CHAPTER 75
Aphthous Stomatitis
Recurrent aphthous ulcers (RAUs), also called aphthous
stomatitis and canker sores, are the most common oral
mucosal lesions, affecting 20% of the population in
North America. They appear as recurrent ulcers with cir-
cumscribed margins with erythematous halos and gray or
yellowish floors (Fig. 75.1).
RAUs affect the nonkeratinized or poorly keratinized
mucosa of the mouth and oropharynx. No specific test
is available for RAUs, and diagnosis is made from the
patient’s history and clinical findings.
PATHOPHYSIOLOGY
RAUs appear to be multifactorial in origin, with a strong
component of immune mediation. Histologically, there
is an increase in immunoglobulin (Ig)E–bearing lym-
phocytes along with an increase in the number of mast
cells and tumor necrosis factor-alpha (TNF-alpha) in the
prodromal stages.1 Cytotoxic action of lymphocytes and
monocytes seem to cause the ulceration, but the exact
trigger is not clear.
The three main clinical variations are as follows2:
• Minor aphthous ulcers: Commonly less than 5 mm
in diameter, these are the most common form (80%).
Typically one to five ulcers may be present at any one
time, and they usually heal without scarring in 7 to 14
days.
• Major aphthous ulcers: These ulcers, which are less
common, are larger and deeper than minor aphthous
ulcers, tend to have irregular edges, and are more
FIG. 75.1  □  Recurrent aphthous ulcers. The ulceration seen on the
labial mucosa is surrounded by a characteristic erythematous
halo. (From Zitelli BJ, Davis HW. Atlas of pediatric physical diag-
nosis. 5th ed. St. Louis, 2007, Mosby.)
David Rakel, MD
painful. They affect the lips, soft palate, and orophar-
ynx and can take up to 6 weeks to heal, often leaving a
considerable scar. Major and minor RAUs can be as-
sociated with Behçet’s syndrome and human immuno-
deficiency virus (HIV) infection.
• Herpetiform RAUs: Measuring 1 to 3 mm in diameter,
herpetiform RAUs often occur in groups of 10 to 100
that commonly coalesce to form large, irregular areas
of ulceration. These are not as deep as major aphthous
ulcers. They heal without scarring in 7 to 14 days and,
despite their name, are not associated with the herpes
or any other virus.
Minor and major RAUs usually begin in childhood or
early adolescence and have a tendency to resolve natu-
rally later in life. Herpetiform RAUs appear later in life
compared to minor and major RAUs, usually in the third
decade (Box 75.1).
INTEGRATIVE THERAPY
Lifestyle
Toothpaste
Sodium lauryl sulfate is a common detergent used in tooth-
pastes that has been shown to precipitate RAUs.21 Other
ingredients may also affect RAUs, so a good question to
ask patients with newly developed RAUs is whether they
have recently changed toothpaste. CloSYS, Tom’s of Maine,
The Natural Dentist, Burt’s Bees, and Squigle are examples
of brands of toothpaste that do not contain sodium lauryl
sulfate.
Nutrition
Several nutritional deficiencies have been associated
with RAUs. Vitamin B12, iron, and folic acid have been
the most studied nutrients and have been found to be
commonly deficient in patients with RAUs.3 Labora-
tory evaluations for red cell folate, serum vitamin B12,
and ferritin levels should be included in any evaluation
of RAUs.
Vitamins B1,4 B2, B6, and B12 have also been found to
be deficient in some patients with RAUs.5
Laboratory evaluation for red cell folate, serum vitamin B12,
and ferritin levels, as well as a complete blood count, should
be ordered in the evaluation of recurrent aphthous ulcer-
ation. HIV infection should be considered if the patient is at
risk for this infection.
747
748 PART II  Integrative Approach to Disease
BOX 75.1   Etiology of Recurrent Aphthous
Ulceration
The origin of recurrent aphthous ulceration seems to be multi-
factorial and can include one or several of the following factors:
• Familial and genetic basis
• Nutritional deficiencies: vitamins B1, B2, B6, and B12,
folic acid, iron
• Stress
• Stopping smoking
• Menstruation
• Food allergies (cow’s milk and gluten most common)
• Sensitivities to toothpastes (sodium lauryl sulfate)
• Medications
Antineoplastic (methotrexate, daunorubicin, doxorubi-
cin, hydroxyurea)
Angiotensin-converting enzyme inhibitors (captopril
most common)
Antimicrobials
Metformin
Barbiturates
Griseofulvin
Nonsteroidal antiinflammatory drugs (NSAIDs)
Sulfonamides
Quinidine
Penicillamine
• Physical trauma
• Systemic conditions
Celiac disease
Crohn’s disease
Human immunodeficiency virus infection
Neutropenia and other immune deficiencies
Neumann bipolar aphthosis
Behçet’s syndrome
MAGIC (mouth and genital ulcers with inflamed
cartilage)
 
Diet
A few patients with RAUs have gluten-sensitive enterop-
athy and improve considerably with a gluten-free diet.6
The diagnosis is usually made by jejunal biopsy or by
assay of tissue transglutaminase IgA with a positive anti-
endomysial antibody. Although no evidence in the litera-
ture shows that gluten-free diets help patients with RAUs
who do not have gluten sensitivity,7 anecdotal observa-
tions indicate that some patients without gluten sensitiv-
ity may benefit from a gluten-free diet.8 For the patient
with recurring ulcers, a 2- to 4-week therapeutic trial of
gluten avoidance is a reasonable option to assess effect.
The role of food allergies in the pathogenesis of RAUs is
controversial. Several foods—milk, chocolate, coffee, nuts,
strawberries, pineapple, citrus fruits, tomatoes, azo dyes—
and food additives—monosodium glutamate (MSG), benzoic
acid, tartrazine (yellow dye no. 5), and cinnamaldehyde—have
all been suggested as a cause of RAUs9,10 (see Chapter 86).
Honey
Honey has been found to be helpful in healing stasis
ulcers of the legs as well as preventing mouth ulcers in
patients receiving radiation therapy. In 40 patients with
head and neck cancer who were receiving radiation, those
who took 20 mL of honey 15 minutes before therapy and
at 15 minute intervals at the time of therapy, and then
again 6 hours after therapy, developed significantly fewer
mouth ulcers than the saline treated control group.11
Supplements
Glutamine
Glutamine, the most abundant amino acid in the body,
is essential for maintaining intestinal function, immune
response, and amino acid homeostasis during times
of severe stress. Glutamine supplementation has been
found to improve nutritional and immunologic sta-
tus and reduce complications in critically ill patients.12
However, not everyone benefits from supplementation.
Those who have the greatest nutritional deficiency are
thought to have the best clinical response.13 Supple-
mentation with glutamine is beneficial during times
of skeletal muscle wasting because most of glutamine
is produced in skeletal muscle, and glutamine deple-
tion raises the incidence of oral and gastrointestinal
ulcerations. This amino acid has been found to reduce
the duration and severity of oral stomatitis in patients
undergoing chemotherapy.14
Dosage
Glutamine can be purchased in powder form. The patient
should mix 4 g of powder in water, swish in the mouth, and
swallow four times daily. If glutamine is used with chemo-
therapy, it should be taken on the day of chemotherapy and
then used for 4 days after completion of each treatment.
Precautions
Grittiness of the oral solution may be unpleasant. Glutamine
is otherwise well tolerated. It may cause mania in patients
with bipolar disease.
Vitamin B12
A randomized, double-blind trial using 1000 mcg of sub-
lingual vitamin B12 taken daily before sleep for 6 months
in 58 patients with RAU showed that those in the treat-
ment arm of the trial had significant reduction in ulcer
formation, and 74% (compared with 32% in the pla-
cebo group) reported “no aphthous ulcer status” after 6
months. The response was not predicted by the baseline
serum vitamin B12 levels; study subjects with normal B12
levels still responded to therapy.15 Metformin can cause
B-vitamin deficiency. Consider supplementing if patients
on this medicine have RAU.30
Dosage
The dose of vitamin B12 is 1000 mcg sublingually daily for
ulcer prevention.
Precautions
Vitamin B12 therapy is safe. The body excretes any excess
into the urine, with the resulting classic bright yellow color-
ation seen with vitamin B supplementation.

Botanicals
German Chamomile (Matricaria recutita)
Chamomile is used for its antiinflammatory properties in
the treatment of dyspepsia, leg ulcers, and oral mucositis.
When used as a mouthwash, it has been found to pre-
vent oral mucositis associated with radiation therapy and
chemotherapy.16
Dosage
Make an oral rinse with 10 to 15 drops of German cham-
omile liquid extract in 100 mL warm water, and use three
times daily.
Precautions
The plant has allergic potential but is otherwise safe.
Licorice (Glycyrrhiza)
Licorice, which has antiinflammatory action, has been
used as a mouthwash and is available in oral disks.17 A
randomized, double-blind study using a Glycyrrhiza oral
patch compared with placebo patch showed significantly
faster resolution of ulcers in the Glycyrrhiza-treated
group at 8 days.18
Dosage
To use licorice as a mouthwash, mix half of a teaspoon of
licorice extract with a quarter cup of water, swish, gargle,
and expel the mouthwash four times daily for symptomatic
aphthous ulcers.
A product called CankerMelt contains 30-mg Glycyrrhiza
extract. The disk is applied to the ulcer and allowed to dis-
solve over time; then a new disk is applied every 6 hours.
Precautions
If the mouthwash is not swallowed, side effects are rare.
Licorice can cause sodium retention and hypokalemia if it
is swallowed. Care should be taken with the use of licorice
in patients with hypertension because licorice ingestion can
worsen the condition.
Although research is limited, many patients find pain relief
due to the tannins found in tea leaves (Camellia sinensis). A
brewed black or green tea bag can be applied to the ulcer as
needed.
Homeopathy
Several homeopathic remedies have been used histori-
cally to treat RAUs. Unfortunately, all of the evidence
for their use is anecdotal. A classical homeopath would
75  Aphthous Stomatitis 749
look for a constitutional remedy that fits the whole
patient. Symptomatic remedies that may help are as
follows:
• Mercurius solubilis is indicated if the RAUs are associ-
ated with foul breath and increased salivation.
• Borax is indicated if the RAUs are brought on by cit-
rus or acidic foods. The mouth usually feels dry even
though some saliva may be present.
• Arsenicum album is indicated in patients with RAUs
that are brought on by stress and eased with hot
drinks.
Dosage
All the preceding remedies are best given initially at a po-
tency of 6X or 6C four times daily (the X and C refer to the
potency, which is the extent of dilution of the remedy). They
should be discontinued when the RAUs begin to improve
(see Chapter 115).
Mind-Body Therapy
Stress, both emotional and physical, triggers RAUs.
Emotional and environmental stress may precede 60%
of first-time aphthous ulcer cases and be involved in
21% of recurrent episodes.8 The pathogenesis may
involve the known alteration of the immune response
from stress, the depletion of B vitamins, or may be
unknown.
Meditation and stress reduction techniques, such as
guided imagery and hypnosis, have been shown to be use-
ful in the management of RAUs.19,20
Pharmaceuticals: Antiinflammatory Agents
Amlexanox
The only prescription medication approved by the U.S.
Food and Drug Administration (FDA) for treatment of
aphthous stomatitis is amlexanox (Aphthasol) 5% paste.
It accelerates healing through an unknown mechanism
that inhibits release of inflammatory mediators (hista-
mine and leukotrienes) from mast cells, neutrophils, and
mononuclear cells. This agent has no direct analgesic
properties.
Dosage
Apply 0.5 cm to the sore with fingertip four times daily after
meals and at bedtime. Start at the onset of symptoms and
stop with resolution. If no resolution has occurred in 7 days,
reevaluation is warranted. Amlexanox is dispensed in a 5-g
tube.
Precautions
This agent may cause minimal burning on application. Rash,
diarrhea, nausea, and worsening stomatitis have been report-
ed in less than 1% of cases.
750 PART II  Integrative Approach to Disease
Triamcinolone and Dexamethasone
Steroids such as triamcinolone and dexamethasone
reduce inflammatory mediators but do not decrease the
frequency of RAU occurrence.
Dosage
For triamcinolone acetonide: 0.1% in carboxymethyl cellu-
lose paste (Kenalog in Orabase), apply 0.5 cm to the sore
two or three times daily. Start at the onset of symptoms and
stop with resolution. If no resolution has occurred in 7 days,
reevaluation is warranted. This agent is dispensed in a 5-g
tube.
For dexamethasone (Decadron) oral solution: 0.5 mg/5
mL, rinse the mouth with one teaspoon (5 mL) for 2 min-
utes and spit out, three times daily after meals and once at
bedtime.
Precautions
Thrush may occur.
Pharmaceuticals: Analgesic Agents
A helpful approach is to avoid spicy, salty, and vinegar
containing foods that may irritate and increase pain of
the ulcers. The following analgesic agents may also be
useful:
Viscous Lidocaine (Xylocaine 2% solution)
This agent provides anesthetic properties that diminish
pain while eating.
Dosage
To use viscous lidocaine (Xylocaine 2% solution), swish 15
mL and expel, every 3 hours or before meals, as needed for
pain relief. Do not use more than eight doses daily. This
agent is dispensed in 50-, 100-, and 450-mL bottles.
Precautions
Care should be taken not to ingest large amounts of viscous
lidocaine because of its potential for cardiotoxicity. Benzo-
caine gel (10% to 20%) is a safer alternative, particularly for
use in children.
Pharmaceuticals: Mouthwashes
Chlorhexidine Gluconate
Chlorhexidine gluconate 0.12% oral solution (Peridex
or Periogard oral rinse) is a mouthwash that has been
shown to reduce the incidence, duration, and discomfort
of RAUs.22 It does not, however, appear to be as effective
as the other pharmaceutical topical agents.23
Dosage
Swish 15 mL for 30 seconds and expel, twice daily. Chewing
sugarless gum after using this mouthwash can help reduce
tooth discoloration.
Precautions
This agent can cause stinging when it is first used, reversible
discoloration of the teeth and tongue after 1 week of use,
transient disturbances of taste, and burning sensation of the
tongue.
Tetracycline–Fluocinolone Acetonide–
Diphenhydramine Mouthwash
For more severe cases, a formula containing tetracycline,
fluocinolone acetonide, and diphenhydramine can be
used. Tetracycline is thought to work through antimi-
crobial and antiinflammatory mechanisms. Fluocinolone
and diphenhydramine work through antiinflammatory
and anesthetic mechanisms. This mixture has been found
to be very helpful in severe cases of RAUs resulting from
immunosuppressant therapy.
Dosage
Mixing this formula requires the help of a pharmacist. Most
pharmacies are able to comply with these directions. The
following should be mixed together to make a total of 150
mL:
• Tetracycline: At a concentration of 500 mg per 5 mL
(which a pharmacist makes by dissolving a 500 mg
capsule in 5 mL of water) for a total of 60 mL
• Diphenhydramine syrup (Benadryl): 12.5 mg/5 mL for
a total of 60 mL
• Fluocinolone acetonide 0.01% solution (Synalar) for a
total of 30 mL
Swish 10 mL and expel four times daily until the ulcers
resolve. Do not use for more than 7 days at a time.
Precautions
Tetracycline should not be given to children younger than
9 years because it stains the teeth. Fluocinolone, like most
steroids, can cause thrush if it is used for extended periods.
For severe cases, a trial of tetracycline–fluocinolone ace-
tonide–diphenhydramine mouthwash is indicated before us-
ing systemic therapy.
Systemic Pharmaceuticals
For cases resistant to topical therapy, consider the fol-
lowing systemic pharmaceuticals, in descending order as
discussed in the following.
Colchicine
Colchicine has been used for stomatitis associated with
Behçet’s disease.24 It has also been found to be ben-
eficial for RAUs in patients without this disorder and
is even more effective when combined with systemic
steroids.25

Dosage
The dose is 0.6 mg orally twice daily. It may be increased to
three times daily as tolerated with regard to gastrointestinal
side effects.
Precautions
The most common side effects are gastrointestinal, consist-
ing of diarrhea, nausea, and cramping. Colchicine can also
cause thrombocytopenia and aplastic anemia.
Systemic Steroids
No good studies have been conducted on the use of sys-
temic steroids for RAUs. These agents should be used
cautiously in immunocompromised hosts.
Dosage
The dose of prednisone is up to 40 to 60 mg/day for 5 days.
If longer use is needed, taper the dosage over 10 to 14 days.
Precautions
In patients with HIV infection, adverse reactions include
cushingoid facies, thrush, reactivation of herpes simplex vi-
rus, and accelerated progression of Kaposi sarcoma.26
Thalidomide
Thalidomide has efficacy in healing oral aphthae. In two
trials involving difficult cases, thalidomide completely
healed 48% to 55% of ulcers, compared with 7% to 9%
in patients receiving placebo. This effect was temporary,
however; many of the patients treated had recurring
symptoms.27
PREVENTION PRESCRIPTION
Have patients:
• Avoid oral trauma from biting, dental proce-
dures, brushing, and eating of rough foods.
• Avoid toothpaste that contains sodium lauryl
sulfate.
• Ensure adequate nutrition by consuming seven to
nine servings of fruits and vegetables daily.
• Avoid trigger foods; cow’s milk protein and
wheat (gluten) are most common.
75  Aphthous Stomatitis 751
Dosage
The dose is 200 mg/day orally.
Precautions
Because of the potential for teratotoxicity and irreversible
peripheral neuropathy, this treatment should be used only
for the most serious, intractable cases.
Because of the elevation of tumor necrosis factor-alpha
(TNF-alpha) in recurrent aphthous ulceration, some people
with resistant cases related to autoimmune conditions may
benefit from a TNF inhibitor drug such as infliximab, etan-
ercept, or adalimumab. These medications also pose a sig-
nificant risk resulting from inhibition of immune function.28
Cautery With Silver Nitrate
The use of silver nitrate sticks to provide chemical cau-
tery was found to reduce pain significantly compared with
placebo, but it did not reduce healing time. The study
involved only one application. Clinicians contemplating
this therapy should consider pretreating the ulcer with
2% viscous lidocaine and then painting the ulcer with the
silver nitrate stick until it turns completely white.29
Therapies to Consider
Traditional Chinese Medicine
Chinese medicine views RAU as a condition caused by
heat in the stomach; it can also be caused by yin deficiency
or toxic heat. Treatment is with topical watermelon frost
or internally with formulas that cool stomach heat and
clear toxic heat, such as dao chi pian or niu huang jie du
pian. Although no reliable studies on the use of traditional
Chinese medicine in the treatment of RAUs have been
conducted, referral to a Chinese medicine practitioner is
a valid approach if other treatments are not indicated or
are unsuccessful.
• C onsider a B 100 complex vitamin daily for recur-
ring cases.
• Help patients learn how to change their inter-
pretation of stressful information and events to
reduce physical consequences (see Chapters 94
and 100).
• Avoid the use of medications associated with
recurrent aphthous ulcers (see Box 75.1).
752 PART II  Integrative Approach to Disease
THERAPEUTIC REVIEW
The most important issue in dealing with recurrent aphthous
ulcers (RAUs) is to exclude systemic conditions, particularly
Behçet’s syndrome (mouth, genital, and eye ulcers). Because
the origin of RAUs is multifactorial, a simple list of treatments
is not applicable; a good history helps focus on the triggers
and can lead to a specific treatment plan. The following is a
guide to the most common causes and treatments of RAU.
LABORATORY EVALUATION
• Identification of nutritional deficiencies should be the
first step in treating RAUs.
• Order laboratory measurements of serum ferritin,
red cell folate, and serum vitamin B12. Replace these
nutrients if the patient is deficient.
• Giving 250 mg of vitamin C with iron is often helpful
to assist with iron absorption.
NUTRITION
• If you suspect celiac disease, assess the patient for
tissue transglutaminase immunoglobulin A and anti-
endomysial antibodies.
• Identify any foods that trigger the RAUs and consider
elimination (see Chapter 86).
• Consider using honey, 20 mL before, during, and
after radiation therapy of the head and neck to reduce
the severity of mouth ulcerations. cellulose paste (Kenalog in Orabase): 0.5 cm
SUPPLEMENTS
• B vitamins (vitamins B1, B2, B6, B12)
• Because the cost and potential harm of B vitamins
are low, a 3-month trial of one B 50 complex
vitamin pill daily can be used to see whether the
frequency of RAUs is reduced. A B 50 complex
vitamin contains approximately 50 mcg or mg of
each B vitamin.
• Vitamin B12, 1000 mcg sublingually daily for 6
months, has been found to reduce the incidence
of ulcers. mixed together to make 150 mL; 10 mL swished
• Glutamine
• Mix 4 g of powder in water, swish, and swallow
four times per day.
• This is best for RAUs resulting from severe dis-
ease or injury or in patients undergoing chemo-
therapy. • Prednisone: 40 to 60 mg per day for 5
BOTANICALS
• Licorice (Glycyrrhiza) mouthwash: Mix half teaspoon
of licorice extract in a quarter cup of water; swish
and expel four times per day. CAUTERY
• CankerMelt disks contain 30 mg Glycyrrhiza extract.
The disk is applied to the ulcer and allowed to dis-
solve over time; then a new disk is applied every 6
hours. tion. B
Key Web Resources
Dentist.net: This consumer site sells sodium lauryl sulfate–
free toothpastes.
OraHealth: This company developed oral adhering disks that
allow the medicinal application of specific treatments for
recurrent aphthous ulcers.
REFERENCES
References are available online at ExpertConsult.com.
HOMEOPATHY C 1
• Mercurius solubilis is indicated if the RAUs are as-
sociated with foul breath and increased salivation.
Use 6X or 6C potency four times per day until healing
begins.
• Borax is indicated if the RAUs are brought on with
citrus or acidic foods. The mouth usually feels dry
even though some saliva may be present. Use 6X or
6C potency four times per day until healing begins.
• Arsenicum album is indicated in patients whose
RAUs are brought on by stress and eased with hot
drinks. Use 6X or 6C potency four times per day until
healing begins.
MIND-BODY THERAPY C 1
• Because stress is often a component of RAUs, stress
reduction techniques, such as meditation and guided
imagery, are usually advisable to include in
management (see Chapter 94).
PHARMACEUTICALS
• Topical therapy
• Amlexanox (Aphthasol) 5% paste: 0.5 cm applied
to sore four times daily B 1
C 1
• Triamcinolone acetonide 0.1% in carboxymethyl
B 1
applied to the sore three to four times
daily
• Viscous lidocaine (Xylocaine 2% solution):
15 mL swished every 3 hours as needed for B 2
pain
• Chlorhexidine gluconate 0.12% oral solution
(Peridex or Periogard oral rinse): 15 mL rinsed B 2
and expelled twice daily
• Tetracycline 500 mg per 5 mL to make 60 mL,
fluocinolone acetonide solution (Synalar) 30 mL,
B 1
and diphenhydramine syrup (Benadryl) 60 mL, C 2
and expelled four times daily
• Systemic Therapy
• Colchicine: 0.6 mg twice daily, increased to
three times daily as tolerated in terms of B 2
B 1
gastrointestinal side effects
days C 2
• Thalidomide: 200 mg per day; used only for
most severe cases B 3
B 2
• Premedicate with 2% viscous lidocaine and paint the
ulcer once with silver nitrate stick until it turns white.
• This technique helps reduce pain but not ulcer dura-
2
http://www.dentist.net/sls-free-toothpaste.asp
http://www.orahealth.com/
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