Japanese Dental Science Review (2014) 50, 40—46

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Review Article

Oral ulcerations due to drug medications

Yoshinori Jinbu a,*, Toshio Demitsu b

a
Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan
b
Department of Dermatology Saitama Medical Center, Jichi Medical University, Saitama, Japan

Received 9 July 2013; received in revised form 4 December 2013; accepted 5 December 2013

KEYWORDS Summary Ulcers are common symptoms observed in the oral cavity and some ulcerations are
Oral ulceration; induced by drug medications. When ulcers show typical clinical findings differential diagnosis may
Drug medication; be easy, but the exact diagnosis is often difficult. We reviewed differential diagnosis of oral
Differential diagnosis ulcerative diseases, clinical characteristics of drug-induced oral ulcerations and drugs inducing
oral ulcerations. Many kinds of drugs have been reported to cause oral ulcerations. Among them,
non-steroidal anti-inflammatory drugs are popular and well-known. However, several recent
reports have described oral ulceration associated with relatively new drugs for the treatment of
chronic disorders such as, diabetes, angina pectoris, rheumatoid arthritis, and osteoporosis. We
reviewed these new drugs and also reported typical cases of drug-induced oral ulcerations.
# 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2. Oral ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4. Clinical features of drug-induced oral ulceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
5. Drugs inducing oral ulcerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
6. Treatment of drug-induced oral ulcerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
7. Case presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
7.1. Case 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
7.2. Case 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7.3. Case 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7.4. Case 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7.5. Case 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

* Corresponding author. Tel.: +81 285587390; fax: +81 285448669.

E-mail address: jinbu@jichi.ac.jp (Y. Jinbu).

1882-7616/$ — see front matter # 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jdsr.2013.12.001
Oral ulcerations 41

1. Introduction 3. Differential diagnosis

Many kinds of adverse reactions induced by drug medica-
tions in the oral cavity are now well recognized [1—3].
Among these, the most frequent are dry mouth (hyposa-
livation), dysgeusia, and stomatitis. Stomatitis is a general
term for disturbance of oral epithelial cells and covers
several types of oral mucosal symptoms. Oral mucosal
symptoms caused by drugs can be further divided as fol-
lows: (1) lichenoid reaction/lichen planus; (2) ulcers; (3)
erythema multiforme; (4) pigmentation; (5) autoimmune
vesiculo-bullous disease; (6) infections; (7) tumors (fibro-
vascular hyperplasia); (8) swellings (angioedema); and (9)
keratosis [1]. This paper focuses on ulcers and/or erosions
in the oral cavity induced by pharmacotherapy, with an
emphasis on new drugs for the treatment of chronic dis-
eases such as diabetes, angina pectoris, rheumatoid arthri-
tis and osteoporosis.
2. Oral ulcers
Oral ulcers are common symptoms observed in the oral cavity
and include traumatic, infective, aphthous, ulceration
related to dermatoses, drug-induced, ulceration as a mani-
festation of systemic disease, and ulceration due to malig-
nancy (Table 1) [4—6]. When ulcers show typical clinical
findings, differential diagnosis may be easy; however, the
exact diagnosis is difficult in most cases, and histopatholo-
gical diagnosis may be needed.
Careful examination of the oral mucosa is the most important
factor for determining a provisional diagnosis. Patients are
often confused by the term stomatitis, and the precise nature
of the complaint should be confirmed. The age, sex, and
dental and medical histories of the patient may provide
useful information, and the number, shape, size, and location
of lesions must also be carefully observed [7,8].
Traumatic ulceration is caused by mechanical, thermal, or
chemical irritants. The most frequent causes are ill-fitting
dentures, sharp-edged crowns or bridges, and tooth decay.
The ulcer floor is usually clear and ulcer margins do not
typically show induration on palpation, but sometimes show
bleeding, granular appearance, or induration resembling
malignant tumor.
Viral infection is generally associated with multiple small
aphthous ulcerations. The initial presentation is fluid-filled
vesicles, but these rapidly break down to form small, round,
painful ulcers with ragged margins that often fuse to form
large, irregular ulcers. Viral infections in the oral cavity are
most commonly due to herpes simplex virus (HSV)-1, vari-
cella-zoster virus (VZV), coxsackie virus and cytomegalo-
virus. Acute herpes zoster causes eruption of multiple
small, painful vesicles that rapidly rupture to form punctate
or confluent ulcers in a portion of the trigeminal nerve
distribution [7].
Aphthous ulceration is the most common type of oral
ulceration and improves within 10—14 days. The lesions
usually occur in non-keratinizing epithelium and form small,

Table 1 Chronic oral ulcers.

Diagnosis Clinical features

Drug-induced ulcers Single, isolated ulcers, located on the side of the tongue, surrounded by an
erythematous halo and resistant to usual treatments
Erosive lichen planus Areas of atrophy, erosions or painful ulcers, generally resistant to conventional
treatments
Pemphigus vulgaris Bullae appear in oral cavity (posterior region), forming painful ulcers with necrotic
fundus and erythematous halo
Mucous membrane pemphigoid Spontaneous onset of bullae that readily rupture, giving rise to a highly painful
ulcerated area (most common areas are palate and gingiva)
Lupus erythematosus Erythema and oral ulcers, without induration and accompanied by whitish striae and a
tendency to bleeding
Reiter’s syndrome Arthritis, urethritis, conjunctivitis and oral ulcers similar to those of recurrent aphtous
stomatitis
Tuberculosis Primary tuberculosis: deep, irregular, persistent and painful ulcer on the tongue, with
rolled border and granulation tissue in the fundus
Secondary tuberculosis: chronic ulcer, painful and indurated
Mycosis Mycoses give rise to chronic ulcers on the oral mucosa, most commonly in
immunocompromised patients
Other bacterial and parasitic diseases Klebsiella and Leishmania spp. can produce chronic oral ulcers in HIV-infected patients
Eosinophilic ulcer Large ulcer, generally in the tongue, with raised, indurated borders and white-yellowish
fundus that may resemble a malignant lesion. Persists for weeks or months
Oral squamous cell carcinoma Can produce ulcers (exophytic, endophytic or mixed). Metastatic lesion can appear as
ulcers in the oral cavity
Munoz-Corcuera et al. [5].
HIV, human immunodeficiency virus.
42
round or oval ulcers covered with pseudomembrane sur-
rounded by an erythematous halo. Similar lesions have been
seen in association with various systemic conditions, such as
Behçet’s disease, Crohn’s disease, celiac disease and ulcera-
tive colitis [9—11]. Major-type aphtha appear as large, pain-
ful ulcers and healing may result in mucosal scarring; this
type of ulceration can mimic other diseases, such as malig-
nant lesions. The exact etiology of aphthous ulceration is
unclear, but some altered local immune response is consid-
ered as a predisposing factor.
Lichen planus varies in clinical appearance. The typical
type of oral lichen planus (OLP) shows bilateral and sym-
metrical white lace-like patterns of buccal mucosa, but
ulceration is frequently seen in the lesion [12,13]. This
ulceration is usually surrounded by fine reticular white lines
radiating from its border. Another type of ulceration
involves focal red granular areas co-existing with a typical
white reticular pattern. The etiology of OLP is unclear, but
the mechanism appears to be immunologically mediated.
Some drugs and metal allergies can cause similar lesions,
known as oral lichenoid lesions (OLL), but both clinical and
histopathological diagnosis is often very difficult. Quite
similar lesions are seen in patients with graft-versus-host
disease and collagenous diseases such as systemic lupus
erythematosus.
Pemphigus vulgaris is an autoimmune bullous disease with
autoantibodies against desmosome-related proteins desmo-
glein 1 and/or 3 [14—16]. Oral lesions develop in about 70% of
cases, and over 50% of cases show oral lesions as the initial
manifestation. Painful, shallow, irregular ulcers with friable
adjacent mucosa are a characteristic feature and lateral
shearing force on the mucosa can produce a surface slough
or induce vesicle formation (Nikolsky sign). Histologically,
intraepithelial acantholysis is characteristic. Blood analysis
for autoantibodies against desmoglein 1 and 3 using enzyme-
linked immunosorbent assay and immunofluorescence are
useful for diagnosis.
Bullous pemphigoid is also an autoimmune disease with
autoantibody against BP180NC16a, a component of hemides-
mosome [17]. Formation of firm blisters against an erythe-
matous background is the main cutaneous symptom. In the
oral cavity, multiple well-defined or diffuse ulcers are seen.
Histopathologically, subepithelial blistering with numerous
eosinophils is seen. The level of BP180 antibodies correlates
with disease activity.
Mucous membrane pemphigoid shows redness with ero-
sions, gray-white vesicles or blisters on the oral mucosa
[18,19]. Desquamation of the gingiva is a typical finding with
this disease. Immunofluorescence microscopy reveals a linear
arrangement along the basement membrane zone of immu-
noglobulin (Ig)G, C3 and occasionally IgA. Circulating auto-
antibodies are detected by indirect immunofluorescence
microscopy, but the titer is usually very low. Autoantibody
against the cellular fragment of BP180 may be pathogenic in
some cases, while antibodies against laminin-332 may be
pathogenic in others.
In erythema multiforme or erythema exudative multi-
forme, oral mucosal lesions appear a few days after the
onset of symmetrical target skin lesions [20,21]. Severe
widespread painful erosions covered with a gray-white pseu-
domembrane associated with ocular and genital lesions are
seen. Erosive and hemorrhagic cheilitis with bleeding crusts
Y. Jinbu, T. Demitsu
is a characteristic symptom, induced by pharmacotherapy or
viral infection. Triggering drugs include sulfonamides, pirox-
icam, non-steroidal antirheumatic agents, allopurinol, bar-
biturates, phenytoin, pyrazolone derivatives, and sulfones.
Exposure of the oral cavity to radiation induces wide-
spread mucosal erythema, atrophy, ulceration, and pseudo-
membrane formation. These pathologies are caused by
destruction of the germinative layers of oral mucosal epithe-
lium and enhanced by intraoral bacterial infection.
Squamous cell carcinoma is the most frequent malignancy
of the oral mucosa. In the early stages, white or red-white
focal surface lesions are seen, while ulceration with indura-
tion and elevated margins is characteristic in later stages.
The surface shows a granular and/or necrotic appearance
with easy bleeding.
4. Clinical features of drug-induced oral
ulceration
Typical oral ulcers due to drugs are clinically classified into
two types. The first is widespread mucositis and ulceration,
mainly caused by cytotoxic drugs used for anti-tumor che-
motherapy. Widespread sloughing and ulceration arise within
days of commencing therapy, with the associated pain often
requiring opioid therapy and alteration or cessation of che-
motherapy. Such cytotoxic drugs include 5-fluorouracil,
methotrexate, bleomycin, and cisplatin. Immunosuppressive
agents may also cause oral ulceration through opportunistic
secondary infections involving organisms such as Gram-nega-
tive bacteria and fungi.
The second type is fixed drug eruption, showing repeated
development of treatment-resistant ulcers [22]. Single or
multiple large ulcerations are seen on every site of the oral
mucosa. Generally, the ulceration is larger than aphthous
ulceration, with a flat surface showing slightly white appear-
ance. The margin of the ulcer is clear and often slightly
raised; however, the ulcers are unaccompanied by any
induration. They often resemble traumatic and decubital
ulcers, but no irritant factors are apparent in their vicinity. A
multiple aphthous ulceration type has also been reported
[8]. Topical steroids are ineffective for these forms of
ulceration [8]. Histopathological examination usually
reveals non-specific ulcer formation with marked infiltration
of inflammatory cells. The molecular mechanisms involved
with these types of oral ulceration have yet to be clarified,
but immunological reactions may play some role in the
process.
5. Drugs inducing oral ulcerations
Many kinds of drugs cause oral ulcerations, including some b-
blockers, immunosuppressants, anticholinergic bronchodila-
tors, platelet aggregation inhibitors, vasodilators, protease
inhibitors, antibiotics, non-steroidal anti-inflammatory drugs
(NSAIDs), antiretrovirals, and antihypertensives (Table 2)
[1]. Among these, NSAIDs are popular drugs that are well-
known to induce oral ulcerations [23—25]. Several recent
reports have described oral ulceration associated with rela-
tively new drugs for the treatment of chronic disorders such
as diabetes, angina pectoris, rheumatoid arthritis, and osteo-
porosis.
Oral ulcerations 43

Table 2 Drugs inducing oral ulceration. diseases [42]. This drug has been demonstrated to induce
progressive and significant increases in bone mineral density
Antibiotics Gastric ulcer treatments
in women with osteoporosis [43]. Bisphosphonate-related
Anticholinergic Hypoglycemic agents
osteonecrosis of the jaw is a well-established adverse effect
bronchodilators
of bisphosphonates [44,45], but oral ulceration as a result of
Anti-hypertensives Immunosuppressants
taking alendronate has also recently been reported [46—50].
Antiretrovirals Interferons
These oral ulcerations are induced by incorrect use of the
Anti-rheumatic drug Non-steroidal anti-inflammatory
drugs and are caused by the drugs causing direct irritation.
drugs (NSAIDs)
Anti-septics Platelet aggregation inhibitors
Bisphosphonate Potassium-channel activators 6. Treatment of drug-induced oral
b-Blockers Protease inhibitors ulcerations
Corticosteroids Vasodilators
Topical steroids are ineffective against these ulcers [8]. If
ulcers do not show improvement despite topical steroid
treatment for 1—2 weeks, and no signs of malignancy are
Dipeptidyl peptidase (DPP)-4 inhibitors: DPP-4 inhibitors evident, drug exposures must be carefully checked. If a
(e.g., sitagliptin) are newly developed oral hypoglycemic medication is suspected as a cause of oral ulceration, contact
agents that gained approval for release in 2009 in Japan must be made with the prescribing medical doctor to discuss
[26]. DPP-4 inhibitors or incretin enhancers have been intro- the possibility of alternative medications or dose reduction.
duced for the treatment of type 2 diabetes mellitus (T2DM) After cessation, change, or dose reduction of the drug,
[27,28]. This class of glucose-lowering agents enhances levels ulcerations may improve in 1—2 weeks. It is further necessary
of endogenous glucagon-like peptide (GLP)-1 and glucose- to confirm that the drug is really a responsible drug, so
dependent insulinotropic polypeptide (GIP) by blocking the restarting the drug may be important, but is very difficult.
incretin-degrading enzyme DPP-4. DPP-4 inhibitors restore
the deranged islet-cell balance in T2DM, by stimulating meal- 7. Case presentation
related insulin secretion and by decreasing postprandial
glucagon levels. Moreover, DPP-4 inhibitors have demon- 7.1. Case 1
strated beneficial effects on the functional b-cell mass
and pancreatic insulin contents. As prevention and treatment The patient was a 76-year-old woman who presented with
of T2DM and its complications represent major healthcare ulceration of the left tongue margin. Her medical history
issues worldwide, DPP-4 inhibitors are already in wide use in revealed articular rheumatism, diabetes, hypertension, and
clinics around the world. We recently provided the first anemia. She had been treated with indomethacin (75 mg/
report of oral ulceration due to DPP-4 [29]. day) to control pain from articular rheumatism. Ulceration
Nicorandil. Nicorandil belongs to a relatively new class of (20 mm  14 mm) on the left tongue margin with no indura-
potassium-channel activators that are available around the tion was observed (Fig. 1). The surface was flat and clean,
world and in use for the prevention and long-term treatment with no bleeding. The ulcer margin was slightly raised.
of angina pectoris. Adverse effects of nicorandil therapy may Clinically, decubitus ulcer was suspected, but no improve-
include cutaneous vasodilatation, nausea and vomiting, diz- ment was observed after application of a topical steroid. We
ziness, myalgia and rash. Over the past few years, cases in considered the denture was not a cause and instructed the
which nicorandil has caused oral ulceration have been patient to stop taking indomethacin after consulting with her
reported [30—35]. physician. The oral ulceration showed re-epithelialization
Low-dose methotrexate (MTX): MTX is an antifolic agent after 2 weeks [25].
with a well-established history of use in the treatment of
various neoplastic diseases. Low-dose MTX has been widely
used for rheumatoid arthritis (RA) as a disease-modifying
antirheumatic drug [36,37]. Since MTX was approved as an
antirheumatic drug in 1999, use of low-dose MTX has become
widespread in Japan. About 60,000 patients are estimated to
be taking low-dose MTX for the treatment of RA. As general
adverse effects, gastrointestinal toxicity (nausea, vomiting,
abdominal discomfort, anorexia, dyspepsia, diarrhea), hepa-
totoxicity (hepatitis, fibrosis, cirrhosis), myelosuppression
(leukocytopenia, thrombocytopenia, pancytopenia), hyper-
homocysteinemia, hypersensitivity causing pulmonary toxi-
city, central nervous system events (headaches, depression)
and osteoporosis have been described [37]. Some reports
have described stomatitis and oral ulcerations due to low-
dose MTX [38—41].
Alendronate (bisphosphonate). Alendronate is a drug Figure 1 Indomethacin-induced oral ulceration. Ulceration
belonging to the diphosphonate family that has recently on the left tongue margin with no induration. Line shows the
been used in the treatment of osteoporosis and other bone biopsy site.
44 Y. Jinbu, T. Demitsu

Figure 2 Oral ulceration due to low-dose MTX. Ulceration on

the left floor of the mouth with no induration.

7.2. Case 2

The patient was a 71-year-old man with oral mucosal ulcera-

tion of the floor of the mouth and a 6-year history of
rheumatoid arthritis (RA). Medical history included RA,
hypertension, prostatic hyperplasia, and cardiac disease.
He had been treated with methotrexate (MTX) at 8 mg/week.
Ulceration (22 mm  18 mm) on the left floor of the mouth
was seen, showing no induration (Fig. 2). The surface of the
ulceration was flat and clean, with no bleeding. Ulceration
did not improve with corticosteroid treatment. We consid-
ered the denture was not a cause and contacted his physi-
cian. After the dose of MTX was reduced from 8 mg/week to
2 mg/week, oral ulceration greatly improved and re-epithe-
lialization was achieved [40].

7.3. Case 3

The patient was a 77-year-old woman referred with oral

ulceration. Medical history included type 2 diabetes mellitus
and treatment with DPP-4 inhibitors for 1.5 years. Ulceration
(10 mm  7 mm) was apparent on the left labial mucosa
(Fig. 3). The surface of the ulcer was flat and clean, with
no bleeding or induration. Ulcer margins were slightly raised.
As the ulcer remained unimproved despite topical steroid
Figure 4 Oral ulcerations induced by incorrect use of alen-
dronate. Several ulcerations on the lower lip, soft palate, and
upper and lower gingiva.

treatment, the ulcer was surgically resected. However, the

ulcer recurred 3 weeks after surgery. After consultation with
her physician and cessation of DPP-4 inhibitor, re-epithelia-
lization was completed within 16 days [29].

7.4. Case 4

The patient was an 82-year-old woman who complained of

Figure 3 Oral ulceration due to DPP-4 inhibitor. Ulceration on
the left labial mucosa.
oral ulcerations. She had been treated for osteoporosis with
alendronate for 5 years. Several ulcerations on the lower lip,
soft palate, and upper and lower gingiva were observed
(Fig. 4). These ulcers showed irregular shape and were
covered with pseudomembrane. Autoimmune bullous disease
Oral ulcerations
Figure 5 Oral ulcerations due to nicorandil. Multiple ulcers on
bilateral buccal mucosa and bilateral tongue margins.
was clinically suspected, but blood examination showed
negative results. We contacted her physician and alendro-
nate was stopped. Ulcerations showed complete epitheliali-
zation within 7 days. On questioning, she was found to have
been sucking the tablets instead of swallowing them [50].
7.5. Case 5
The patient was a 77-year-old man who complained of
multiple oral ulcers. His medical history included angina
pectoris and atrial fibrillation, and he had been treated with
several drugs. After changing medication to nicorandil, he
noticed multiple oral ulcerations. Multiple ulcers were seen
on the bilateral buccal mucosa and bilateral tongue margins
(Fig. 5). These ulcers were irregularly shaped and the sur-
face was covered with pseudomembrane without indura-
tion. After contacting his physician, nicorandil was changed
to another drug. Ulcerations subsequently improved within 2
weeks.
8. Conclusion
Oral ulcers are common symptoms observed in the oral cavity
and many kinds of drug have been reported to induce oral
ulcerations. When drug-induced oral ulcerations are sus-
pected after careful clinical observation and check of drug
medications, contact must be made with the prescribing
medical doctor to discuss the possibility of alternative med-
ications or dose reduction.
45
Conflict of interest
None declared.
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