Prescribing in practice

Oral ulceration: GP guide to

diagnosis and treatment
Stephen Flint MA, PhD, MB BS, BDS, FDSRCS, FFDRCSI, FICD
Simple mouth ulcers are
usually self-limiting and
rarely present in general
practice. However, severe,
recurrent or persistent oral
ulceration can be extremely
painful and may result from
an underlying systemic
pathology. Dr Flint describes
the different causes of oral
ulcers and discusses treat-
ment options.
Figure 1. Nicorandil ulceration. The ulceration is persistent, painful, deep, punched
out, with little inflammatory halo and no induration. The ulceration may respond to
dose reduction, but usually cessation of the drug is required to allow healing to occur

lceration is one of the most is such a readily accessible source noma (see Figure 2): this typically
U common complaints of
patients who attend their GPs with
of diagnostic information.
Causes of oral ulceration range
presents as an ulcer with a rolled
everted edge and sloughing or
an oral problem and the differen- from the relatively trivial, eg trau- granular base. The exophytic form,
tial diagnosis is extensive. matic ulcers, to the serious, eg oral verrucous carcinoma, is uncom-
However, the artificial distinction cancer or pemphigus vulgaris (see mon but has a better prognosis.
between medicine and dentistr y Table 1). The ulcer is often painless
has led to this important area of The key to appropriate therapy until it involves the periosteum,
disease presentation being over- is accurate diagnosis and this may bone or deep mucosal tissues and,
looked in medical training, and require liaison between general consequently, many patients pre-
many doctors therefore feel inad- and specialist medical and dental sent late with extensive disease
equately prepared to deal with oral practitioners. and a poor prognosis. The key to
mucosal disease. management of this disease is
Although the cause of ulcera- Diagnosis of oral early diagnosis and prompt surgi-
tion is often local, the oral mucosa ulceration cal treatment.
is an important site of manifesta- Ulcers of different causes may have Persistent, painless ulcers that
tion of many systemic conditions ver y similar clinical appearance are found on routine examination,
and oral ulceration may be the ini- and a few important key questions particularly in the elderly, should
tial presentation in such cases. The in the history provide useful diag- thus not be ignored, especially in
oral mucosa can be easily exam- nostic clues. Because of the rich those who smoke or drink alcohol
ined with a good light and a inner vation of the oral mucosa, regularly, or where there is evi-
wooden spatula, and a thorough most ulcers are painful. dence of er ythroplakia or leu-
oral inspection should be part of An important exception to this coplakia. The incidence of oral
every clinical examination since it rule is early squamous cell carci- cancer is increasing.

32 Prescriber 5 March 2006 www.escriber.com

Prescribing in practice

Primary ulcers sents with oral ulcers should prompt

the question of whether the oral
Recurrent aphthous stomatitis complaint is a manifestation of that
minor, major and herpetiform variants; associated with haematinic deficiencies, gastrointestinal disease or the drug therapy.
disease (Crohn’s disease, ulcerative colitis and coeliac disease), congenital and acquired immuno- A few pertinent questions
deficiency and blood dyscrasias; consider Behçet’s, MAGIC, and Sweet’s and PFAPA syndromes about the evolution and chronic-
ity of the ulceration may help the
Trauma clinician to arrive at the correct
usually accidental, or trauma from overextended dentures or sharp teeth; rarely, burns, stomatitis diagnosis. Ulcers may arise de novo
artefacta or trauma to exophytic lesion (primary ulcers) or secondary to
breakdown of vesicles or bullae
Dermatoses (secondar y ulcers) and may be
erosive and atrophic lichen planus, discoid and systemic lupus erythematosus, erythema multi- recurrent or persistent. A previous
forme, linear IgA disease history of trauma is usually offered
by the patient without direct ques-
Malignancy tioning. A systematic enquir y
squamous cell carcinoma usually presents as a persistent primary ulcer; exophytic lesions may be should also be undertaken.
traumatised and fungate Oral examination must be per-
formed with a good light source
Infections and taking a systematic approach
tuberculosis, syphilis, Reiter’s syndrome and acute necrotising ulcerative gingivitis; atypical or signs will be missed. It is essen-
lesions and ‘exotic’ infections in HIV disease, including deep mycoses tial to use an instrument such as a
wooden tongue depressor to exam-
Orofacial granulomatosis ine all the tissues. Wooden instru-
linear or serpiginous ulcers, particularly in the buccal sulci; associations with gastrointestinal ments should be wetted to avoid
diseases and allergies adherence to the oral tissues
which, in patients with extensive
Neutropenic ulcers ulceration, is very painful.
congenital and acquired immunodeficiencies; ulcers lack an inflammatory erythematous halo; may A basic management algorithm
be drug related; atypical viral fungal and bacterial lesions is shown in Figure 3.

Drugs Common causes of oral

aspirin and other caustic burns; cytotoxic drugs often cause mucositis and ulceration; fixed and ulceration
lichenoid drug eruptions, nicorandil and bisphosphonate ulceration The four most common presenta-
tions are trauma, recurrent aph-
Secondary ulcers
thous stomatitis, herpes virus group
Viral diseases infections and dermatoses,
mostly herpes virus group and enterovirus group enanthemata although the differential diagnosis
is extensive (see Table 1). The rarer
Dermatoses disorders should probably be man-
pemphigus (and variants), pemphigoid (and variants), congenital and acquired epidermolysis aged by a team approach through
bullosa, dermatitis herpetiformis and bullous lichen planus specialist centres. Some drugs may
also be the direct cause of oral
Angina bullosa haemorrhagica ulceration.
idiopathic blood blisters, usually on the soft palate
Traumatic ulceration
Table 1. Due to the similar clinical appearance of many oral ulcers, the differential diagnosis is extensive
Traumatic ulceration is usually
Although there are many con- tions may cause or be associated with caused by denture trauma, sharp,
genital or hereditary causes of oral oral ulceration. Further, drug ther- broken teeth or accidents and will
ulceration, they are all very rare. apy for systemic conditions may also resolve within two weeks following
Disorders of the gastrointestinal, cause or worsen oral ulceration. Any dental treatment. Persistence of a
haematological, immunological and patient with a known systemic dis- lesion after removal of the pre-
dermatological systems or viral infec- ease or taking medication who pre- sumed cause, particularly in the

34 Prescriber 5 March 2006 www.escriber.com

Prescribing in practice

elderly, raises the possibility of an

underlying tumour or foreign
body and exploration or biopsy is
indicated. The healing power of
the mouth is remarkable and most
traumatic ulcers resolve unevent-
fully, but occasionally superinfec-
tion occurs.
If the ulcer is infected and the
patient toxic, the antibiotics of
choice in this situation are phe-
noxymethylpenicillin, amoxicillin
or metronidazole. Useful adjuncts
are antimicrobial mouthwashes –
chlorhexidine, povidone-iodine
(Betadine) or benzydamine
(Difflam) – which may also be used
prophylactically.
Figure 2. Squamous cell carcinoma of the tongue. This is the commonest site for oral Artefactual stomatitis is rare
squamous cell carcinoma; the ulcer is persistent, often relatively painless, with raised, and is a difficult diagnosis. Most
rolled edges, necrotic base and indurated on palpation continued on page 40

36 Prescriber 5 March 2006 www.escriber.com

Prescribing in practice

oral ulceration

pre-existing systemic previously healthy

disease, drug therapy

arises de novo vesicles, bullae

oral manifestation?
drug reaction?

primary ulcer secondary ulcer

recurrent persistent febrile: afebrile

constitutional
upset?
longstanding?
skin lesions?
typical not aphthous local cause no local cause
aphthous stomatitis
probable
stomatitis probably viral
dermatosis

investigate or
treat refer? remove cause biopsy symptomatic
refer for
treatment
specialist
investigation
refractory or
change in resolution no resolution resolution no resolution
disease pattern

investigate biopsy refer

predisposing
disease or refer

Figure 3. Recommended management of oral ulceration

patients will deny self-injury and tion. One in three patients has a eg 0.1 per cent triamcinolone ace-
the underlying psychopathology family history and the onset is usu- tonide in carboxymethylcellulose
requires attention. Treatment of ally in the young. Most are non- paste (Adcortyl in Orabase), and
oral lesions is symptomatic. smokers and otherwise healthy. antimicrobial mouthwashes, eg
The diagnosis is clinical and chlorhexidine, povidone-iodine or
Recurrent aphthous stomatitis three variants – minor (see Figure benzydamine.
Recurrent aphthous stomatitis is 4), major and herpetiform – are For maximum benefit treat-
common and may affect 10 per described. The pathogenesis is ment is best initiated in the ‘pro-
cent of the population at some immunologically mediated but dromal’ phase or as soon as the
time during their lives. One in 15 poorly understood. ulcer begins to form. It is impor-
patients have an underlying cause In most patients outbreaks are tant that the oral mucosa is dried
in some series which, if treated, infrequent and respond to simple before applying carboxymethyl-
will ameliorate or cure the condi- treatments such as topical steroids, cellulose preparations so that the

40 Prescriber 5 March 2006 www.escriber.com

 Prescribing in practice

paste will adhere to the mucosa

and cover the ulcer. Some patients
appear to be sensitive to sodium
laur yl sulphate (SLS), and may
respond to an SLS-free toothpaste.
In adults, herpetiform aphthous
stomatitis usually responds to tetra-
cycline mouthrinse and swallow
(but this is contraindicated in chil-
dren due to the problem of dis-
coloration of the developing
teeth).
Patients whose ulcers prove
unresponsive to these therapies
may respond to one of the many
other suggested systemic therapies
(see Table 2). However, there is a Figure 4. Recurrent aphthous ulceration (minor type). These ulcers are common,
dearth of evidence for most of painful, with a yellow-white sloughing base and inflammatory erythematous halo; the
these treatments and many are of ulcers are not indurated and heal spontaneously within two weeks
questionable efficacy, or are unli-
censed in this indication. with interstitial chondritis) may presentation and there may be a
Some over-the-counter med- be a forme fruste (incomplete geographical distribution.
ications may offer some sympto- presentation). PFAPA syndrome Haematinic deficiencies (of iron,
matic relief for patients with (periodic fever, aphthous ulcera- vitamin B12 or folic acid), even in
occasional ulcers, since the disease tion, phar yngitis and adenopa- the absence of frank anaemia,
is self-limiting. More aggressive thy) has a distinct clinical predispose to aphthous stomatitis
prescription-only therapy is indi-
cated in patients with continuous Topical
ulcers and those whose quality of
life is severely affected. However, chlorhexidine beclometazone
accurate diagnosis is paramount benzydamine betamethasone
before embarking on this course. carbenoxolone sucralfate
Recalcitrant major aphthous betadine tetracyclines
ulcers, which may be seen in HIV hydrocortisone HC sodium lauryl sulphate avoidance
disease, may be successfully treated triamcinolone bioadhesives
with triamcinolone acetonide fluocinolone lasers
intralesional injections or thalido-
mide. However, before treatment Systemic
it is important to exclude an levamisole ciclosporin
opportunistic infectious cause, transfer factor amlexanon
such as a deep mycosis. colchicine 5-ASA
Patients with severe aphthosis gammaglobulins zinc sulphate
who are rarely ulcer free, have a azathioprine MAOIs
change in disease pattern or are dapsone contraceptive pill
unresponsive to treatment should thalidomide H2-antagonists
be investigated for an underlying pentoxifylline cromoglicate
cause. Behçet’s syndrome, a triad prednisolone liquorice
of orogenital ulceration with azelastine etretinate
uveitis and variable dermatologi- alfa interferon diclofenac
cal, musculoskeletal and neuro- LongoVital aspirin
logical manifestations, should be prostaglandin E2
excluded. MAGIC syndrome
(mouth and genital ulceration Table 2. Reported treatments for aphthous ulceration

www.escriber.com Prescriber 5 March 2006 41

 Prescribing in practice

as do coeliac disease, Crohn’s dis-

ease and ulcerative colitis, which
may be co-existent or occult. It is
important to ascertain the cause
of, as well to treat, haematinic
deficiencies.
Further predisposing factors
include congenital and acquired
immunodeficiency states, blood
dyscrasias and food allergy.
Occasionally female patients report
premenstrual aphthous ulcers that
have been found to respond to hor-
monal manipulation.

Herpes virus and enteroviral

infections Figure 5. Lichenoid eruption (to a beta-blocker). There is central ulceration, but
Primary herpetic gingivostomatitis peripherally reticular (strial) white lesions are present; the ulceration is persistent and
is caused by the herpes simplex painful, but will resolve completely with cessation of the offending drug
virus (HSV) type I or II and usually
affects children and young adults; varicella zoster virus infection. The enterovirus group infec-
however, it is occasionally seen in High-dose systemic aciclovir treat- tions, such as hand, foot and
older patients, and causes consti- ment is indicated in shingles, par- mouth disease and herpangina
tutional upset with fever and may ticularly if the ophthalmic tend to be seasonal and occur in
be more florid than in the young. division is involved, and may epidemics. Treatment is sympto-
The treatment of this self-limiting decrease the incidence of pos- matic and supportive.
disease is supportive with attention therpetic neuralgia. Oral ulcera-
to rehydration and antipyretic tion may also be seen in infections Dermatoses
analgesia, avoiding aspirin in chil- with Epstein-Barr virus and A number of dermatological con-
dren. Antimicrobial mouth rinses cytomegalovirus infection in the ditions have ulcerative oral mani-
are useful – in those old enough to immunocompromised. festations. Definitive diagnosis of
use them – and may reduce super-
infection and accelerate healing of
the ulcers. Benzydamine mouth-
wash, if held in the mouth for a
period of time, may have a tempo-
rar y numbing effect, which may
make eating easier during the
acute period.
Recurrent herpes labialis may
be treated with idoxuridine in
dimethyl sulfoxide (Herpid) solu-
tion or aciclovir cream applied early
to the lesions, although penciclovir
cream (Vectavir) may have greater
efficacy. Caution should be exer-
cised, however, since HSV strains
that encode for an aciclovir-resis-
tant thymidine kinase have been
reported. The drug may be life-sav- Figure 6. Erythema multiforme. Although there is usually skin involvement (Stevens-
ing in herpetic encephalomyelitis. Johnson syndrome), an isolated oral variant of erythema multiforme can occur. The
Intraoral ulceration is a fea- ulceration is of acute onset, painful, superficial and irregular; often the entire oral
ture of primar y and secondar y mucosa is involved and there is bloody crusting of the lips

www.escriber.com Prescriber 5 March 2006 43

Prescribing in practice

Antimalarials where ulceration is a feature). Discoid and systemic lupus ery-

chloroquine, pyrimethamine Extraoral lesions are not invariable thematosus and graft versus host
and areas of non-ulcerated mucosa disease have a very similar clinical
Antihypertensives usually show some signs of the dis- appearance to lichen planus when
beta-blockers, methyldopa ease. Oral lichen planus is affecting the mucosa, as do
reported to carr y a low risk of lichenoid reactions (see Figure 5)
Antimicrobials malignant change. to a wide range of commonly pre-
azoles, tetracycline The aims of treatment are to scribed drugs (see Table 3). The
convert the ulcerated regions into diagnosis is established by history,
NSAIDs asymptomatic forms by the use of biopsy and serology and patients
aspirin, phenylbutazone, naproxen immunomodulator y drugs and with drug-associated lichenoid
then to maintain the status quo by lesions usually respond to a change
Oral hypoglycaemics regular monitoring and prompt of medication.
tolbutamide, chlorpropamide treatment of relapses. Relapses of Er ythema multiforme Erythema
lichen planus are common and, multiforme (see Figure 6) and
Other unlike the dermatological variant, Stevens-Johnson syndrome may
penicillamine, allopurinol, carbamazepine, levamisole, the disease may be present for have a very florid oral presentation
lithium, lorazepam many decades. and often ‘target lesions’ on the
The mainstays of treatment are skin give the clinical diagnosis.
Table 3. Drugs causing lichenoid reactions (after McCartan steroid drugs given topically, Occasional triggers include
and McCreary) intralesionally or, on occasions, sys- Mycoplasma infection or herpes
these conditions usually involves temically. Maintenance of good virus reactivation, but often the
conventional histopathology sup- oral hygiene and dental health is cause is cryptic. Erythema multi-
ported by direct and indirect also important. Other therapeutic forme may be drug induced from
immunofluorescence. strategies, such as dapsone, grise- a wide range of medications.
Lichen planus Lichen planus is ofulvin, retinoids, topical Those with a well-defined herpetic
a common oral disease and is ciclosporin, tacrolimus and pime- trigger may respond to low-dose,
either asymptomatic (hyper- crolimus, sulfasalazine, pentoxi- continuous prophylactic aciclovir.
trophic, reticular and papular fylline and levamisole have also Treatment regimens range
forms) or symptomatic (erosive, been tried with varying degrees of from simple supportive therapy to
atrophic and bullous variants, success. systemic steroid therapy.
Avoidance of any known drug trig-
gers is obvious.
The blistering dermatoses Pem-
phigus, pemphigoid, linear IgA
disease (a pemphigoid variant),
epidermolysis bullosa acquisita
and dermatitis herpetiformis have
a well-defined immunopathogen-
esis and diagnosis is by immuno-
fluorescent histopathology and
serology.
Clinically, the bullae of pem-
phigus are fragile and are rarely
seen intraorally. Over half of
patients in their first episode of
pemphigus vulgaris have intraoral
lesions that precede the skin
lesions. The bullae of benign
Figure 7. Aspirin burn. This patient had a toothache in the lower first molar tooth and mucous membrane pemphigoid
allowed the aspirin tablet to dissolve over the tooth, causing an acid burn with and epidermolysis bullosa
sloughing of the surrounding mucosa; although not present in this case, central ulcer- acquisita are more robust and are
ation often occurs often blood-filled when seen

44 Prescriber 5 March 2006 www.escriber.com

Prescribing in practice

Figure 8. Bisphosphonate ulceration. A long-standing, nonhealing ulcer of the

attached mucosa of the jaws is present, with exposure of the underlying
hypermineralised, hypovascularised bone; these ulcers pose a very significant
management problem, since surgical removal of any sequestra appears to make
the ulceration worse

intact. Linear IgA disease has sim- be usefully monitored by pem-

ilar features. Intraoral dermatitis phigus autoantibody titre mea-
herpetiformis is rarely seen in iso- surements.
lation and skin lesions are typical. Mucous membrane pem-
Pemphigus vulgaris is treated phigoid, epidermolysis bullosa
with high-dose systemic steroids acquisita and linear IgA disease
with the addition of azathioprine may respond to topical steroid
for a steroid-sparing effect. More preparations, but occasionally the
recently, the use of tacrolimus or patient requires a short course of
mycophenolate mofetil is being systemic steroids for a full response
explored, since they are less toxic to treatment. Linear IgA disease
than azathioprine and may be use- may be steroid unresponsive, when
ful for patients with TPMT (thio- sulphur drugs are the treatment of
purine S-methyltransferase) choice.
deficiency. Patients have to be There is an association with
monitored intensively for any coeliac disease and oral lesions
steroid side-effects or excessive respond to a gluten-free diet or
immunosuppression during this dapsone.
phase of their treatment. Angina bullosa haemorrhagica
Once the lesions have healed, presents with blood-filled bullae
the steroid treatment and aza- that arise rapidly, often on the soft
thioprine dosage are reduced to a palate, following minimal trauma
maintenance level. Treatment can such as eating. Patients become

46 Prescriber 5 March 2006 www.escriber.com

Prescribing in practice

very alarmed with a choking sen- Key points ulceration is associated with nico-
sation. Rupture of the bulla leads randil (Ikorel) therapy (see Figure
to ulceration. There is no demon- • the most common causes of oral 1) and there appears to be a dose
strable immunopathogenesis; how- ulceration are trauma and recur- response. The ulceration is long-
ever, there are some reports that rent aphthous stomatitis standing and will not heal unless
show an association with the use of • any ulcer that does not heal within the drug is withdrawn or at least
steroid inhalers and poor inhaler two weeks of the removal of the the dose reduced.
technique, leading to deposition suspected cause should be biop- The widespread use of the bis-
of high doses of steroid on the soft sied phosphonates in a number of
palate leading to mucosal atrophy • some ulcers are manifestations of indications is now becoming
and capillar y fragility. Such systemic disease or drug therapy recognised as a serious cause of
patients should be instructed on for that disease osteonecrosis of the jaws, pre-
inhaler technique and asked to • some drugs themselves can senting as ulceration of the
gargle after inhaler use. cause oral ulceration attached oral mucosa and dead,
• immunofluorescent histopathol- infected bone exposure (see
Oral ulceration caused by drugs ogy is an important diagnostic Figure 8), which is proving to be a
Drugs themselves can cause oral procedure for blistering disorders serious and ver y difficult man-
ulceration in a number of ways. • serious diseases such as pemphi- agement issue.
They can have a direct effect, be gus or malignancy may present as
associated with fixed drug or oral ulceration Further reading
lichenoid eruption, allergy, er y- • appropriate therapy depends on Oral and maxillofacial diseases. Scully C,
thema multiforme or be chemi- accurate diagnosis Flint SR, Porter SR, et al. London:
cally caustic and cause a burn if Taylor Francis, 2004.
administered or taken inappro- The list of drugs causing Oral lichenoid drug eruptions.
McCartan BE, McCrear y CE. Oral
priately. lichenoid eruptions is presented in
Diseases 1997;(3):58-63.
Oral mucosal burns are seen if Table 3. Although some of the Oral medicine in practice. Lamey P-J,
bisphosphonates are allowed to drugs are rarely used nowadays, Lewis MAO. London: British Dental
dissolve in the mouth rather than since the classes of drugs causing Journal Publications, 1992.
swallowed whole, with copious lichenoid eruptions are so disparate Osteonecrosis of the jaw and bisphos-
amounts of water, sitting upright. it is likely that these types of lesion phonates. Maerevoet M, Martin C,
Classically, patients with toothache are generally under-reported and Duck L. N Engl J Med 2005;7(353):
may place an aspirin over the under-recognised, and the full list 99-102.
affected tooth and cause an acid may include many new drugs. The Persitent nicorandil-induced oral
burn to the mucosa (see Figure 7). importance of this diagnosis is that ulceration. Healy CM, Smyth Y, Flint
Cytotoxic drugs by their ver y the ulceration will resolve with with- SR. Heart 2004; 90(7):e38-41.
nature affect rapidly dividing cells drawal of the drug, or changing the
and cause bone marrow suppres- drug to a different class of drug to Dr Flint is a consultant and senior
sion, hair loss and oral (and other) treat a particular condition. lecturer at the Dublin Dental School
mucositis and, in sufficient dose, Some drugs may cause oral and Hospital and Trinity College,
ulceration. ulceration directly. Oral mucosal Dublin

48 Prescriber 5 March 2006 www.escriber.com