In this era an ever-expanding list of medications is linked to pathological reactions in the oral and perioral region. These adverse drug reactions have a broad spectrum of clinical manifestations that can mimic those of other disease states, including both local and systemic conditions. The clinical manifestations of oral reactions to the more commonly prescribed drugs have been discussed in this article.
Well known clinical patterns of adverse drug reactions
of the oral cavity include xerostomia, swelling and gingival enlargement
, nonspecific ulceration, vesiculobullous or ulcerative mucositis that
mimics other immunological disorders , oro-facial pigmentation. A
patient who complains of any of these signs and symptoms should be
thoroughly questioned regarding medication. If an offending drug can be
identified, its alteration or elimination, in consultation with the
prescribing clinician, will often result in resolution of the clinical
problem.
Drug induced xerostomia
Xerostomia, or dry mouth, is the most common adverse drug-related effect in the oral cavity. To
date, xerostomia has been associated with more than 500 medications.
The synergistic effects of medications have been recognized and are
increasingly common in elderly patients taking multiple medications
(polypharmacy). General drug classes that are strongly associated with
xerostomia include antidepressants and antipsychotics,
antihypertensives, antihistamines, and anticholinergics.
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| Root caries formed in a patient with drug induced xerostomia |
Importantly,
patients with xerostomia are also at increased risk for oral
candidiasis, a superficial infection that may cause mucosal sensitivity
or discomfort, as well as tooth decay that usually affects the cervical
(gumline) and root surfaces. Several different mechanisms account for
drug-related dry mouth, but an anticholinergic action underlies many:
The M3-muscarinic receptors (M3R) mediate parasympathetic cholinergic
neurotransmission to salivary (and lacrimal) glands, but other receptors
may also be involved.
Antidepressants
Early antidepressant medications such as tricyclic antidepressants (TCAs) unfortunately also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, causing dry mouth. Newer antidepressants are essentially serotonin (5-hydroxytryptamine: 5HT) agonists, or block re-uptake of noradrenaline (norepinephrine) and/or serotonin. Members of the newer generation of antidepressants—including the selective serotonin re-uptake inhibitors (SSRIs) and multiple-receptor antidepressants (such as venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone)—target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. The SSRI produce no significant changes in salivation, but dry mouth may still be seen (e.g., fluoxetine).
Antipsychotics
Long-term drug treatment of schizophrenia with conventional phenothiazine antipsychotics such as fluphenazine is commonly associated with dry mouth. However, newly developed antipsychotic drugs with more potent and selective antagonistic activity against the dopamine D(2) receptor may not necessarily be associated with a lower incidence of dry mouth. Olanzapine is an atypical antipsychotic which appears to produce dry mouth.
Antihistamines
The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects including dry mouth. Non-sedating antihistamines—most of which are histamine H1 receptor antagonists, such as acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine, however—are not entirely free from ADRs, though there may be less dry mouth.
Antihypertensives
The ganglion blockers and particularly the beta-blockers
(beta-adrenoceptor antagonists) may cause dry mouth, thought to be
associated with activation of CNS and salivary gland alpha 2-adrenergic
receptors. Such antihypertensive drugs, or sympatholytics (reserpine,
methyldopa, and clonidine), are now little used because of such
prominent adverse drug reactions such as dry mouth. Newer centrally
acting antihypertensives, with selective agonist effects on the
imidazoline I1 brainstem-receptors in the rostral ventromedulla (RVLM),
appear to modulate sympathetic activity and blood pressure without
affecting salivary flow: Moxonidine and rilmenidine are examples of this
new class. ACE inhibitors, which block the ACE enzyme in the
renin-angiotensin-aldosterone system, known to produce dry mouth.
Unfortunately, these associations are confounded by the
fact that xerostomia is a subjective complaint, and some patients who
report oral dryness may have apparently normal salivary gland function.
Other patients whose mouths appear to be clinically dry may have no
complaints. In addition, a certain amount of acinar atrophy and
decreased glandular secretions are considered a normal part of the aging
process. Also habits such as smoking, alcohol
consumption, and even long-term use of caffeinated drinks may contribute
to oral dryness or the perception of dryness. Underlying systemic
diseases such as in non-insulin-dependent diabetes, saliva secretion is
more affected by xerogenic drugs and autonomic nervous dysfunction than
in non-diabetic controls Furthermore, the possibility of an underlying
autoimmune etiology (eg, Sjögren syndrome)
should also be considered in xerostomic patients. The cause for which
the drug is being taken may also be important. For example, patients
with anxiety or depressive conditions may complain of dry mouth even in
the absence of drug therapy or evidence of reduced salivary flow. It is
thus important to recognize that some patients complaining of a
drug-related dry mouth have no evidence of a reduced salivary flow or a
salivary disorder, and there may then be a psychogenic reason for the
complaint.
Thus clinical tests to measure salivary flow (at rest
and under stimulation) should be used cautiously in assessing a patient
with suspected drug-induced xerostomia.
Drug related swellings
Drug-related gingival enlargement
Gingival enlargement is a well-described oral
side-effect of drug therapy. The drugs most commonly implicated in
causing this enlargement are phenytoin, ciclosporin and the
calcium-channel-blockers, nifedipine, diltiazem, verapamil and
amlodipine. Patients receiving therapy with both ciclosporin and
calcium-channel-blockers (e.g., post-cardiac or -renal allograft
recipients) may be sometimes, but not always, particularly liable to
drug-induced gingival enlargement.
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| phenytoin induced gingival hyperplasia |
In general, the gingival enlargement develops within a
few months of the commencement of drug therapy, is usually generalized,
is 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. Other drugs that have been
occasionally reported to cause gingival enlargement include
erythromycin, sodium valproate, phenobarbitone and vigabatrin.
Drug-related lip and mucosal swellings
Drug-induced mucosal swelling predominantly affects the
lips and tongue although rare isolated swelling of the uvula [Quinke’s
disease] can occur and is typically due to type I hypersensitivity
reactions. Among the most common offending agents are ACE inhibitors,
penicillin and penicillin derivatives, cephalosporins, barbiturates,
aspirin, local anesthetic agents, and other NSAIDs. Affected mucosa
typically appears edematous and erythematous within minutes or hours
after exposure to the offending drug giving rise to angio-edema.
Hypersensitivity to latex is an increasing problem in oral health care
and may cause rapid-onset angio-edema in susceptible patients.
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| Drug induced Angioedema |
Non-allergic oral swelling can also arise in response
to angiotensin-converting enzyme (ACE) inhibitor therapy. This adverse
effect occurs in patients, typically in the early weeks of therapy,
although it may occur within a few hours of commencement of treatment,
or after long-term therapy. The swelling usually affects the lips,
although it can be localized to the tongue, and is occasionally fatal.
African-Americans may be at particular risk. The tissue swelling
associated with ACE inhibitor therapy may be due to a rise in levels of
bradykinins and/or altered levels or function of C1 esterase inhibitor.
Plasmacytosis due to ‘tartar control’ toothpastes gives rise to
localized enlargements of the gingivae, tongue, and other oral mucosa.
Drug related salivary gland swelling
Some drugs have been related to salivary gland swelling.
Painless, usually bilateral, salivary gland enlargement (resembling
sialosis) may be an occasional side-effect of phenylbutazone,
oxyphenbutazone or chlorhexidine. The bilateral sialadenitis observed in
one adult following naproxen therapy was thought to be allergic in
origin, since the affected patient also had a cutaneous rash. A similar
mechanism has been proposed to underlie the salivary gland enlargement
caused by intravenous radiological contrast media. Clozapine, a novel
antipsychotic agent, may cause transient salivary gland swelling as well
as sialorrhea.
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| Drug induced parotid swelling |
Non specific ulceration and oral mucositis
Drug-related oral burns
Epithelial necrosis and ulceration may result from
direct application of over-the-counter medications such as aspirin,
hydrogen peroxide, potassium tablets, and phenol-containing compounds to
the mucosa. Aspirin is often used by patients seeking relief from
dental pain.
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| Aspirin burn |
Sodium lauryl sulfate, present in some oral health care
products, particularly dentifrices, may cause mucosal irritation or
ulceration. The affected mucosa appears whitish
and corrugated, with erosion and ulceration of the more severely damaged
areas. The associated discomfort can be severe enough to require
treatment with a major analgesic and/or a local anesthetic or even
discontinuation of the chemotherapeutic agent.
Drug-related aphthous-like ulceration
A number of drugs are implicated in the development of
nonspecific ulceration and oral mucositis, and the lesions are often
associated with an equally nonspecific histologic appearance at biopsy.
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| Nicorandil induced oral ulceration |
These include barbiturates, beta-blockers, dapsone,
NSAIDs, phenazone derivatives, thiazide derivatives, phenolphthalein,
sulfonamides, and tetracyclines. Ulceration of the oral mucosa is a
common adverse effect of a wide variety of antineoplastic agents,
including methotrexate, 5-fluorouracil, doxorubicin, and melphalan
Fixed drug eruptions
Fixed drug eruptions (contact stomatitis or stomatitis venenata) comprise repeated ulceration
at the same site in response to a particular drug and
may be caused by anesthetics, antibiotics, antiseptics, barbiturates,
chewing gum, cosmetics, dental materials, dentifrices, mouthwashes,
phenacetin, sulphonamides, or tetracyclines. The lesions may be
localized to the mouth or can be associated with lesions at other
mucocutaneous sites, and manifest as ulceration, bullae, erythematous
patches, or superficial erosions.
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| Fixed drug eruption on the lip |
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| Fixed drug eruption on skin |
Initially, the lesions are solitary, but with repeated
drug exposure, they may become multiple. these reactions normally
resolve with hyperpigmentation and may recur at the same site with
reexposure to the drug. Repeated exposure to the offending drug may
cause new lesions to develop in addition to "lighting up" the older
hyperpigmented lesions. A wide range of drugs may cause fixed drug
eruption, particularly paracetamol, barbiturates, phenacetin, pyrazolone
derivatives, sulphonamides, and tetracyclines, as may agents such as
cinnamon.
Drug-related mucositis
Cytotoxic drugs are very commonly associated with
mucositis and ulceration, which arises consistently with many
chemotherapy regimens,particularly those involving methotrexate,
5-fluorouracil, doxorubicine, melphelan, mercaptopurine, or bleomycin .
Such reactions can be so severe as to be treatment-limiting on occasion.
Widespread sloughing and ulceration arise within days of commencement
of therapy, the associated pain often requiring opioid therapy and/or
alteration or cessation of chemotherapy. The ulceration may be a portal
of entry for infection and hence a potential cause of septicemia. Drugs
such as phenylbutazone that can cause agranulocytosis may also induce
oral ulceration.
Immunosuppressive agents may also cause ulceration.
Ulcers in iatrogenically immunocompromised individuals may have a
herpesvirus etiology, or occasionally other infective causes.
Opportunistic infection secondary to cytotoxic chemotherapy may cause
oral ulceration. In particular, herpes simplex virus 1, varicella
zoster, and cytomegalovirus give rise to oral ulceration, while, less
commonly, ulceration may be due to Gram-negative bacterial infections (e.g., pseudomonas, klebsiella, Escherichia coli, enterobacter, or proteus) or to exogenous bacteria such as tuberculosis, or to fungi such as mucormycosis or even candidosis.
vesiculobullous or ulcerative mucositis that mimics other immunological disorders
Oral drug reactions that bear striking clinical,
histopathologic, and even immunopathologic resemblance to idiopathic
lichen planus, erythema multiforme (EM), pemphigoid, pemphigus, and
lupus erythematosus (LE) are well recognized, and the list of reactions
in each category is constantly expanding. Clinically, any oral site can
be affected; however, the posterior buccal mucosa (cheeks), the lateral
borders of the tongue, and the alveolar mucosa are most commonly
involved. Lesions may be isolated, although bilaterally symmetric
involvement is not uncommon.
Oral lichenoid reactions
Initially described in association with antimalarial
medications, lichen planus–like or lichenoid drug reactions have
subsequently been reported in association with many other agents. Both
papuloreticular and erosive manifestations may be observed; the latter
is characterized by shallow irregular ulcerations or erosions with a
peripheral border of fine keratotic striae that often appear to radiate
from the center of the lesion. Although drug-induced lichenoid reactions
tend to be erosive and unilateral compared with the typical bilateral
presentation in idiopathic lichen planus. Currently, NSAIDs and ACE
inhibitors appear to be among the most frequently cited offenders.
Interestingly, agents used in the treatment of lichen planus (eg,
hydroxychloroquine, dapsone, levamisole) have themselves led to adverse
lichenoid eruptions. Lichenoid reactions also may follow the use of HIV
protease inhibitors antihypertensive agents, antimalarials,
phenothiazines, sulphonamides, tetracyclines, thiazide diuretics, and
many others. The exact pathogenic mechanism by which drugs may cause
LP-like disease are not known. However, in LP, quite different
immunological mechanisms are involved. Histopathological features not
significant from idiopathic lichen planus. Thus 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.
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| Oral lichenoid reaction |
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 that is, lesions that clinically and
histologically resemble LP closely, but have an identifiable etiology.
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. Some of
these oral lesions may improve after substitution of the amalgam by
other materials. Composite restorations have also been implicated in
oral lichenoid reactions and so the wholesale replacement of amalgams as
a possible treatment is not necessarily warranted.
Erythema multiforme (EM) like reactions
As with idiopathic or virally induced cases (the latter
often due to the herpes simplex virus), the disease has a rapid onset
with a variable expression that can range from lesions limited to the
oral mucosa to widespread mucocutaneous involvement. Drug-induced EM is
frequently linked to agents such as sulfonamides, sulfonylureas, and
barbiturates, among others. Oral lesions start as erythematous macules
or patches that lead to short-lived vesicles or bullae, followed by
ragged and shallow ulcerations that may become extensive. Hemorrhagic
ulceration and crusting of the labial vermilion zone is common. Any
intraoral site can be involved, but the attached gingival and palatal
tissues are often relatively spared. Lesional discomfort can lead to
decreased fluid intake and dehydration.
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| Drug induced Erythema multiforme on lips |
A variety of lesions, including classic target or bull's eye lesions, can affect the skin.
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| Target lesions on skin |
More severe forms of disease include EM major (Stevens-Johnson syndrome)
and toxic epidermal necrolysis (TEN, Lyell syndrome). In addition to
the oral and skin lesions, conjunctivitis of the ocular mucosa and
urethritis of the genital mucosa are typical findings in patients with
EM major. Over three-quarters of EM major cases and virtually all cases
of TEN represent adverse drug reactions. In TEN, widespread
mucocutaneous epidermolysis results in diffuse bullae formation and
subsequent denudation that affects significant proportions of the skin
and mucosal surfaces. Severe dehydration, electrolyte imbalances, and
secondary infections are potentially life-threatening sequelae, and even
with aggressive therapy the mortality rate is greater than 30%.
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| TEN |
Pemphigoid like reactions
Pemphigoid like reactions can be limited to the oral
mucosa, or they can affect other mucosal or cutaneous sites. Clinically,
lesions appear as relatively sturdy vesicles or bullae that break down
into shallow ulcerations. Generalized or multifocal involvement of the
gingival tissues may be observed, with marked erythema and erosion of
the superficial gingiva, a pattern that has been called desquamative
gingivitis. Thiol-containing drugs and sulfonamide derivatives are among
the most commonly involved medications, as are the therapeutic classes
of NSAIDs, cardiovascular agents, antimicrobials, and antirheumatics .
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| celecoxib induced vesiculobullous lesion |
Circulating autoantibodies to basement membrane
components may or may not be detectable. The relatively young age of the
patients at onset (the disease affects those younger than 70 y) may
help distinguish this disease from idiopathic bullous pemphigoid or
idiopathic cicatricial pemphigoid, because these latter conditions
typically appear in persons aged 60-80 years. In addition, oral
involvement may be more common in drug-induced bullous pemphigoid than
in the idiopathic counterpart.
Pemphigus like reactions
Pemphigus like reactions can have features of either
pemphigus vulgaris or pemphigus foliaceous, although pemphigus
foliaceous is uncommon in the oral cavity. Traditionally, drugs that
are capable of inducing pemphigus are divided into two main groups
according to their chemical structure. Drugs containing a sulfhydryl
radical (thiol drugs or SH drugs) and non-thiol or other drugs, the
latter often sharing an active amide group in their molecules.
Thiol-containing drugs are the most common cause of pemphigus like
reactions. Pemphigus vulgaris may occasionally be associated with drugs
with active thiol groups in the molecule. Drugs implicated include
penicillamine, phenol drugs, rifampicin, diclofenac, and, rarely,
captopril, other ACE-inhibitors, and other drugs. 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 components.
Drug-related Lupoid Reactions
Systemic lupus erythematosus (SLE) may be induced by a
wide variety of different drugs. Indeed, over 70 agents 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 chlorpromazine, isoniazid,
methyldopa, penicillamine, and quinine, as well as whole groups of drugs
such as anticonvulsants, beta-blockers, sulphonamides, and others.
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| Drug induced lupoid reaction in oral mucosa |
The possible pathogenesis of drug-related SLE may have
an immunogenetic basis, and affected patients have some of the
immunological features of classic SLE. Clinically, the oral lesions of
drug-induced LE may simulate those of erosive lichen planus, 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 lichen planus on the
hard palate may be helpful in differentiating it from drug-induced LE.
Drug related mucosal pigmentation
Drug-related superficial transient discoloration
Superficial transient discoloration of the dorsum of the
tongue and other soft tissues and teeth may be of various colors,
typically yellowish or brown, and may be caused by some foods and
beverages (such as coffee and tea), some habits (such as tobacco, betel,
and crack cocaine use), and some drugs (such as iron salts, bismuth,
chlorhexidine, or antibiotics), especially if these also induce
xerostomia (such as psychotropic agents). When such discoloration
noticeably affects the posterior dorsum of the tongue, and the filiform
papillae are excessively long and stained dark brown or black, the term
‘black hairy tongue’ is used, but this is less common than other
superficial discolorations.
Stomatitis has been reported after the use of proton
pump inhibitors (PPIs) such as lansoprazole with amoxicillin , and
discolored tongue or glossitis has been recorded after the use of
lansoprazole plus antibiotics such as clarithromycin with or without
amoxicillin or lansoprazole alone.
Drug-related intrinsic pigmentation
Localized areas of pigmentation of the mucosa may be due
to amalgam, while gingival pigmentation can arise secondary to the gold
or metal alloys of crowns. Heavy metal salts were previously reported
to cause pigmentation, particularly of the gingival margin. Blue,
blue-grey, or brown mucosal pigmentation can be an adverse effect of
antimalarials, phenothiazines, and phenytoin. Amiodarone may cause a
grey orofacial and oral mucosal pigmentation.
Minocycline has increasingly been reported to cause
widespread blue, blue-grey, or brown pigmentation of the gingivae and
mucosae. While much of this pigmentation may reflect discoloration of
the underlying bone and roots of teeth, there is also inherent
pigmentation of the oral mucosa, including the tongue.
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| Drug induced pigmentation |
Oral contraceptives may, albeit rarely, cause melanotic
pigmentation, as can cyclophosphamide, busulphan, and ACTH. In HIV
disease, drug-induced melanotic pigmentation may arise following therapy
with clofazimine zidovudine and/or ketoconazole, the pigmentation being
variably diffuse or macular-like Kaposi’s sarcoma of the mouth is a
rare complication of immunosuppression, manifesting as a blue, red, or
purple macule, papule, nodule, or area of ulceration, typically on the
palate or gingivae, but able to affect other oral mucosal sites.
