JEADV ISSN 1468-3083

ORIGINAL ARTICLE
Blackwell Publishing Ltd

Oral manifestations of adverse drug reactions: guidelines

F Femiano,* A Lanza, C Buonaiuto, F Gombos, R Rullo, V Festa, N Cirillo
Stomatology Clinic, School of Medicine and Surgery, University of Naples 11, Naples, Italy

Keywords Abstract
adverse drug effects, drug reactions, oral
mucosal reactions, oral reactions, side-effects Background Adverse drug reactions are noxious and unintended responses
to a medicinal product.
*Corresponding author, Via Francesco Girardi 2; Many drugs have the potential to induce adverse reactions in the mouth. The
S. Antimo (NA) 80029; Italy, extent of such reactions is unknown; however, because a lot of them are
tel. +39 081 8304248;
asymptomatic, many are believed to go unnoticed. Adverse oral drug reactions
fax +39 081 5665477;
are responsible for oral lesions and manifestations that can mime local or
E-mail: femiano@libero.it
systemic disease.
Received: 17 October 2007, Their pathogenesis, especially of the mucosal reactions, is largely unknown and
accepted 24 October 2007 appears to involve complex interactions between the drug in question, other
medications, the patient’s underlying disease, genetics and lifestyle factors.
DOI: 10.1111/j.1468-3083.2008.02637.x Aim In this study, we have listed the principal signs and symptoms of oral and
perioral adverse drug reactions and the responsible drugs. Diagnosis for adverse
drug reaction is not easy given also the limited utility of laboratory tests. The
association between a drug and an adverse drug reaction is mostly based on the
disappearance of the reactions following discontinuance of the offending drug.
Sometimes, it is useful to perform rechallenge tests reintroducing the drug to
establish cause and effect.
Conclusions Knowledge of adverse drug-induced oral effects helps health
professionals to better diagnose oral disease, administer drugs and improve patient
compliance during drug therapy and may foster a more rational use of drugs.

a causal relationship between a medicinal product and an

Introduction
In medical practice, a drug is often given to a patient in
order to prevent an anticipated disease, or to treat a
manifest disease. Two types of effects can be expected
after the administration of a drug to a patient. The first
type of effect is the intended effect, the reason why the
drug was given to the patient. The second type of effect is
the unintended, unwanted or noxious effect. These effects
are referred to as adverse drug reactions (ADRs).1
An ADR is defined by the World Health Organization
(WHO) as a drug response that is noxious and unintended
and occurs at doses normally used in humans for
prophylaxis, diagnosis or therapy of a disease or for the
restoration, correction or modification of a physiological
function.2
All noxious and unintended responses to a medicinal
product related to any dose should be considered ADRs.
The phrase ‘responses to medicinal products’ means that
adverse event is at least a reasonable possibility (i.e. the
relationship cannot be ruled out).3
The terms ‘adverse reaction’ and ‘adverse effect’ are
often used interchangeably, but it is the drug that has an
adverse effect, whereas it is the patient who suffers an
adverse reaction.
An adverse event is any untoward medical occurrence
in a patient to whom a medical product is administered
and does not necessarily have to have a causal relation-
ship with this treatment.
A reaction, unlike an event, is characterized by the fact
that a causal relationship between the drug and the
occurrence is indeed suspected.2 In addition, we must
distinguish between an adverse event that is an adverse
outcome occurring while a patient is taking a drug, but is
not (necessarily) attributable to it.4
The terms ‘drug reaction’, ‘drug hypersensitivity’ and
‘drug allergy’ are often improperly considered to be

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Oral adverse drug reactions
synonyms. Drug reactions encompass all adverse events
related to drug administration, whatever the aetiology.
Drug hypersensitivity is as an immune-mediated response
to a drug in a sensitized patient. Drug allergy is restricted
specifically to a reaction mediated by IgE. A drug allergy
is an immunologically mediated reaction that exhibits
specificity and recurrence upon re-exposure to the
offending drug. Complicating factors of drug reactions
include the myriad clinical symptoms and multiple
mechanisms of drug–host interaction, many of which are
poorly understood.5
Classification of ADRs
The pharmacological classification of ADRs distinguishes
between dose-related and non-dose-related reactions,
which are the equivalent for type A and type B reactions,
respectively.
Type A reactions (defined ‘augmented’) represent
approximately 80% of the total ADRs.
They are dose dependent and predictable and are based
on the pharmacology of the drug. Pharmacology can be
further subdivided into primary or secondary.
Type A primary reactions include abnormal reactions
due to excessive action of the primary pharmacology of
the drug (gingival bleeding after the use of anticoagulant
drugs), whereas a type A secondary reaction is an effect
of the secondary pharmacology of a drug [e.g. taste
alteration during use of angiotensin-converting enzyme
inhibitors (ACEI)].6
Approximately 15% to 20% of adverse drug events are
caused by an unpredictable reaction to drugs, and these
represent type B reactions (defined ‘bizarre’).
These reactions may or may not be dose-related. In this
group are included idiosyncratic reactions that cannot be
predicted from the known pharmacology of the drug.
Type B reactions can be divided into immunological and
non-immunological reactions.
The majority of type B reactions are immune-mediated
side effects like hypersensitivity reactions. Clinically, these
immune-mediated side effects are very heterogeneous
and can be subdivided according to different pathomech-
anisms and classified into four categories described by
Coombs and Gell. Type I reactions are due to IgE medi-
ation and mainly cause urticaria, anaphylaxis and asthma;
type II reactions are based on immunoglobulin-mediated
cytotoxic mechanisms, accounting mainly for blood cell
dyscrasias; type III reactions are immune complex mediated
(e.g. vasculitis); and type IV reactions are mediated by T
cells, causing so-called delayed hypersensitivity contact
dermatitis elicited by small chemicals has been documented.
Several oral reactions to systemic medications are
non-immunologic and therefore not antibody dependent.
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Table 1 Classification of ADRs based on the drug reaction
Type of reaction Mnemonic
A = Dose-related Augmented
B = Non-dose-related Immunological Type I
reactions
Bizarre Type II
Type III
Type IV
Non-immunological Idiosyncratic
reactions reactions
C = Dose and Continue
time-related
D = Time-related Delayed
E = Withdrawal End of use
F = Unexpected Failure
failure of therapy
These drugs can affect mast cells, causing chemical
mediators of inflammation to be released. Drug overdose
and toxicity also can lead to non-immunologic drug reactions
and the release of chemical mediators of inflammation.
In non-immunologic reactions are included all idio-
syncratic reactions in reactive metabolite syndromes.
Recently, other types of reaction have been added
because some adverse reactions cannot be comfortably
classified by the binary system detailed above. For example,
adverse reactions may depend on duration of treatment in
addition to dose (e.g. osteoporosis from corticosteroids).
To overcome this trouble, an enhanced classification has
been introduced that takes into account both parameters
of dose and time. (Table 1) The reactions related to both
dose- and time-labelled type C (defined ‘continuous’),
whereas delayed reactions are labelled as type D (defined
‘delayed effects’); type E are those reactions – defined
‘withdrawal reactions’ – that appear after many years of
treatment (e.g. bladder carcinoma after treatment with
cyclophosphamide). Finally, reactions occurring after
drug withdrawal (e.g. seizures after stopping phenytoin)
are referred to as type F (also defined ‘failure of therapy’).
It is also necessary to emphasize that some drug reactions
may occur in everyone, whereas others occur only in suscep-
tible patients.4,7,8 In this regard, a further classification of
adverse reactions to drugs is possible in relationship to the
action of drugs and the susceptibility of patients (Table 2).7,9,10
Pathogenetic mechanisms
Several pathogenetic mechanisms can cause ADRs, which
may be related to patient- or drug-dependent factors.
Patient risk factors include age (prevalently in neonates
and the elderly), sex (more common in women),
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Table 2 Classification of ADRs based on the action of the drug and the susceptibility of patients

Classification of adverse reactions to drugs

Reactions that Drug overdose Toxic reactions linked to excessive dose or impaired excretion, or both
may occur in Drug side-effect Undesirable pharmacological effect at recommended doses
anyone Drug interaction Interference of a drug on the effectiveness or toxicity of another drug

Reactions that Drug intolerance A low threshold to the normal pharmacological action of a drug
occur only in Drug idiosyncrasy A genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme deficiency
susceptible Drug allergy An immunologically mediated reaction
subjects Pseudoallergic reaction A reaction with the same clinical manifestations as an allergic reaction but lacking immunological specificity

underlying disease (more common in patients with renal
or hepatic disease for reduction of the ability to metabolize and
clear a drug), genetics (differences in metabolizing enzymes
may explain response variability) and prior drug reactions.
Drug factors include route of administration (more
common with topical and intramuscular administration
and less so with intravenous administration; oral route is
safest), duration (more common with chronic or frequent
use rather than short-term or intermittent use), dose and
variation in metabolism.
Factors predisposing to pharmacological ADRs include
drug pharmacokinetic or pharmacodynamic abnormali-
ties and drug interactions. The metabolic conversion of
drugs to chemically reactive products is a prerequisite for
many idiosyncratic drug reactions. Increased levels of
reactive drug metabolites, their impaired detoxification or
decreased cellular defence against reactive drug products
seems to be an important initiating factor. Oxidative
reactive drug metabolites are found in organs and cells
preferentially affected by idiosyncratic drug reactions.11
Furthermore, drug bioavailability may depend on
patient’s genetic background. There is in fact genetic-based
variability in drug absorption, metabolism and disposition
as well as the way drugs interact with receptors. All of the
major human enzymes responsible for the modification of
functional groups by oxidation, hydroxylation or con-
jugation with endogenous constituents exhibit common
polymorphism at the genomic level. Among the important
enzyme families that contribute to the process are the
cytochrome P450 system (CYP) and N-acetyltransferases.
CYP encompasses a large gene superfamily that catalyses
the metabolism of a wide range of xenobiotics, including
most drugs. There are different isoforms of CYP and they
are distributed differently in people with the appearance
development of a different phenotype with no, normal,
increased and reduced or inactive enzyme activity, some
of which may result in idiosyncratic pharmacological
responses to prescribed medications.12–15
Several local or multifocal manifestations of ADRs can
mime a pathology or be precursory signs of systemic
diseases. This should be born in mind because the correct
diagnosis and the elimination and substitution of the drug
responsible allow an early recovery without therapy, or
with a minimal pharmacological contribution.
The aim of this study is to stimulate clinicians to become
familiar with the most important ADRs and the drugs
responsible in order to distinguish manifestations due to
ADRs from those depending on the clinical history of the
disease. Furthermore, because in many cases, drugs can
be responsible for oral and perioral adverse reactions
(OAPDRs), in this paper, we analyse the most frequent
patterns of oral involvement and list responsible drugs
and management. These clinical patterns require clinicians
to search for a possible cause-and-effect relationship with
a particular medication discovered from medical history
before formulating diagnoses for other diseases.
Main patterns of oral and perioral ADRs
Drug-related xerostomia
Xerostomia or dry mouth is the most common adverse
drug-related effect in the oral cavity. Despite a large
number of medications – to date, more than 500 – list dry
mouth as an adverse effect, relatively few drugs have been
demonstrated to affect salivary function in controlled
clinical studies. This apparent disparity may reflect the
subjective sensation of oral dryness due to qualitative
alterations of saliva rather than actual changes in salivary
flux. The synergistic effects of medications have been
recognized and are increasingly common in elderly
patients taking multiple medications (polypharmacy).
In addition, habits such as smoking, alcohol consumption
and even long-term use of caffeinated drinks may
contribute to oral dryness or the perception of dryness.16
Dry mouth can reduce or alter the sensation of taste as
well as impair speech and impede the swallowing
function. Dry mouth is one frequent symptom in several
diseases that are unrelated to drug use, of which the most
common is Sjogren’s syndrome.

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The principal mechanism of drug-induced xerostomia is
an anticholinergic or sympathomimetic action.
The M3-muscarinic receptors (M3R) mediate parasym-
pathetic cholinergic neurotransmission to the salivary
(and lachrymal) glands, but other receptors may also be
involved. The drugs implicated most commonly in xeros-
tomia include tricyclic antidepressants, antipsychotics,
benzodiazepines, atropinics, beta-blockers, antihistaminics
and H2-receptor antagonists.17
Some newer therapies that may cause drug-induced
xerostomia include omeprazole, anti-HIV protease
inhibitors, trospium chloride, elliptinium, tramadol, the
nucleoside analogue HIV reverse transcriptase inhibitor
didanosine and new-generation antihistamines. Besides
systemic retinoids, antithyroid agents, chlorhexidine,
cytotoxics, ganglion-blocking agents, iodides, phenothi-
azines and sulphonamides may cause dry mouth.18
Diuretics may contribute to dry mouth by causing
dehydration and thus salivary gland hypofunction.
Alpha1-adrenergic agents may result in altered saliva
composition and secretion rates.
Dry mouth has been reported in about 20% of hyper-
tensives treated with beta-adrenergic blockers; these
may decrease the total protein content of whole-mouth
saliva.
The administration of ACEIs may cause dry mouth
due to the reduction of the salivary flow rate, whereas
sodium-channel blocker drugs are associated with dry
mouth because of their anticholinergic effect.19
Drug-induced salivary hypofunction leads to complaints
of dryness at baseline resting levels, although sensation in
response to stimuli (such as food or salivary flow rate testing
with citric acid stimulation) is normal. Sometimes,
patients with anxiety or depressive conditions may report
dry mouth even in the absence of drug therapy.
Drug-induced xerostomia is a reversible phenomenon.
Thus, if this is the case, discontinuation of the causative
agent will lead to normalization of salivary function.18
Drug-related taste disorders
Taste disturbances can be considered OPADRs. Many
drugs induce taste sensation abnormalities, but the
mechanisms by which medications alter taste sensation
are not well understood. Drugs may cause a loss of taste
acuity (hypogeusia), distortion in perception of the
correct taste of a substance (dysgeusia) or loss of taste
sense (ageusia). This distortion may manifest as an
unusual, bitter, metallic taste, a change in taste perception
or a distaste for food. Taste disturbances seem to occur
through two mechanisms.
One mechanism is that the excretion of the drug or its
metabolites into saliva acts by interfering with the chemical
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composition or flow of saliva. Another mechanism of
drugs causing taste disturbance may be by affecting the
taste receptor function or signal transduction, and this
may cause an unpleasant taste. Many chemosensory
disorders affect both taste and smell, and often, patients
refer to a taste deficit that is actually anosmia (e.g. inability
to detect olfactory stimulants).20 Such disturbances are
usually reversible but it may take some months after drug
cessation. Sulfhydryl compounds are a common cause of
taste disturbance. In many patients, penicillamine causes
partial or total loss of taste. Impaired or salty taste is a
frequent complaint associated with captopril, whereas
penicillamine has been known to cause a partial or total
loss of taste, and enalapril on the other hand, with metallic,
sweet, salt dysgeusia, and taste loss.21
Taste disturbances tend to be self-limiting and reversible
within 2 to 3 months, even if the drug is continued.
Systemic griseofulvin can render certain foods profoundly
tasteless, the effect gradually worsening as long as the
patient is taking the drug. In addition, other drugs
especially those used for gastrointestinal disorders may
cause some degree of loss of taste or altered taste as
follows: tripotassium dicitrato bismuthate chelate, clari-
thromycin, lansoperazole, anti-HIV protease inhibitors,
terbinafine, intravenous pentamidine and isotretinoin. Anti-
thyroid drugs can induce taste disturbance because of the
negative influence on the maturation of fungiform papillae
and reduction of taste receptors with a reduction in taste.
ACEIs as a drug class are associated with taste
disturbances.22,23
Drug-related oral ulceration
Several cases of oral mucosal ulceration following drug
use have been reported and described as oral ulcers or
aphthous-like ulcers.
The terms ‘oral ulceration’ and ‘aphthous stomatitis’
are commonly used synonymously in reports on oral
ADRs (OADRs); however, aphthae usually commence in
the second decade of life as recurrent oral ulcerations and
usually wane during the fourth decade.24 In contrast,
drug-induced ulcerations are present mostly in older age
groups and not always as a recurrent pattern. Such lesions
are also described as non-specific ulceration. Epithelial
necrosis and ulceration may result from direct application
to the mucosa of over-the-counter medications such as
aspirin, hydrogen peroxide, potassium tablets and
phenol-containing compounds. Fixed drug eruptions in
the oral cavity often appear initially as areas of oedema
and erythema that lead to localized, non-specific ulceration.
The labial mucosa is most commonly involved.25
A number of drugs are implicated in the development
of oral ulcers, including sulphonamides, barbiturates,
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Femiano et al.
beta-blockers, non-steroidal anti-inflammatory drugs
(NSAIDs), phenolphthalein, dapsone, salicylates and
tetracycline. Ulceration of the oral mucosa is a common
adverse effect in a wide variety of antineoplastic agents,
including methotrexate, melphalan, 5-fluorouracil and
doxorubicin.26
Sodium lauryl sulphate may predispose to ulcers similar
to aphthous ulceration. There are also case reports of
aphthous-like ulceration following the use of beta-blockers
such as labetalol, alendronate, captopril, nicorandil, some
NSAIDs, mycophenolate or sirolimus, protease inhibitors,
tacrolimus and sulphonamides, although the exact
pathogenic mechanisms are unclear in all of these.27
Drug-related gingival enlargement
One of the most common adverse effects of drugs on the
periodontium is gradual and generalized overgrowth of
the fibrous component of the gingiva.
In general, gingival enlargement develops within a few
months of the commencement of drug therapy. It is
usually generalized, only partly associated with poor oral
hygiene and local plaque accumulation, and responds
variably to improved plaque control and/or withdrawal or
reduction of drug therapy. Non-neoplastic enlargement,
or overgrowth of the gingival tissues, was recognized in
patients who used phenytoin.28 More recently, calcium
channel blockers (members of the dihydropyridine class
of medications), cyclosporin and the antiepileptic drug
sodium valproate have been associated with this reaction.
Within the calcium channel blocker family, nifedipine,
diltiazem, verapamil and amlodipine are among the most
commonly reported causative agents. Tissue enlargement
typically occurs within 1 to 3 months after drug therapy
is initiated and begins in the superficial gum tissues
between the teeth (interdental papillae). The anterior
segments are more frequently involved than posterior
areas, but generalized involvement is not uncommon.29
The correlation with the process of fibroblast proliferation
for phenytoin, cyclosporin and the CCBs has a different
pathogenetic mechanism. Phenytoin-induced gingival
overgrowth may result from mast cell-mediated androgen
activity in the gingiva. Cyclosporine has been shown to
increase the fibroblast production of collagen and matrix
while decreasing collagenase activity.30
Nifedipine (along with other CCBs) seems to inhibit Ca
uptake within gingival fibroblasts with blockage of the
adherence of fibroblasts at their lipopolysaccharide-
stimulated/macrophage-induced death. The pattern of
gingival overgrowth is clinically similar among all of these
medications. The overgrowth generally starts as a painless
enlargement of the papilla and proceeds to include the
gingival margin, eventually developing to cover a
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Oral adverse drug reactions
substantial portion of the crown of the tooth. Occasionally,
the gingiva may appear papillary or multinodular.31,32
Unlike most drug adverse reactions, gingival overgrowth
becomes evident within months of drug administration.
Its pathogenesis is usually traced back to the increased
production of collagen by gingival fibroblast, which may
account for the lack of rapid resolution after drug dis-
continuation. Indeed, if the medicament is discontinued,
the overgrowth is not readily resolved, although resolu-
tion has been reported in cases of cyclosporin. Histological
analysis reveals accumulation of dense, mature collagenous
fibres and widely distributed fibroblasts within the corion
of patients’ gingival tissue. The overgrowth may cause
accumulation of dental plaque, which may account for
the different degrees of inflammation found on histology.
Because the drugs that cause this oral disorder cannot
be readily withdrawn, treatment usually takes the form
of surgical excision via gingivectomy or gingivoplasty.33
Recurrence is common; thus, rigid oral hygiene and
frequent dental visits are essential. Children and teenagers
are more susceptible to phenytoin and cyclosporin-induced
overgrowth than adults, suggesting that hormones, espe-
cially androgens, are important contributing factors.34,35
The clinicians must know these clinical aspects of ADRs
in formulating differential diagnoses with oral manifestation
of leukaemia.
Drug-related movement disorders
Tardive dyskinesias (TDs) are involuntary movements of
the tongue, face, lips, trunk and extremities. They occur
in patients who are treated with long-term dopaminergic
antagonist medications. The pathophysiology of TD is not
well understood, although it has been hypothesized that
central dopamine blockade plays a role. Acute movement
disorders also are assumed to result, in part, from the
blockade of dopamine receptors by dopamine antagonists.
Several classes of non-neuroleptic medications have also
been linked to dyskinesias, including antidepressants,
antiemetics, oral contraceptives and anxiolytics.36
Clinically, TD is characterized by repetitive, involuntary,
purposeless movements; features of the disorder may
include tongue protrusion, grimacing and puckering, lip
smacking and rapid eye blinking; rapid movements of the
arms, legs and trunk also may occur.37
There is no standard treatment for TD so treatment is
highly individualized. The first step generally involves
stopping or minimizing use of any neuroleptic drugs;
however, this option is not always feasible for patients
with a severe underlying condition. Replacing the neuroleptic
drug with substitute drugs may help some patients.
Drugs such as benzodiazepines, adrenergic antagonists
and dopamine agonists may also be beneficial.38
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Drug-related mucosal pigmentation
Various drug mechanisms can induce pigmentary changes
in the mucosa. Some drugs, such as oral contraceptives,
stimulate melanocytic activity. Others, including pheno-
thiazines and heavy metals such as silver, mercury and gold,
become lodged within the oral mucosa and alter pigmentation
directly.39 Antimalarials produce a slate grey or yellow
pigmentation, whereas clofazimine produces a characteristic
red colour. Tetracycline can permanently stain teeth if
taken during early childhood or pregnancy. Amiodarone
produces a characteristic slate blue discoloration in
sun-exposed areas.40
Minocycline has increasingly been reported to cause
widespread blue, blue-grey or brown pigmentation of the
gingiva and mucosa due to the interaction of the drug
with the bone during its formation. Although much of
this pigmentation may reflect discoloration of the under-
lying bone and roots of teeth, there is also inherent
pigmentation of the oral mucosa, including the tongue.41
The problem is related to both the dosage and duration of
drug therapy. Skin cells and the cells of other organs in affected
patients have been found to contain myelin-like lysosomal
structures and membrane-bound granules. This generalized
derangement of lysosomal storage may also be the basis
for other adverse effects of amiodarone such as interstitial
alveolitis, acute hepatitis and disturbed thyroid function.42
Other medications, including quinilone, hydroxyquinilone
and amiodoquine have been known to induce oral
pigmentation mostly on the tongue, palate and buccal
mucosa. Clinically, these areas are often flat, macular,
localized or multifocal, and they do not always resolve
after the drug is eliminated. Black, hairy tongue is a
separate entity that results from elongated threadlike
papillae that become stained brown or black due to
chromogenic bacteria, extrinsic staining such as tobacco,
oral antibiotics or antacids containing bismuth.40 Often,
the pigmentation of the oral mucosa caused by the use of
oral contraceptives does not produce complete regression
of the pigmentation after cessation of the drugs. Oestrogens
are well known to induce high levels of cortisol binding
globulin contributing to a decreased portion of plasma-
free cortisol and as a result produces a hypersecretion of
ACTH, a β-melano-stimulating hormone. The latter may
cause increased oral pigmentation. Direct contact with, or
ingestion of, a medication containing metals may cause
discoloration of the oral tissue. It is also possible that these
medications containing metal pigments extravasate from
vessels in foci of increased capillary permeability. Thus,
the colour changes are most common along the gingival
margin, where metallic sulphides form. Although this con-
dition usually resolves within weeks or months after the metal
is withdrawn, these pigmented lesions can be permanent.42
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Drug-related angioedema
Angioedema is a common clinical manifestation of
a group of allergic conditions with different aetiologic
pathways. It is defined as a rapid swelling of the lips and
adjacent structures in susceptible patients following
contact with an allergen or medication. Angioedema
develops quickly within the oral and perioral area as a
painless swelling of the lips, anterior cheek or tongue.43
Swelling subsides within 24 to 48 h after contact with the
suspected allergen of medication has ceased. Two forms
of angioedema have been described: hereditary and
acquired. Hereditary angioedema is a rare autosomal-
dominant trait that results from a deficiency of the C1
esterase inhibitor (C1INH) of the complement cascade.
Compared with acquired angioedema, swellings usually
result from mild trauma to the affected areas. Acquired
angioedema is the more common form and frequently
results from recent ingestion of a medication.44 Most cases
of acquired angioedema are mediated by an IgE immune
reaction, particularly when penicillin or other antimicrobials
are implicated. Acquired angioedema can be non-immune
in origin; NSAIDs such as indomethacin are frequently
the cause of such reactions. These medications seem to act
directly on the mast cell and destabilize the membrane,
which leads to degranulation and the release of chemical
mediators of inflammation.45 In other cases, medications
such as ACEIs (e.g., enalopril and captopril) cause non-
immune mediated angioedema. In some cases, ACEI
therapy causes localized angioedema affecting the tongue
alone. ACEknown as kinase II, is the primary inactivator
of bradykinin, a potent vasodilator and mediator of capillary
leakage. ACEIs inhibit the metabolism of bradykinin by
blocking kinase II. Increased tissue levels of bradykinin
are thought to induce angioedema.43
Drug-induced pemphigus
Pemphigus is a group of potentially life-threatening
diseases characterized by cutaneous and mucosal blister-
ing. Pemphigus vulgaris is the most common form and
frequently involves the mouth.
Drug-induced pemphigus is not uncommon variant of
idiopathic pemphigus. Traditionally, drugs that are cap-
able of inducing pemphigus are divided into two main
groups according to their chemical structure: thiol drugs
and non-thiol drugs. Some of these drugs induce antibody
formation, which results in acantholysis due to a mechanism
that is identical to that found in idiopathic pemphigus.
Other drugs are postulated to induce acantholysis directly
in the absence of antibody formation. Thiol drugs are
reported most frequently as the cause of drug-induced
pemphigus. Penicillamine, captopril and enalopril or
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Femiano et al.
other ACEIs are the thiol drugs associated most often with
drug-induced pemphigus. Non-thiol drugs (sharing an
active amide group in their molecules) are more likely to
induce acantholysis due to immune mechanisms consistent
with an autoimmune pemphigus process.46
The clinical features of drug-induced pemphigus mimic
those of pemphigus vulgaris or foliaceus, and affected indi-
viduals can have variable levels of circulating antibodies to
epithelial components and to expected antigens (e.g. desmo-
gleins 1 and 3). Besides epithelial damage being due to the
action of these antibodies, some of the implicated drugs are
thiols that may induce a fall in local levels of plasminogen
activator inhibitor, leading to increased plasminogen activation
and epithelial damage. Thiols such as penicillamine may
also interfere in cell membrane cysteine links, potentially
leading to antibody generation and epithelial damage.
In drug-induced pemphigus vulgaris, the relatively
fragile vesicles are rarely observed at clinical examination,
and most cases are characterized by irregular ulcerations
with ragged borders that may coalesce to involve large
areas of the mucosa.
Patients may have circulating autoantibodies to the
desmosomal components41 These patients often have
clinical (blisters), histologic (acantholysis), immunologic
(skin-fixing autoantibodies) and prognostic features
similar to idiopathic pemphigus vulgaris.46
Lichenoid drug reactions
Lichenoid drug reactions and lichen planus (LP) exhibit
similar clinical and histologic findings.
LP is a chronic inflammatory disorder in which
the keratinocyte is the main target of a T-lymphocyte
immunologically mediated attack, with release of tumour
necrosis factor-alpha, and similarities to a delayed hyper-
sensitivity response.
Clinically, lichenoid lesions are indistinguishable from
oral LP (OLP); both demonstrate erythematous erosions
and ulceration with focal areas of radiating strie. Histological
analysis of these two conditions reveals similar, some-
times overlapping, features. However, two factors distin-
guish lichenoid drug reactions from LP. First, lichenoid
reactions are associated with the administration of a drug,
contact with a metal, foodstuffs or a comorbid systemic
disease. Second, lichenoid reactions often resolve when
the offending agent is eliminated. The prevalence of oral
lichenoid drug reactions seems to be increasing, most likely
due to the realization that they have an aetiology that is
distinct from idiopathic LP.47 The increased occurrence
may result from the numerous new categories of medica-
tions, for which the risk of lichenoid reactions is increased.
Since the advent of antimalarial therapy, there have
been an everincreasing list and spectrum of drugs that may
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Oral adverse drug reactions
give rise to mucocutaneous LP-like eruptions (lichenoid
reactions). Apart from these drugs, gold is probably the
most common agent recognized as initiating a lichenoid
reaction. Gold salts can cause a range of mucocutaneous
lesions of which oral lichenoid lesions may be the first.48
The drugs now most commonly implicated in lichenoid
reactions are NSAIDs and ACEI. Lichenoid reactions
may also follow the use of HIV protease inhibitors, anti-
hypertensive agents, antimalarials, phenothiazines, sulphona-
mides, tetracyclines, thiazide diuretics and many others.49
The exact pathogenic mechanism by which drugs may
cause LP-like disease is not known.
Clinical identification of lichenoid drug reactions has
been based largely on subjective criteria: Sometimes, the
oral lichenoid lesions are unilateral and more erosive, but
these features are by no means invariable; however, these
features are by no means invariable. Histology may help;
lichenoid lesions may have a more diffuse lymphocytic
infiltrate and contain eosinophils and plasma cells, and
there may be more colloid bodies than in classic LP, but
there are no specific features, and immunostaining is
usually non-contributory, although basal cell cytoplasmic
antibodies may be found.47 The most reliable means to
diagnose lichenoid reactions is if the reaction remits
with drug withdrawal and returns on rechallenge, but
frequently, this is not possible because of the need to
ensure patient safety. Dental restorative materials may
also be associated with lichenoid lesions. Most patients
with OLP have no evidence of any association with dental
restorative materials. However, contact with or proximity
to restorations involving amalgams or other materials
causes some lichenoid reactions (i.e., lesions that clinically
and histologically resemble LP closely) but have an
identifiable aetiology. These reactions are presumably due
to allergic or toxic reactions to compounds released or
generated, the Koebner phenomenon or possibly due to
plaque accumulated on the surfaces of the restorations.50
Lupus-like disorders
Systemic lupus erythematosus (SLE) may be induced by
a wide variety of different drugs. Several drugs have
been implicated in causing drug-induced lupus. The most
commonly implicated agents of drug-induced SLE
are procainamide and hydralazine, although drugs less
commonly associated include methyldopa, chlorpromazine,
penicillamine, isoniazid and quinine as well as whole
groups of drugs such as anticonvulsants, sulphonamides,
beta-blockers and others.51 Lupus-like oral lesion is like
lupus lesion, and it is characterized by an erythematous
erosive central area surrounded by an edge with whitish
radiating striae and small red points. Clinically, the oral
lesions of drug-induced LE may simulate those of erosive
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Oral adverse drug reactions
LP, with irregular areas of erythema or ulceration
bordered by radiating keratotic striae. These lesions may
affect the palate, buccal mucosa and gingival or alveolar
tissues. The rarity of LP on the hard palate may be helpful
in differentiating it from drug-induced LE.52
Drug-related multiform erythema
Erythema multiforme (EM) is a hypersensitivity reaction
characterized by macules, papules and vesicles on the
extremities and trunk, which often appear in a targetoid
(iris) configuration. Fever usually accompanies the
reaction. The most common cause of erythema multiform
is infection, followed by drug sensitivity. Herpes simplex
virus is most frequently the infective organism, but
mycoplasma may also be responsible.53,54 The disease is
thought to be initiated by depositing immune complexes
in the superficial microvasculature in the tissues or a
direct cell-mediated immune reaction. Indeed, the main
targets are the surface epithelium and the walls of
superficial blood vessels in the lamina propria. Skin and
mucosal reactions range from mild erythema to widespread
necrosis, ulceration and epithelial sloughing.24 The onset
of EM usually occurs within days or weeks after the
offending drug is ingested. Medications most commonly
associated with EM include NSAIDs, anticonvulsants,
sulphonamides, phenobarbital, carbamazepine, phenytoin,
allopurinol, trimethoprim, sulphonamide and penicillin.
EM may evolve into the more serious Stevens–Johnson
syndrome, an extensive blistering disease involving two
or more mucous membranes.53 The disease can be life
threatening, with 5% mortality. Unlike EM, Stevens–
Johnson syndrome is usually drug induced. Signs and
symptoms generally appear within 1 to 3 weeks of drug
initiation. Incriminating drugs for both EM and Stevens–
Johnson syndrome include sulphonamides; aromatic
anticonvulsants, such as phenobarbital, phenytoin and
carbamazepine; penicillins; quinolone; cephalosporins;
NSAIDS; and allopurinol. Skin lesions have concentric
rings of erythema, producing what is often referred to as
a ‘target’ or ‘bull’s-eye’ appearance, typical of EM. Oral
lesions (along with skin lesions) occur in approximately
70% of EM patients. Lesions can occur anywhere in the oral
cavity, although they tend to spare the gingiva. A haemorrhagic
crusting on the lips can be especially prominent.53
Drug-related gingival bleeding
Gingival bleeding is an uncommon adverse effect, but
some drugs may directly or indirectly cause bleeding
gums. The gums may bleed spontaneously or following
oral hygiene procedures or eating. Bleeding may result
from anticoagulants and drug interactions, which increase
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Femiano et al.
the bleeding time. A number of drugs have adverse effects
that may directly or indirectly cause gingival bleeding.
The adverse effects on the periodontal tissues may result
in gingival bleeding. Patients taking anticoagulants such
as warfarin or heparin may develop gingival bleeding.55
Drug-related oral burning
Sometimes, a number of drugs can provoke a subjective
sensation of oral burning in the absence of evident oral
lesion.
Enalapril and sometimes other ACEI, such as captopril
and lisinopril, may on rare occasions cause a scalding-type
sensation in the mouth. Oral burning can be also caused
by drugs responsible for a change in salivary composition
with consequent subjective dry mouth.56
Antithyroid drugs have a negative influence on the
maturation of fungiform papillae and of taste buds in
supertaster subjects. The reduction in taste causes the
release of inhibition on the somatic-sensorial sensitivity of
the trigeminal nerve in subjects with a larger number of
taste papillae and the subsequent onset of oral burning
(tongue, palate, lip), a feeling of heat in the mouth and a
feeling of swelling in the lips and tongue.57
Drug-related osteonecrosis of the jaws
Osteonecrosis of the jaws (ONJ) is a recently described
adverse reaction of bisphosphonate (BP) therapy and is
characterized by exposure and necrosis of areas of the
jawbone.
Bisphosphonates are non-metabolized analogs of
pyrophosphate that localize to bone and prevent or
ameliorate skeletal complications. The various bisphos-
phonates, approved for clinical use, differ based on
structural alterations of the so-called R-2 side chain. These
R-2 side chains determine the cellular effects and efficiencies
as inhibitors of bone resorption. Indeed, alendronate,
risedronate, pamidronate, zoledronic acid and ibandro-
nate, the aminobisphosphonates, have much higher
potency due to their nitrogen side chain.
BPs significantly reduce the rate of bone turnover,
primarily by inhibiting osteoclastic activity.58 Once
deposited on the surface of bone, bisphosphonates are
internalized by osteoclasts, causing disruption of osteoclast-
mediated bone resorption. However, there are two
additional important functions to be emphasized: they
exert antitumour effects (thus their use for multiple
myeloma and bone metastases or in osteoporosis
therapy); and they have antiangiogenesis properties (they
prevent blood vessels from developing), resulting in
decreased circulating levels of vascular endothelial
growth factor (VEGF).
© 2008 The Authors
Femiano et al.
Thus, decreased blood vessels in the area makes healing
more difficult in the presence of infection or trauma.
Prolonged use of bisphosphonates may suppress bone
turnover sufficiently to allow microdamage of bone to
develop.59 Thus, patients undergoing BP-based therapy
are more susceptible than healthy individuals of develop-
ing osteonecrosis, although the precise reason for the
elective localization on the jaws still remains to be
established.
Clinically, ONJ is characterized by exposure of necrotic
bone in the mandible or maxilla, which may be asympto-
matic or associated with significant pain. The mandible
is affected more often than the maxilla to a ratio of 2 : 1.
The exposed bone appears as areas of yellow-white, hard
bone with smooth or ragged borders. Painful ulcers may
develop in soft tissue touching the ragged bone.58 No
definitive treatment has been established, although a
closely monitored conservative regimen seems to be
preferred to a primary surgical treatment.
Conclusion and discussion
The importance of ADRs is often underestimated,
although they are common and can be life threaten-
ing, and lead to unnecessary expense. Every healthcare
professional shares a responsibility for identifying the risk
factors of ADRs and using that knowledge to reduce their
occurrence. Most naturally occurring diseases may be
mimicked by drug reactions, and accurate diagnosis
depends on the degree of clinical alertness. If a patient is
taking medicines, and develops an illness or pathological
condition, the differential diagnosis should include the
possibility of an ADR.
Several oral lesions and symptoms caused by drug
reaction can simulate systemic diseases and be treated
with local or sometimes systemic medical treatment.
Various patient- and drug-related factors contribute to
the risk of ADRs. Patient factors include age (highest
prevalence in the newborn and the elderly), sex (more
common in women), genetics (differences in metabolizing
enzymes may explain response variability), underlying
disease (more common in patients with disease, which
decreases the ability to metabolize and clear a drug) and
prior drug reactions.60 Drug factors include route of
administration (more common with topical and intra-
muscular administration and less so with intravenous
administration), duration (more common with protracted
treatment), dose and variation in metabolism. Reactions
are more common for drugs with low therapeutic indices,
high levels of drug–drug interactions and a tendency to
form reactive intermediates or toxins.61
The American Academy of Dermatology has developed
guidelines of care for cutaneous ADRs. Five issues to
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Oral adverse drug reactions
consider in a drug eruption are (i) assessment of the erup-
tion, (ii) probability of a relation between the eruption
and the drug, (iii) potential seriousness of the eruption,
(iv) management, and (v) prevention of recurrence.
The first step is to find out whether the oral manifestation
started after the use of a specific medicinal product, and it
is then necessary to determine whether the illness could
be due to the drug.
The initial history should include a recording of all
prescription and non-prescription drugs taken within the
last month, including dates of administration and dosage.
The temporal relationship between drug intake and the
onset of clinical symptoms is critical. Unless the patient
has been previously sensitized to a drug, the interval between
starting therapy and the onset of reaction is rarely less
than 1 week or more than 1 month. Patients should be
asked about previous drug exposure and reactions.
The quality of evidence presented for oral reactions
being drug-induced is variable.
The association between a drug and an OPADR is
mostly based on the disappearance of the reactions
following discontinuance of the offending drug. Some
OPADRs have been verified by rechallenge or laboratory
tests.27,45,62
In patients on multiple drugs, most authors consider the
latest-introduced drug as the offending drug.
If several medicines could be causative, the drugs least
likely to result in harm if withdrawn should be withdrawn
first, preferably one at a time, depending on the severity
of the reaction. If the reaction is likely to be dose related,
dose reduction should be considered. If a patient cannot
manage without a drug that has caused the adverse
reaction, providing symptomatic relief while continuing
the essential treatment is a possible consideration.
In general practice, ADRs are often mild and self-
limiting, but a problem arises if the patient is labelled as
allergic to a drug, and therefore, the patient is denied this
drug or group of drugs in the future.3,63
The goal of diagnostic testing is to evaluate biochemical
or immunological markers that confirm activation of a
particular immunopathologic pathway to explain the
suspected adverse drug effect. Laboratory evaluation is
guided by the suspected pathological mechanism.64
Several diagnostic tests can help to identify a suspected
drug allergy; however, most have limited usefulness
because many allergic reactions result from drug metabolites,
which cannot be detected. Non-specific hypersensitivity
tests include a blood eosinophil count and measurement
of the IgE level. For immediate-type reactions, determining
the tryptase level may be helpful because tryptase is a
marker of mast cell degranulation. Immediate-type IgE
reactions can be identified through skin testing and the
radioallergosorbent test; however, only a few drugs can be
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Oral adverse drug reactions
tested this way. Skin biopsy can be a helpful diagnostic
test for identifying a drug eruption. The presence of
eosinophils, oedema and inflammation all suggest hyper-
sensitivity. Vasculitis and necrotic changes may suggest
EM, Stevens–Johnson syndrome or toxic epidermal
necrolysis. Patch testing is an important tool in evaluating
the possibility of allergic contact dermatitis.27,62 As a test
for reactivity, the application of specific allergens to the
patient’s skin for 48 to 72 h may identify an allergen to be
avoided. Photopatch testing helps to evaluate photoallergic
reactions; the approach is similar to standard patch testing
except that the patient is exposed to both the drug and
ultraviolet light. Perhaps the most sensitive and specific
diagnostic test for drug eruptions is the rechallenge.62,65
To come to the point, the behaviour of the clinician
regarding oral lesions and symptoms in patients taking
one or several drugs is very difficult due to the absence of
specific diagnostic tests. For this reason, the clinician can
only appeal to clinical examination and to anamnestic
data to formulate the diagnosis of OAPDRs excluding the
hypothesis of local and systemic diseases. The manage-
ment of OAPDRs is complex. In some cases, management
may be limited to drug cessation and palliative symptom
management; in other cases, more aggressive therapy
may be indicated.
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