion production could include biting the mucosa, tooth brushing, a dental injection or
certain sharp foods.1 Trauma is not an associated factor in RAS development in all patients, but it should
be considered precipitating factor.2
Microbial Factors
Numerous researchers have attempted to explain the cause of RAS by way of some viral or
bacterial factor. Several strains of streptococci and viruses have been suggested as causes, but to date,
have not been proven conclusively.1,2 It has been shown that lymphocytic responses to Streptococcus
sanguis and S. mitis in patients with RAS was not different than that of control groups.6 Several
investigators have reported that there was not evidence to support the theory of viruses as a cause of RAS
based upon cultures, antibody titers, cytology or electron microscopy. 6
Genetic Factors
Genetic factors seem to play one of the biggest roles in patients with RAS. The presence of RAS
is certainly increased in patients with a positive family history.6 Approximately 50% of first-degree relatives
of patients with RAS also are RAS sufferers.7 Patients with a family history tend to develop RAS at an
earlier age, and more severely than those patients with no positive family history.1 There is also a high
correlation of RAS between identical, but not nonidentical twins.1
Nutritional Factors
Vitamin deficiencies have frequently been noted in RAS patients.1,2 Deficiencies in vitamins B1, B2,
B6, B12, folic acid, iron or zinc have been shown to occur twice as often in RAS patients versus control
groups.1 Approximately 20% of RAS patients studied in various trials have been noted to be deficient in
2
at least one of the hematinics.1 Other studies; however, have shown little relationship between nutritional
deficiencies and RAS.1
One area that has received considerable attention is the relationship of RAS to food allergies.
Many people have various food allergies. Elimination diets instituted in various RAS patients have
demonstrated an improvement or resolution of symptoms in 25-75% of patients.7 Certain patients
subjectively correlate the development of RAS lesions with the consumption of certain antigenic foods
which may include nuts, chocolate, cereals, tomatoes, cheese, cow’s milk, or citrus fruits.1 Conversely,
at least one investigator has proven no causal relationship between RAS development and the consumption
of foods that are commonly allergenic such as strawberries, tomatoes and walnuts.7
Table II. Factors associated with RAS.
Local
Oral truama (biting, tooth brushing)
Microbial
Various viruses?
*Genetic
Nutritional
Vitamin deficiencies (B vitamins, Fe, Zn)
Food allergies
Tobacco Use (Inverse Relationship)
Stress
* Most Likely Cause
3
Smoking and Tobacco Use
There actually appears to be an inverse relationship in the development of RAS and use of any form
of tobacco.6,7 This inverse relationship has been proven in at least one epidemiological study where all
participants who used tobacco in at least one form had a lower incidence of RAS than non tobacco users.7
The inverse effect of smokeless tobacco and RAS development was demonstrated in a study of
major league baseball players.4 Members of seven major league baseball teams, 1456 players, were
studied during spring training in 1989 and 1990. The men ranged in age between 17 and 63 years of age.
Thirty seven percent of the participants were current smokeless tobacco (ST) users, while 17% were
former ST users, and 44% were non ST users. After controlling for the confounding variables of age, race,
cigarette smoking, alcohol consumption and dental hygiene, ST users were found to have significantly less
incidence of RAS than non ST users.4 The suggested mechanism is an increased keratinization of the oral
mucosa.4 The authors further suggested that nicotine is probably the most likely protective factor.4
Stress
The factor of stress in the development of RAS is controversial.1 Patients have often subjectively
associated the appearance of RAS with increased stress.1 Studies have attempted to quantify the
relationship of stress and RAS, and have shown an incidence as high as 66% among medical and dental
students, which is higher than the reported incidence in the general population of 10-20%.1 Environmental
4
or emotional stress has been reported to precede the first RAS outbreak in 60% of patients, and in
approximately 21% of recurrent cases.1
CLINICAL CHARACTERISTICS
The clinical characteristics of RAS are important since no specific diagnostic test is available.1 The
major characteristics of RAS are a recurrence of one or more painful ulcers at intervals of days to months.1
Approximately 10% of patients record monthly recurrences, but most sufferers report three or four
episodes of new lesions per year.5 The ulcers are almost always located on the non-keratinized mucosa
of the mouth, which may include the buccal mucosa, the floor of the mouth, and the bottom surface of the
tongue.1
Clinicians tend to divide RAS into three clinically distinct groups.1,2,6,7 The three groups consist of
minor, major and herpetiform lesions.1,2,6,7 The clinical characteristics of each type of RAS lesion is
summarized in Table II.
5
Table II.1,2,6,7 Clinical characteristics of RAS.
RAS Classification
Characteristics
Minor
Major
Herpetiform
% of RAS cases
70-87%
7-20%
7-10%
Total lesions per occurrence
1-5
1-10
< 150
Size (diameter) of lesions
< 1cm
> 1cm
1-2mm
Lesion morphology
Shallow, round to
Deeper with raised,
Shallow, may
oval
irregular border
coalesce
Time to completely heal
7-14 days
Up to 6 weeks
7-10 days
Scars upon healing
No
Yes
No
PHARMACOLOGIC MANAGEMENT
The management of RAS is generally non specific, and is instituted with the following goals: to
relieve pain, to reduce the size and duration of ulceration, to alter the course of new ulcer formation. 2,5
Many treatments, both topical and systemic have been trialed in the treatment of RAS.1,2,5,6,7 Table II lists
some of the agents which have been utilized in the management of RAS.
6
Table III. 1,2,5,6,7 Agents utilized in the management of RAS.
Topical Therapies
Glucocorticoid creams/ ointments
Triamcinolone (Kenalog in orabase)
Clobetasol propionate (Temovate)
Glucocorticoid elixirs
Dexamethasone
Antimicrobial rinses
Chlorhexidene gluconate (Peridex)
Listerine antiseptic
Tetracycline oral rinse
Analgesics
Lidocaine viscous solution
Protectants
Sucralfate
Miscellaneous
5-aminosalicylic acid
á-interferon rinse
Systemic Medications
Glucocorticoids
Prednisone
Immunomodulators
Azathioprine
Cochicine
Miscellaneous
Thalidomide
7
Topical Medications
Topical therapies have received the most attention in the treatment of RAS. These agents are
generally without significant adverse effects, are easily applied, and in the case of topical anesthetics,
provide immediate relief from pain.
Antimicrobial Mouth Rinses
Mouth rinses are probably the initial treatment of most practitioners for the treatment of RAS.
These rinses are employed to control the mucositis by reducing secondary microbial contamination.7
Mouth rinses which are most commonly utilized include chlorhexidene gluconate and Listerine.1,2,5,8,9
Although chlorhexidine is considered relatively innocuous, long term use may stain teeth.1 Chlorhexidine
may alter taste sensation; therefore, it should not be used within 1 hour of mealtime.1
Although
chlorhexidine is widely used for the treatment of RAS, trials which demonstrate a benefit are scarce.
Benzydamine, chlorhexidine and placebo mouthwashes were compared in a controlled trial for their
effects on RAS.9 Each of 18 patients used a benzydamine hydrochloride 0.15% mouthwash, chlorhexidine
gluconate 0.2% mouthwash and a placebo mouthwash for a 3 month period in this 9 month trial. Fifteen
mL of the mouthwashes were used for 2 minutes every 4 hours. The patients were not aware of which
product they were using in each of the phases of the trial. During the trial period, each patient kept an ulcer
diary which recorded pain index and severity, record of new ulcers, size of the ulcer, and any side effect
of the mouthwash. It was interesting to note that analysis revealed that there were no significant differences
between any of the treatment arms in regard to size, number of ulcers, site frequency or pain severity.9
Listerine mouthrinse was compared to placebo (5% hydroalcoholic) rinse in a double-blind,
controlled trial of 160 young adult subjects.5 All patients enrolled had a history of RAS in the 6 months
8
prior to the study. Subjects randomly received either the Listerine or hydroalcoholic solution. The patients
rinsed for 30 seconds twice daily for 6 months. The Listerine and hydroalcoholic rinse demonstrated a
significant reduction in the incidence of RAS from baseline, but only the Listerine reduced the duration of
ulceration and the severity of pain associated with RAS.5
Topical Corticosteroids
Topical corticosteroids are non invasive, relatively benign in regards to adverse effects, and have
proven to be a beneficial treatment of RAS in numerous studies.6,8,10 The use of coticosteroids in the
management of RAS is based on the assumption that RAS is an acute inflammatory reaction, and that
steroids are potent antiinflammatory agents.6 It is most advisable to use high potency agents in the oral
cavity since these allow for less frequent (2-3 times daily) applications. Eventhough these potent topical
agents may be used for extended periods, the risk of hypothalamic axis suppression is very slight, and is
not generally considered a risk.11 The only major problem with the long term use of these agents is the
occurrence of oral candidiasis, which may necessitate the need for antifungal lozenges or mouth rinses.6
Clobetasol propionate 0.05% was combined in an oral paste in a 1:1 mixture in a trial of 24 patients
with various oral vesiculoerosive diseases.10 Seven of the 24 patients had persistent major recurrent
aphthous stomatitis. The medicated paste (final concentration 0.025%) was applied to the lesion 2-3 times
daily for a period of 2 weeks or until the next clinic follow-up visit, which was a mean period of 1 month.
Five of the seven RAS patients had a complete remission with no major adverse reactions.10
At least one study has compared the effectiveness of topical corticosteroids and chlorhexidene
gluconate for trestment of RAS.8 The study compared the efficacy of pain control of the two medications
utilized to treat RAS when each was placed under a physical barrier of cyanoacrylate.8 Chlorhexidine is
9
generally administered as a mouth rinse, but was administered topically in this study. Thirty patients with
a positive history of RAS were randomized into one of three groups. Group I received triamcinolone
acetonide 0.025% followed by isobutyl cyanoacrylate dressing. Group II received application of 0.12%
chlorhexidine digluconate followed by isobutyl cyanoacrylate dressing. Group III was the placebo group
which received isobutyl cyanoacrylate dressing alone. The patients were asked to complete a diary and
return for regular visits during the 12 week study visit. The study revealed a highly significant difference
between the two treatment groups and the placebo group in regards to pain control, but there was no
difference between the two treatment groups themselves.8 There was no difference in any of the groups
with respect to the duration of the lesions.8 Again, it must be noted, that the topical administration of a
chlorhexidine under a paste is certainly a novel approach, and is not FDA approved for use in this manner.
Another approach which was utilized in a case of severe major RAS, was to combine a topical
corticosteroid and an oral immunosuppressant agent.12 A 32 year old woman was evaluated for treatment
of severe RAS after presenting with a mjor aphthous ulceration of the anterior one third of her tongue. This
lesion had persisted for 3 months, and had caused much pain, diffulty in speaking, and even weight loss.
Treatment was initiated with azothiaprine 50mg, one tablet twice daily and ibuprofen, 600mg tablets taken
four times daily. After 10 days, the patient was instructed to rinse her mouth with 5ml of dexamethasone
elixir (0.1mg/ml) after meals and at bedtime, and then expectorate. Within three months of the initiation of
this treatment, the lesions had healed and the patient reported no adverse effects to any of the
medications.12
ORAL MEDICATIONS
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Corticosteroids
Vincent states that most aphthae patients in his practice seem to respond adequately to topical
steroids, but systemically administered steroids are occasionally necessary.6 He further recommends, if
systemic steroids are necessary, a burst dose of 40-60 mg of prednisone administered one hour after
arising in the morning for 5 consecutive days.6 This short course of treatment, without a tapering schedule,
generally does not result in appreciable adrenal suppression. 6 Certain HIV seropositive patients may benefit
froma a more prolonged course of systemic corticosteroids.2 A 60mg starting dose of prednisone may be
administered and subsequently tapered over a period of 2 weeks.2
Thalidomide
A novel approach to the treatment of RAS involves the use of thalidomide.13,14,15 Thalidomide was
originally utilized in the early 1960's a sedative, and was widely prescribed to pregnant women in Europe.
Thalidomide was withdrawn from the market in 1962, when it was discovered that it was a potent
teratogen. 15 Thalidomide was subsequently found to be a useful therapy in a number of various
inflammatory diseases including leprosy and discoid lupus erythematosus.15 Thalidomide was FDA
approved in 1998 for use in the treatment of leprosy.
A multicenter, randomized, crossover, double-blind, placebo controlled trial demonstrated the
usefulness of thalidomide in the treatment of RAS.15 Seventy three patients were enrolled in this study. All
patients had severe RAS of greater than 6 months duration. The patients in the trial were randomized to
receive thalidomide 100 mg tablet or placebo administered nightly for 2 months. Thalidomide treatment
resulted in a complete response in 48% of patients, whereas, only 9% of placebo patients registered a
complete response. The thalidomide patients also reported a significantly greater decrease in total number
11
of ulcerations versus the placebo group. The thalidomide patients also reported a much higher incidence
of adverse effects. Seventy five percent of thalidomide patients reported drowsiness during treatment.15 The
study did demonstrate the efficacy of thalidomide in the treatment of RAS.15 It must be noted that
thalidomide is a potent teratogen, and is currently not indicated for any treatment in the United States other
than leprosy, so its use in RAS is purely academic at this point.
Colchicine
Colchicine is a novel treatment that has proven beneficial in all types of RAS.16,17 Gatot reported 4 cases
where colchicine therapy was of substantial benefit.16 The four patients ranged in age from 25-39 years.
All had a long history of RAS, and were seeking help for their conditions. Colchicine was administered as
0.6-1.2 mg daily, with therapy being interrupted in two patients secondary to complaints of nausea. One
patient was able to resume treatment at a dose of 0.6mg administered 5 days per month, whereas the other
patient who stopped the medication, suffered recurrence of RAS after one month. The remaining patients
reported no significant recurrence while on colchicine therapy.16
Twenty patients were enrolled in an open label 4 month study to determine the effectiveness of
colchicine in the recurrence of RAS and the pain associated with this syndrome.17 The patients served as
their own controls. The first 2 months of the study was utilized to gather baseline data, and for the remaining
2 months, colchicine was administered 0.5mg three times daily. Patients were asked to record
pain/discomfort scores on a daily basis, and were examined weekly for ulcer counts. The mean aphthae
count decreased by 71%, and the mean pain scores decreased by 77%. Only two patients did not
subjectively respond to colchicine treatment. Four patients complained of minor adverse effects which
included nausea, abdominal cramps, diarrhea and urticaria. None of the adverse effects necessitated
12
discontinuation of therapy.17
SUMMARY
Recurrent aphthous stomatitis may be a manifestation of inflammatory, autoimmune or connective
tissue diseases; however, most cases are idiopathic.1,17 The incidence ranges greatly, but may be as high
as 60% in certain populations.2 The lesions are generally self limiting and resolve within 7-10 days;
however, major ulcerations may persist for months and be debilitating.2 A variety of topical and systemic
medications have been utilized with varying degrees of success.
The pharmacist should review a patient’s symptomatology to accurately determine if the complaint
is indeed RAS. There are other oral diseases that may be mistaken for this syndrome, such as herpes
simplex. The goal of therapy is to decrease pain, promote healing and prevent reoccurrence.
Patients should be instructed to follow general rules of oral hygiene. These measures could include
regular tooth brushing and oral rinses of antiseptic solutions. The patient should be cautioned against any
unnecessary roughness while brushing to avoid further mucosal injury. If these general measures are
unsuccessful, the next logical course is a trial of topical anesthetic (benzocaine 20%) in a protectant dental
paste (Orabase-B). This will protect the lesion, allow it to heal and numb the pain.
Topical steroids in a dental paste (ie: Kenalog in Orabase) or chlorhexidene gluconate mouth rinse
may be the next course of action. These are prescription products, so the patient will need to visit a dentist
or physician. The patient should apply the paste directly to the lesion 2-3 times daily, or rinse with the
chlorhexidine solution 3-4 times daily. Although topical steroids will probably suffice in the majority of
routine RAS patients. Those patients with major or resistant aphthae, may require alternative therapies such
as oral steroids, colchicine or immunosuppressants.
13
If the outbreak is particularly severe, or is of the major type, oral corticosteroids are probably
indicated. There is no one proven drug or regimen; however, “burst” doses of prednisone (40-60mg daily
x 5 days) has proven to be of benefit in one trial, and did not result in adrenal cortical suppression. 6
References
1.
Rees TD, Binnie WH. Recurrent aphthous stomatitis. Dermatol Clinics. 1996;14:243-56.
2.
Ship J. Recurrent aphthous stomatitis. An update. Oral Surg Oral Med Oral Path Oral Radiol
Endod. 1996;81:141-7.
3.
Embil JA, Stephens RG, Manuel FR. Prevalence of recurrent herpes labialis and aphthous
ulcers among young adults on six continents. Can Med Assoc J. 1975;113:627-30.
4.
Grady D, Ernster VL, Stillman L, Greenspan J. Smokeless tobacco use prevents aphthous
stomatitis. Oral Surg Oral Med Oral Pathol. 1992;74:463-5.
5.
Meiller TF, Kutcher MJ, Overholser CD et al. Effect of an antimicrobial mouthrinse on
recurrent aphthous ulcerations. Oral Sug Oral Med Oral Pathol. 1991;72:425-9.
6.
Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis.
Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol.
1992;74:79-86.
7.
Woo SB, Sonis ST. Recurrent aphthous ulcers: A review of diagnosis and treatment. J Am
Dent Assoc. 1996;127:1202-13.
8.
Miles DA, Bricker SL, Razmus TF, Potter RH. Triamcinolone acetonide versus chlorhexidine
for treatment of recurrent stomatitis. Oral Surg Oral Med Oral Pathol. 1993;75:397-402.
9.
Matthews RW, Scully CM, Levers BGH, Hislop WS. Clinical evaluation of benzydamine,
chlorhexidine, and placebo mouthwashes in the management of recurrent aphthous stomatitis.
Oral Surg Oral Med Oral Pathol. 1987;63:189-91.
10.
Lozada-Nur F, Huang MZ, Zhou G. Open preliminary clinical trial of clobetasol propionate
ointment in adhesive paste for treatment of chronic oral vesiculoerosive diseases. Oral Surg
Oral Med Oral Pathol. 1991;71:283-7.
14
11.
Plemons JM, Rees TD, Zachariah NY. Absorption of a topical steroid and evaluation of
adrenal suppression in patients with erosive lichen planus. Oral Surg Oral Med Oral Pathol.
1990;69:688-93.
12.
Brown RS, Bottomley WK. Combination immunosuppressant and topical steroid therapy for
treatment of recurrent major aphthae. Oral Surg Oral Med Oral Pathol. 1990;69:42-4.
13.
Nicolau DP, West TE. Thalidomide: Treatment of severe recurrent aphthous stomatitis in
patients with AIDS. Ann Pharmacother. 1990;24:1054-6.
14.
Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad
Dermatol. 1985;12:85-90.
15.
Revuz J, Guillaume JC, Janier M et al. Crossover study of thalidomide vs placebo in severe
recurrent aphthous stomatitis. Arch Dermatol. 1990;126:923-7.
16.
Gatot A, Tovi F. Colchicine therapy in recurrent oral ulcers. Arch Dermatol. 1984;120:994.
17.
Katz J, Langevitz P, Shemer J, Barak S, Livneh A. Prevention of recurrent aphthous stomatitis
with colchicine: An open trial. J Am Acad Dermatol. 1994;31:459-61.
15
Continuing Education Questions
1.
Patients who have demonstrated a local colonization of
greater risk of developing RAS than someone who does not have this colonization.
Have a 5x
a.
b.
c.
d.
Streptococcus sanguis
Staphylococcus aureus
Candida tropicalis
None of the above have a proven causal relationship to the development of RAS
2.
Which of the following is true regarding the use of tobacco and the development of RAS?
a.
b.
c.
d.
Pipe smokers frequently develop severe RAS
Tobacco users typically have lower incidence of RAS than do non-tobacco users.
Tobacco users usually have a higher incidence of RAS than do non-tobacco users
Cigar smokers tend to have a higher incidence of RAS than do users of smokeless tobacco
3.
Which of the following is NOT a characteristic of the majority of RAS cases.
a.
b.
c.
d.
Lesions are shallow, and round to oval in shape.
Lesions are usually <cm in diameter
Lesions usually scar upon healing
Lesions generally heal completely within 14 days.
4.
A goal for the management of RAS includes:
a.
b.
c.
d.
Relieve pain
Reduce the size and duration of ulceration
Alter the course of new ulcer formation
All of the above are goals of therapy
5.
Chlorhexidine mouth rinse may have the following adverse effect:
a.
b.
c.
d.
Often sensitizes the oral mucosa
Long term use often stains teeth
Intensification of scarring upon healing of the ulcer
Can induce angioedema if swallowed
6.
Which of the following is TRUE regarding the use of topical steroids in the treatment of RAS?
a.
It is advisable to use lower potency agents
16
b.
c.
d.
Corticosteroid pastes require hourly application
These agents frequently cause hypothalamic axis suppression if used for >5 days.
Topical corticosteroids may induce oral candidiasis.
7.
Which of the following is a recommended schedule for the use of oral corticosteroids in the
treatment of RAS?
a.
b.
c.
d.
Prednisone 40-60 mg QD x 5 days
Prednisone 10mg BID x 14 days
Dexamethasone 10mg QD x 10 days
Methylprednisolone 4mg QID x 3 days
8.
Thalidomide has shown some benefit in th treatment of RAS, but certain problems are
associated with its use. Which of the following are problems associated with the use of thalidomide?
a.
b.
c.
d.
Teratogenicity
Sedation
Only FDA approved for the treatment of leprosy
All of the above are potential problems concerning thalidomide
9.
When dispensing a prescription for colchicine in the treatment of RAS, the pharmacist should
council the patient that:
a.
b.
c.
d.
Ulcers should disappear within 3 days of beginning the medication
Nausea, diarrhea, and abdominal cramping may occur
Never concomitantly administer colchicine while utilizing topical steroids
Colchicine generally induces lesions within the first week of beginning therapy
10.
The theory behind using topical steroids combined in a dental paste include
a.
b.
c.
d.
Allow ulcer protection while delivering the steroid to the site of inflammation
Provides immediate analgesia after administration
Provides protection against future outbreaks of new lesions
Decrease antimicrobial resistance of various oral pathogens
17