Current opinion on drug-induced oral reactions: a comprehensive review.

Abstract

The aim of this comprehensive review is to present an update to our previous review about drug-induced oral reactions. All drugs that may cause adverse effects in the mouth and related structures are reviewed.
Every drug can produce untoward consequences even when used according to standard or recommended methods of administration. Adverse drug reactions can involve every organ and system of the body and are frequently mistaken for signs of underlying disease. The mouth and associated structures can also be affected by many drugs or chemicals. Good oral health including salivary function is very important in maintaining whole body health. Drug reactions can be categorized as to the parts of the oral complex such as the oral mucosa and tongue, periodontal tissues, dental structures, salivary glands, cleft lip and palate, muscles, and nerves.
This review suggests the number of drugs and chemicals that can produce adverse or toxic reactions in the oral cavity are on the rise. An updated listing of offending drugs is provided along with current strategies for dealing with adverse reactions.
Clinicians must constantly update their knowledge of drugs used by their patients. Attention must be paid to their toxic and unwanted effects that in many cases may be similar to characteristics of common diseases.
Dentists and specialists of oral diseases should be aware of adverse drug oral reactions for better diagnosis of oral diseases, administration of drugs, and patient compliance during drug therapy.

Full text

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The Journal of Contemporary Dental Practice, Volume 9, No. 3, March 1, 2008
Current Opinion on Drug-induced Oral Reactions:
A Comprehensive Review
Aim: The aim of this comprehensive review is to present an update to our previous review about drug-induced
oral reactions. All drugs that may cause adverse effects in the mouth and related structures are reviewed.
Background: Every drug can produce untoward consequences even when used according to standard or
recommended methods of administration. Adverse drug reactions can involve every organ and system of the
body and are frequently mistaken for signs of underlying disease. The mouth and associated structures can
also be affected by many drugs or chemicals. Good oral health including salivary function is very important in
maintaining whole body health. Drug reactions can be categorized as to the parts of the oral complex such as
the oral mucosa and tongue, periodontal tissues, dental structures, salivary glands, cleft lip and palate, muscles,
and nerves.
Review Results: This review suggests the number of drugs and chemicals that can produce adverse or toxic
reactions in the oral cavity are on the rise. An updated listing of offending drugs is provided along with current
strategies for dealing with adverse reactions.
Abstract

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The Journal of Contemporary Dental Practice, Volume 9, No. 3, March 1, 2008
Introduction
The oral cavity may be the target organ for a
number of diverse abnormalities that develop
from side effects of medications. In theory, all
drugs are capable of inducing adverse side
effects, the most serious of which include
blood dyscrasias, altered immune responses,
immediate or delayed hypersensitivity reactions,
and predisposition to oncogenic changes. Any
of these effects can present oral manifestations,
and mucositis can occur as either a direct or
secondary effect of drug use.
Considering the aging of the population along with
widespread and increased use of prescription,
over-the-counter, and herbal remedies, dentists
can expect to encounter oral side effects from
medication use among their patients. A survey of
3302 patients visiting the Stomatology Center at
Baylor College of Dentistry revealed 66% were
taking prescription drugs and 42% were taking
two or more prescription medications daily. Since
many patients regularly take prescription and
nonprescription medications, dentists always
should take thorough medical histories and be
aware of medication-related problems and their
potential effects on diagnosis and treatment
planning.
1-3
The three most frequent oral side-effects
encountered with the 200 most frequently
prescribed drugs for 1992 were xerostomia,
dysgeusia, and stomatitis with prevalence rates
of 80.5%, 47.5%, and 33.9%, respectively.
4
The 2003 review of drug-induced oral reactions
published by Abdollahi and Radfar
subjects shown in Table 1. (page 15)
5 included the
The present review re-evaluated the literature
since 2003 to provide an update of drug-related
data on drug-induced oral reactions. Sections on
oral mucositis, fluorosis, osteonecrosis of jaws,
and a review of diagnosis and management
strategies for each of these reactions have been
added.
Oral Allergic Reactions
Recent evidence suggests the incidence of
allergic responses within the oral cavity is rapidly
increasing.
3
Systemic medications can cause allergic
reactions in the mouth as a fixed drug eruption
called stomatitis medicamentosa. Fixed
drug eruptions are localized hypersensitivity
reactions that recur in the same site each time
the causative drug is ingested. They feature
erythematous eruptions on the skin and mucous
membranes and often heal with residual
hyperpigmentation. Oral lesions can also be
erosive and ulcerated. They may occur on the
gingiva and palate, although the buccal mucosa,
lips, and tongue are more frequently involved.
Lesions associated with fixed drug eruption
usually appear within 24 hours post-ingestion of
the drug. Delayed reaction (up to two weeks) has
Conclusion: Clinicians must constantly update their knowledge of drugs used by their patients. Attention must
be paid to their toxic and unwanted effects that in many cases may be similar to characteristics of common
diseases.
Clinical Significance: Dentists and specialists of oral diseases should be aware of adverse drug oral reactions
for better diagnosis of oral diseases, administration of drugs, and patient compliance during drug therapy.
Keywords: Oral reactions, drug reactions, adverse drug effects, side effects, oral mucosal reactions
Citation: Abdollahi M, Rahimi R, Radfar M. Current Opinion on Drug-induced Oral Reactions: A Comprehensive
Review. J Contemp Dent Pract 2008 March; (9)3:001-015.

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The Journal of Contemporary Dental Practice, Volume 9, No. 3, March 1, 2008
oral ailments. It is a common condition which is
characterized by multiple recurrent small, round,
or ovoid ulcers with circumscribed margins,
erythematous haloes, and yellow or grey floors.
The term “recurrent aphthous stomatitis” should
be reserved for recurrent ulcers confined to the
mouth and seen in the absence of any systemic
cause.
9-11
Drugs with potential to cause aphthous-like ulcers
are shown in Table 4.
The diagnosis of aphthous ulcers is invariably
based upon the history and clinical findings. The
proper treatment of aphthous ulcers depends on
the frequency, size, and number of the ulcers.
Patients who experience minor aphthous ulcers
experience significant relief with appropriate
topical therapy such as tannic acid (zilactin),
orabase, diclofenac, or amlexanox paste. In
patients with more severe disease, use of a
topical glucocorticoid is an effective therapy to
decrease both the size and healing time of the
ulcers, especially when the medication is used
early in the developing stage of the lesion.
16
Burning Mouth Syndrome
Burning mouth syndrome (BMS) is synonymous
with stomatodynia, oral dysaesthesia,
glossodynia, glossopyrosis, and stomatopyrosis
characterized by oral mucosa pain, with or
without inflammatory signs, and without a specific
lesion. The pain feels like a moderate to severe
burning sensation occurring more frequently on
the tongue but can also occur on the gingiva,
lips, and jugal (malar) mucosa. It can worsen
during the day as a result of stress and fatigue,
excessive speaking, or by ingesting spicy/hot
foods. The burning can be diminished with cold
food and leisure. This syndrome may occur due
to xerostomia or radiotherapy; endocrine disease
such as diabetes mellitus, hypothyroidism, and
menopause; medication; nutritional deficiencies
including iron, vitamin B complex, folic acid
and zinc; neuralgia; dental prostheses; allergy;
infection; and psychiatric disorders such as
depression and anxiety.
17-19
Angiotensin converting enzyme inhibitors (ACEIs)
are a class of medications that can cause BMS.
ACEI-induced burning sensation of the tongue,
throat, and palate has been described as being
been noted after use of ampicillin for example.
Withdrawal of the causative drug results in
resolution of the lesions. Drugs with potential to
cause fixed drug eruptions are shown in Table 2.
Oral contact allergic reactions or stomatitis
venennata has increased in recent years
because of the increased use of oral hygiene
products, esthetics related products, dental
restorative materials, and the establishment of
infection control procedures that mandate the
wearing of latex gloves for dental treatment
procedures. The reaction may develop from days
to years post-exposure to the causative agent.
There are various types of oral contact allergic
reactions. Allergic gingivo-stomatitis features
intense hyperemic inflammation of the gingiva,
with or without involvement of the buccal and
labial mucosa. On occasion angular cheilitis
and glossitis are present and involvement of
the vermilion border of the lips and perioral skin
has been described. The condition was first
reported in the 1960s and proved to represent
a contact allergic reaction to an ingredient in
chewing gum, toothpaste, or mints. Subsequently,
candies, cough drops, dentifrices, mouthrinses,
topical fluorides, other therapeutic agents, and
a variety of food products have been implicated.
Dentifrice hypersensitivity reactions appear to be
more common since the advent of tartar-control
toothpastes.
reaction or the most severely involved, perhaps
because the antigen is in intimate contact with the
gingiva during toothbrushing. In most instances
the reactions appear to be induced by the
flavoring agents in the dentifrices, often cinnamic
aldehyde, a common allergen.
potential to cause oral contact allergic reactions
are shown in Table 3.
3,4 The gingiva is often the only site of
3,5Compounds with
Aphthous-Like Ulcers
Ulcers resembling recurrent aphthous stomatitis
but have systemic causes are often termed
aphthous-like ulcers. Examples include
Behçet’s syndrome, gastrointestinal diseases
such as gluten-sensitive enteropathy or
inflammatory bowel disease, immunodeficiency
syndromes such as infection with the human
immunodeficiency virus (HIV), cyclic neutropenia,
and adverse reactions to medications. Recurrent
aphthous stomatitis (also referred to as aphthae
or canker sores) is one of the most common

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The Journal of Contemporary Dental Practice, Volume 9, No. 3, March 1, 2008
necrolysis). More than half the cases have
no known cause, while half are caused by
medications, infections, immunotherapy, or
illnesses.
by drugs, however, 80% of cases are found with
Stevens–Johnson syndrome. The oral lesions
disappear within 14 days of drug withdrawal.
Drugs with potential to cause EM are shown in
Table 7.
30-32Only 4% of EM reactions are caused
5
There are no specific diagnostic tests for EM.
Therefore, the diagnosis is mainly clinical, and
it can be difficult to differentiate between it and
viral stomatitis, pemphigus, toxic epidermal
necrolysis, and sub-epithelial immune blistering
disorders. Spontaneous healing can be slow. Up
to two or three weeks of healing time is typical
for minor EM and up to six weeks for major EM
cases. Treatment is indicated but controversial,
and care by a specialist should be sought.
Supportive care is important. A liquid diet and
even intravenous fluid therapy may be necessary.
Oral hygiene should be improved with 0.2%
aqueous chlorhexidine oral rinses. The use of
corticosteroids is controversial but minor EM
may respond to topical corticosteroids. Patients
with major EM such as the Stevens-Johnson
syndrome may need to be admitted for hospital
care. Major EM patients should be referred for
treatment with systemic corticosteroids or other
immunomodulatory drugs.
30,33
Oral Ulceration
Ulceration is a breach in the oral epithelium,
which typically exposes nerve endings in the
underlying lamina propria, resulting in pain or
soreness, especially when eating spicy foods
or citrus fruits. Patients vary in the degree to
which they suffer of soreness in relation to an
similar to the scalding caused by hot coffee or
pizza and so called scalded mouth syndrome.
Cases of “scalded mouth” caused by ACEIs such
as captopril, lisinopril, and enalapril have been
described.
mouth” is uncertain, but it may be a subclinical
manifestation of lichen planus. A list of drugs that
can induce BMS is shown in Table 5.
20
21-23 The mechanism of ACEI “scalded
The diagnosis of BMS is based upon the history,
clinical findings, and physical examination.
Usually, the classic BMS patient presents with a
chief complaint of a burning, scalding, or tingling
feeling in the mouth and may complain of a
persistent bad or uncommom taste or altered
taste perception. It is important to note pain/
burning sensations usually increase in intensity
at the end of the day but very rarely interfere
with sleep. In the past two decades a variety of
different therapies for BMS have been proposed,
including the use of benzodiazepines, tricyclic
antidepressants, gabapentin, trazodone, selective
serotonin reuptake inhibitors, amisulpride,
topical capsaicin, alpha-lipoic acid, and cognitive
behavioral therapy. Variable, unpredictable, and
often discouraging outcomes have been reported,
leading to the impression BMS therapy is always
difficult and often unsuccessful. Treatments
proven to be effective in controlled double-blind
studies are cognitive behavior therapy, topical or
systemic clonazepam, and alpha lipoic acid.
19,27
Glossitis
Glossitis is inflammation of the tongue
characterized by swelling and intense pain that
may be referred to the ears. Salivation, fever,
and enlarged regional lymph nodes may develop
during an infectious disease, after a burn, or
other injury.
glossitis are shown in Table 6.
28 Drugs having the potential to cause
Erythema Multiforme
Erythema multiforme (EM) is an acute reactive
mucocutaneous inflammatory and hypersensitivity
reaction characterized by a skin eruption, with
symmetrical erythematous edematous or bullous
lesions of the skin or mucous membranes.
EM is a disorder with variations ranging from
self-limited, mild, exanthematous, cutaneous
lesions with minimal oral involvement to a
progressive, fulminating, severe disease with
extensive mucocutaneous epithelial necrosis
(Stevens-Johnson syndrome and toxic epidermal

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The Journal of Contemporary Dental Practice, Volume 9, No. 3, March 1, 2008
scalp, and the nails. Oral lichen planus is usually
a persistent disorder and may persist for many
years despite several treatment strategies. Some
drugs can induce oral disorders resembling
lichen planus and are said to be oral lichenoid
drug reactions. Oral lichenoid drug reactions are
uncommon.
drug-induced oral lichenoid eruptions disappear
after drug withdrawal. Lichenoid drug eruptions
rarely affect the buccal mucosa. A characteristic
white lace pattern may be present. It is thought
drugs causing lichenoid reactions only uncover
the latent disease of lichen planus or amplify a
previous disorder rather than inducing the disease
de novo.
30,43,44Unlike true oral lichen planus,
5Such drugs are listed in Table 10.
Clinical presentation and histopathological
investigation may help with the diagnosis.
Management of drug-induced oral lichenoid
eruptions involves withdrawal or replacement of
the offending medication. If this approach is not
possible, then the corticosteroids, tacrolimus, and
psoralens are used to treat this disorder.
45
Color Changes of the Oral Mucosa and Teeth
Mucosal Pigmentation
Oral discoloration may be superficial due to
extrinsic or deep due to intrinsic (in or beneath
mucosa) causes.
Extrinsic discoloration is rarely of consequence
and is usually caused by habits that include the
following:
• Use of tobacco or betel nut.
• Consumption of colored foods or beverages
(such as liquorice, beet root, red wine, coffee,
and tea).
• Use of drugs (such as chlorhexidine, iron
salts, crack, cocaine, minocycline, bismuth
subsalicylate, and lansoprazole).
oral ulceration. Ulcers and erosions can also
be a final common manifestation of a spectrum
of conditions. These conditions include the
following:
• Epithelial damage resulting from trauma
• An immunological attack as in lichen planus
• Pemphigoid or pemphigus
• Damage due to an immune defect as in HIV
disease and leukemia
• Infections such as herpes viruses
• Tuberculosis and syphilis
• Cancer
• Nutritional defects such as vitamin
deficiencies
• Some gastrointestinal diseases
• Medications
37
The number, persistence, shape, character of
the edge of the ulcer, and the appearance of
the ulcer base should be noted for diagnosis.
Treatment includes prescribing a chlorhexidine
0.2% mouthwash, maintaining good oral
hygiene, a benzydamine mouthwash or spray,
application of a topical lidocaine solution or
carboxymethylcellulose paste or powder may
reduce pain from these ulcers.
33
Drugs and chemicals that may cause local
irritation and ulceration of the mouth include those
listed in Tables 8 and 9.
Vesiculo–Bullous Lesions
The exact mechanism of this tissue reaction is
unclear, but it appears to be the consequence
of a direct irritant. Patients using steroid inhalers
for more than five years are more prone to
the development of oral blistering. This type of
reaction has also been reported for naproxen
and penicillamine.
presence of other mucosal or cutaneous lesions,
the histological examination, and the finding
of perilesional antibodies on the mucosa. The
symptomatic treatment of oral bullous lesions
includes the adherence to a specific diet, use of
analgesics, and the prevention or treatment of a
superimposed infection.
5 The keys to diagnosis are the
42
Oral Lichenoid Reactions
Lichen planus is a chronic systemic disease of
established immune-mediated pathogenesis. It
commonly involves the mucosa of the oral cavity
but can involve other sites, such as the skin,
vulvar and vaginal mucosa, the glans penis, the

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Dental Discoloration
Numerous drugs are known to have the capability
of causing either extrinsic or intrinsic tooth
discoloration. Extrinsic stains are located on
the surface of the tooth and are most easily
removed by external cleaning. Drugs that are
well-recognized as causing extrinsic discoloration
include chlorhexidine, oral iron salts in liquid
form, essential oils, and co-amoxiclav. Intrinsic
stains are located within the tooth structure and
are accessible only by bleaching. Some extrinsic
stains that remain on the tooth for a long time can
become intrinsic. By recognizing the likely cause
of the stain, the dentist can better inform a patient
about the rate at which the teeth may lighten in
color and the limitations of improvement to be
expected following treatment.
Tetracycline can cause the most common
distracting, generalized type of intrinsic
discoloration. It is hypothesized to occur by the
joining of the tetracycline molecule with calcium
through a chelation process and a subsequent
incorporation into the hydroxyl apatite crystal
of the tooth during the mineralization stage
of development.
potential to cause tooth discoloration are listed in
Table 12.
50-52 Drugs and chemicals with
Black Hairy Tongue (Lingua villosa nigra)
In this condition there is an elongation of the
filiform papillae of the tongue to form hair-like
overgrowth which becomes stained brown or
black due to the proliferation of chromogenic
microorganisms. Black hairy tongue can be seen
with the administration of oral antibiotics, poor
dental hygiene, and excessive smoking in adults.
Drugs and chemicals with potential to cause black
tongue include those listed in Table 13.
5
The primary causes of intrinsic mucosal
hyperpigmentation include:
• Amalgam or other tattoo
• Nevus
• Melanotic macule
• Neoplasms (e.g., malignant melanoma
or Kaposi’s)
• Pigmentary incontinence
• Peutz-Jegher’s syndrome
• Racial pigmentation
• Localized irritation such as the use of tobacco
or betel
• Drugs such as antimalarials and oral
contraceptives
• Pregnancy
• Addison’s disease
47
The exact mechanism of tissue discoloration by
many drugs is uncertain but generally resolves
within weeks to months when the offending
drug is withdrawn. However, sometimes the
discoloration is permanent.
For antimalarial drugs like chloroquine and
mepacrine (quinolones), the deposit of melanin
or iron in mucosal tissues has been suggested.
Long-term use of phenothiazines, especially
chlorpromazine, produces widespread mucosal
pigmentation which is caused by the accumulation
of a drug metabolite in the tissue. Pigmentation
of the oral mucosa can also be caused by the
use of oral contraceptives, and cessation of the
drug does not produce complete regression of
the pigmentation. Estrogens are well known to
induce high levels of cortisol binding globulin
which contributes to the decrease of a portion
of plasma free cortisol and as a result produces
a hypersecretion of ACTH and β-melanocyte-
stimulating hormone. The later may cause the
increased oral pigmentation.
induced oral pigmentation consequent to the
interaction of the drug with bone during its
formation is common. Almost all cases of intraoral
pigmentation represent minocycline staining of
the underlying bones without involvement of the
overlying oral mucosa surfaces.
5Minocycline-
Pigmented lesions of the tongue (dark macular
patches) are reported to occur in heroin addicts
who inhale the smoke.
potential to cause oral pigmentation are listed in
Table 11.
48 Drugs and chemicals with

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regimens for colorectal cancer, the prevalence of
mucositis is reportedly approximately 15–20%.
The combining of different chemotherapeutic
drugs further increases the possibility of mucositis
from 40% of patients treated with standard
chemotherapy regimens to 70% of patients
treated with a combination of chemotherapeutic
drugs. In patients receiving cancer chemotherapy
the frequency and severity of mucositis is
mainly dependent on the type(s) and dose of
cancer chemotherapeutic agents used but also
patient characteristics such as age, nutritional,
buccodental, and hematological status play a
role. Cisplatin, 5-fluorouracil (5-FU), etoposide,
and melphalan are particularly stomatotoxic.
Mucositis is common with doxorubicin,
vinblastine, taxanes, and methotrexate but
uncommon with sparaginase and carmustine.
A healthy gingival status as well as good oral
hygiene during chemotherapy is associated with a
lower incidence and severity of mucositis.
56-58
The diagnosis of mucositis is clinical and based
on the use of known stomatotoxic therapy, and
the appearance, timing, and location of oral
lesions. Chemotherapy-induced mucositis occurs
on the movable mucosa and rarely affects the
dorsum of the tongue, the hard palate, or the
gingiva. Methods have been developed to reduce
exposure of the mucosa to chemotherapeutic
drugs. The use of ice chips (cryotherapy) to
produce mucosal cooling and subsequent blood
vessel constriction is thought to result in the
reduction of exposure of mucosal tissues to the
chemotherapy agent.
Propantheline is another agent that might
reduce the topical exposure of the oral mucosa
to chemotherapeutic drugs excreted in saliva
Therapeutic options of modest benefit include
increasing hydration and salivation, brushing
the tongue with a soft toothbrush enhanced
by previous application of 40% urea solution,
applying topical retinoids or salicylic acid, or
undergoing surgical excision.
54
Postmortem Pink–red Coloration
Tooth coloration of this nature is due to
hemolysis and exudation of hemoglobin to the
dental pulp which is enhanced in the presence
of moisture and increased venous pressure.
Specific conditions of death associated with
this phenomenon include drowning, aspiration
pneumonitis, and suffocation. Overdoses with
barbiturates, dichloralphenazon, and carbon
monoxide also demonstrate similar findings.
29
Oral Mucositis
Oral mucositis is a common toxicity associated
with both head and neck radiation and
chemotherapy used for the treatment of cancer.
Mucositis can present different levels of severity,
ranging from a minor erythema, edema, or a
burning sensation to the development of large
and painful ulcers that limit basic oral functions
such as eating, swallowing, and talking. The
more severe cases can even interrupt the
oncological treatment. The early clinical sign of
chemotherapy-induced mucositis is erythema
presenting at about four to five days following
chemotherapy infusion. Patients also often
complain of burning and intolerance of spicy
foods at this stage. Seven to ten days after
chemotherapy ulcers may develop with marked
discomfort often requiring opioid intervention and,
in many cases, causing patients to alter their
diet. Lesions are seen mostly on the movable
tissues of the buccal mucosa and the lateral and
ventral surfaces of the tongue. The hard palate
and gingiva appear not to be susceptible to
chemotherapy-induced mucositis.
Chemotherapy-induced mucositis lasts
approximately one week and generally heals
spontaneously by 21 days after infusion. The
prevalence of oral mucositis after chemotherapy
is 30% to 70% and can increase to 90% in bone
marrow transplant cases. Mucositis has been
reported to occur in over 50% of patients being
treated with fluorouracil, adriamycin, and cytoxan
for nodepositive breast cancer. For patients being
treated with the most common chemotherapy

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Cyclosporine-A has been shown to increase the
fibroblast production of collagen and protein.
This leads to extracellular collagen and matrix
formation and a decrease in collagenase activity.
The increased levels of interlukin-6 and TGF-β
and the decreased levels of gamma-interferon
observed during cyclosporine-A therapy may
favor the fibroblast synthesis of collagen.
keratinocyte growth factor receptor has been
reported to be up-regulated by cyclosporine-A,
and there is evidence cyclosporine-A regulates
cytokine expression in gingival tissue.
60 The
61
62
There is evidence mast-cell mediated androgen
action in the gingiva in response to phenytoin
could contribute to gingival overgrowth.
The incidence of phenytoin-induced gingival
overgrowth is approximately 50%, but it is
higher in both teenagers and institutionalized
epileptics.
apparent during the first three months after
starting phenytoin and is more rapid in the first
year. Unlike phenytoin, cyclosporine-induced
hyperplasia is reversible following cessation of
drug use.
63
64Gingival overgrowth usually becomes
64
Nifedipine, the most commonly used calcium
channel blocker, induces gingival enlargement
in 20% of the cases.
felodipine, nitrendipine, and verapamil also
induce gingival overgrowth. The dihydropyridine
derivative isradipidine does not induce gingival
overgrowth. Inhibition of apoptosis by nifedipine
and resultant epithelial hyperplasia has been
reported.
gingival hyperplasia accompanies submandibular
gland dysfunction evidenced by the reduction
of salivary flow rate and concentrations of
EGF, calcium, and total protein.
evidence nifedipine inhibits both the adherence-
and lipoploysaccharide-stimulated macrophage-
induced death of fibroblasts which results in
gingival overgrowth.
prescribed to organ transplant patients to reduce
the nephrotoxic effects of cyclosporine and, thus,
an additive effect on the gingival tissues is usually
observed.
65Amlodipine, diltiazem,
65 It has been shown nifedipine-induced
66 There is also
67Nifedipine is frequently
68
The incidence of gingival overgrowth by oral
contraceptives is not rare and resolves when
the drug is withdrawn. There is evidence the
accumulation of metabolic products of the
naturally occurring sex hormones in gingiva is an
by altering salivation. Use of antifungal agents
such as fluconazole also seems to be effective in
prevention of chemotherapy-induced mucositis.
Palifermin has also been approved for the
treatment of chemotherapy-induced mucositis.
Benzydamine and povidone may have a place in
a treatment regimen. None of the other available
interventions for the management of mucositis,
including low energy laser therapy, has been
shown to be reliably effective in clinical trials.
56
Gingival Hyperplasia
Gingival hyperplasia or gingival overgrowth is
characterized by an accumulation of extracellular
matrix within the gingival connective tissue,
particularly the collagenous component, with
various degrees of chronic inflammation.
Phenytoin, cyclosporine-A, calcium channel
blockers, and oral contraceptives are main
causative agents of drug-induced gingival
hyperplasia. The prevalence rate of this disorder
has been reported to vary: 10% to 50% for
phenytoin; 8% to 70% for cyclosporine-A; and
0.5% to 83% for nifedipine.
59
The growth starts as a painless, beadlike
enlargement of the interdental papilla and
extends to the facial and lingual gingival
margins. The enlargement is usually generalized
throughout the mouth but is more severe in
the maxillary and mandibular anterior regions.
Plaque removal and maintaining good oral
hygiene may provide benefits in terms of rapid
recovery and limitation of the severity of the
lesion but the lesion does not completely resolve.
It is hypothesized fibroblasts in non-inflamed
gingiva are less active, or even quiescent, and
do not respond to circulating systemic drugs. In
contrast, fibroblasts within inflamed tissue are in
an active state and responsive to drug therapy
as a result of inflammatory mediators and the
endogenous growth factors. It is known causative
drugs inhibit Ca
which correlates with the rate of fibroblast
proliferation. Drug variables, plaque-induced
inflammatory changes in the gingival tissues,
and genetic factors should be considered.
The latter determines the heterogeneity of the
gingival fibroblast and could also influence drug
pharmacokinetics and pharmacodynamics.
2+uptake by gingival fibroblasts
5
Several mechanisms have been suggested for
the etiology of drug-induced gingival hyperplasia.

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has encountered. The composition of saliva is
altered in various diseases such as inflammatory
bowel disease, diabetes, periodontitis, and
organophosphate poisoning making it useful as a
diagnostic factor in these diseases.
70-75
Salivary gland secretion from the major and
minor glands is mainly under neural control
influenced by the autonomic nervous system,
although various hormones may also modulate
its composition. In general, parasympathetic
stimulation increases salivation, while sympathetic
stimulation produces more viscous saliva and,
therefore, appears to depress salivation.
Salivary gland function can be affected by a
variety of drugs that can produce xerostomia or
ptyalism.
52,76
Xerostomia may be due to both the reduced
salivary flow rate and to a decrease in salivary
calcium and phosphate concentration caused by
such drugs as amphetamines.
as causes of reduced salivation include
mainly those with cytotoxic, anticholinergic,
sympathomimetic, or diuretic activity.
salivary flow rate and reduced levels of secretory
proteins or enzymes may cause destructive
effects on oral and dental health and the rate
of wound due to lower levels of specific growth
factors being present. Salivary mucins and
growth factors are involved in the maintenance
of mucosal integrity. Mucins have the ability to
trap water thus protecting the mucosa from injury
through desiccation, while growth factors may
assist in tissue regeneration. Epidermal growth
factor which is secreted from salivary glands has
a potential role in oral wound healing.
5 Drugs recognized
76 An altered
77
important factor in the pathogenesis of chronic
gingivitis. The prevalence and percentage of
incidence is uncertain. Maintenance of adequate
plaque control is important for gingival health
during the administration of oral contraceptives.
Other drugs with potential to cause gingival
hyperplasia are listed in Table 14.
5
The treatment options for drug-induced gingival
enlargement should be based on the medication
being used and the clinical presentation of each
particular case. Consideration should be given
first to the possibility of discontinuing the drug
or of changing medication. It has been shown
cyclosporin-induced gingival enlargement can
spontaneously resolve if the drug is substituted
by tracolimus.
Drug substitution is a second alternative. There
is also preliminary evidence the antibiotic
azithromycin may aid in decreasing the severity
of cyclosporin-induced gingival enlargement. If
any drug substitution is attempted, it is important
to allow six-12 months to elapse between
discontinuation of the offending drug and the
possible resolution of gingival enlargement before
a decision to implement surgical treatment is
made.
The clinician should also emphasize plaque
control as the first step in the treatment of drug-
induced gingival enlargement. Although the
exact role played by bacterial plaque in drug-
induced gingival enlargement is unclear, there
is evidence good oral hygiene and frequent
professional removal of plaque decreases the
degree of the gingival enlargement and improves
overall gingival health. If gingival enlargement
persists, despite drug substitution attempts and
good plaque control, it needs to be treated by
periodontal surgery.
69
Salivary Glands
The most important functions of saliva are to
facilitate digestion by lubricating and initiating
the chemical processing of food and to protect
the mucosa and teeth. Saliva is protective
through a cleansing action as well as through
the antimicrobial action of various salivary
components such as mucin, histatins, lysozyme,
and lactoferrin and through the function of specific
antibodies to a range of microorganisms the host

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a result of excess fluoride intake during the
period of enamel formation. It has been defined
as being “a dose response effect” caused
by fluoride ingestion during the pre-eruptive
development of teeth. This change in the enamel
is characterized by altered appearance of the
tooth ranging from fine white lines to pitting or
staining of the enamel.
of dental fluorosis includes de-fluoridation of
drinking water in endemic areas, cautious use
of fluoride supplements, and supervision of the
use of fluoride toothpaste by children below five
years of age. The anesthetically objectionable
discoloration of fluorosed teeth can be managed
by bleaching, micro-abrasion, veneering, or
crowning.
105Preventive management
106
There have been several reports of the effects
on dental development of pre- and post-natal
administration of anticonvulsants. Pre-natal
exposure to anticonvulsants has been shown
to cause a significant increase in mesiodistal
crown dimensions of the posterior maxillary
teeth-specifically, primary molars and their
permanent premolar successors, as well as
permanent molars. Hypodontia and disturbance
in root formation were also observed following
anticonvulsant administration.
used for the treatment of childhood cancer have
consistently shown at diagnosis and the start
of treatment children younger than five years of
age exhibit abnormal dental development.
The severity of dentofacial-developmental and
tooth-related abnormalities secondary to the
therapy is related to the age of the child, the
dosage, and the duration of treatment. Dental
abnormalities include tooth agenesis, arrested
tooth development, microdontia, and disturbances
affecting enamel, dentin, and cementum.
107 Studies on drugs
107,108
52
Bisphosphonate-associated osteonecrosis of jaws
is a serious oral complication of bisphosphonate
treatment involving the exposure of necrotic
maxillary or mandibular bone. The clinical
presentation may closely simulate dental
abscesses, toothaches, denture sore spots, and
osteomyelitis. This disorder most commonly
occurs in patients who received intravenously
administered bisphosphonates (zoledronic
acid, pamidronate) to control hypercalcemia in
metastatic bone disease. However, some reports
implicated oral alendronate or risedronate used
to treat osteoporosis.
109,110,111 The prevalence of
Common oral manifestations resulting from
decreased salivary flow include increased dental
caries, fungal infections, bacterial infections,
aphthous lesions, and dysphagia. Therefore, it
is essential to substitute, reduce, or suppress
any xerostomizing medication. Pliocarpine and
bethanechol have been suggested to be of
potential use in the management of drug-induced
xerostomia.
78
Sialorrhoea or ptyalism, the condition of
increased salivary flow, is uncommon. Salivary
hypersecretion is usually caused by physiological
factors such as menstruation or early pregnancy,
local factors such as teething, oral inflammatory
lesions, food, medications, or by nasogastric
intubation.
are clearly associated with sialorrhoea are
antipsychotics, particularly clozapine, and direct
and indirect cholinergic agonists that are used
to treat dementia of the Alzheimer type and
myasthenia gravis. Sialorrhoea is also caused by
certain heavy metal toxins (mercury and thallium);
from exposure to irreversible acetylcholinesterase
inhibitors (insecticides and nerve agents); and by
a few other drugs such as yohimbine, mucosa-
irritating antibiotics. The treatment of medication-
induced sialorrhoea is often only symptomatic
and is designed to decrease saliva to amounts
that can be swallowed. Most pharmacological
approaches reduce cholinergic tone; either
systemically using atropine-related oral
anticholinergics or more locally using a sublingual
ipratropium spray; or by increasing adrenergic
tone using a clonidine patch. Recently, botulinum
injections into the parotid gland have been used
successfully to treat refractory cases.
79Major medication groups that
80
Systemic drug therapy can also produce pain and
swelling of the salivary glands.
81
Table 15 lists drugs and chemicals with potential
to disturb the function of salivary glands.
Effects on Dental Structure
Some drugs have the potential to cause physical
damage to tooth structure. Table 16 summarizes
the categories of drugs and the subsequent
possible damage that can result.
Enamel fluorosis is a hypomineralization of
enamel characterized by greater surface and
subsurface porosity than in normal enamel as

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Patients generally describe an elevated headache
and tightness in their jaw, tongue, and facial
structures.
Illegal drugs, such as methamphetamine cocaine
and 3,4-methylenedioxymethamphetamine
(Ecstasy), and legal prescription stimulants, such
as methylphenidate, phentermine, pemoline,
dextroamphetamine, amphetamines, and
diethylproprion, have been reported to induce
bruxism and dystonic extrapyramidal reactions.
All stimulant drugs have the potential to cause
extrapyramidal reactions. They are being used
in greater numbers to treat obesity and as
stimulants for children who have attention deficit
hyperactivity disorder, narcolepsy, and even for
severe depression. Table 17 shows a list of drugs
that have potential to induce oral motor disorders.
With the exception of bruxism, all of the other
motor disorders require a neurologic consultation
to achieve a definitive diagnosis. Although the
dentist will not perform this examination, it is
necessary to identify whether a patient has had
an accurate assessment before participating in
the management of the patient.
114
The general rule for treatment is to withdraw the
offending medication in the hope the dyskinesia
or dystonic reaction goes away. Fortunately, acute
dystonic reactions secondary to drugs disappear
upon discontinuation of the medication. However,
this may take days to months, depending
upon the drug, its dose, and the patient. If the
suspected medication cannot be stopped or if the
motor hyperactivity is severe, diphenhydramine
or benztropine are administered intravenously or
intramuscularly to treat the motor hyperactivity.
It should be noted amantadine and intravenous
diazepam have been shown to be effective
for recurrent neuroleptic-induced dystonic
reactions.
114
Taste Disorders
Many drugs induce abnormalities of taste by
mechanisms not yet fully understood. The
alternation in taste may be simply a blunting
or decreased sensitivity in taste perception
(hypogeusia), a total loss of the ability to taste
(ageusia), or a distortion in perception of the
correct taste of a substance, for example, sour
for sweet (dysgeusia). A wide range of drugs
give rise to dysgeusia or hypogeusia either by
osteonecrosis of the jaws among individuals who
received intravenous biphosphonates is 0.8% to
12%.
and specific laboratory investigation for the
levels of markers of bone turnover including
N-telopeptide and C-telopeptide help with the
diagnosis. The management of this disorder
presents a challenge to dentists as there is no
effective treatment for this condition at present.
Patients with asymptomatic exposed bone may
be best treated with systemic antibiotics such
as penicillin or clindamycin, an oral antimicrobial
rinse such as chlorhexidine, and close follow-up
regimen.
112,113The clinical presentation, histopathology,
113
Oral Motor Disorders
Some drugs can induce oral motor hyperactivity.
These medications and illegal drugs produce
a motor response that is classified better
as an unspecified extrapyramidal syndrome
(EPS) reaction. EPS responses typically have
three presentations: dystonia, akathisia, and
parkinsonism. Dystonic reactions consist of
involuntary, tonic contractions of skeletal muscles.
Akathisia reactions occur as a subjective
experience of motor restlessness. Patients may
complain of an inability to sit or stand still or a
compulsion to pace or cross and uncross their
legs. Parkinsonian reactions manifest themselves
as tremor, rigidity, and akinesia, which shows as
a slowness in initiating motor tasks and fatigue
when performing activities that require repetitive
movements (bradykinesia). When a medication
or drug induces a dystonic EPS reaction, it
typically involves the muscles of the head, face,
and jaw that produce spasm, grimacing, tics, or
trismus. Most of the literature has focused on the
more severe acute dystonic EPS reactions that
occur with use of antipsychotic medications. In
addition to the antipsychotics, several antiemetics
with dopamine receptor–blocking properties
have been associated with tardive dystonia.
These include prochlorperazine, promethazine,
and metoclopramide. Of course, other less
severe reactions occur that vary in intensity
and even wax and wane over time. The most
commonly reported offending agents other than
neuroleptics are the selective serotonin reuptake
inhibitors (SSRIs) and the stimulant medications
and illegal drugs. SSRIs (e.g., fluoxetine,
fluvoxamine, paroxetine, sertraline, citalopram,
and escitalopram) are reported to produce the
side effect of increased clenching and bruxism.

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either with conventional chemicals or using an
electrogustometer.
120
Termination of drug therapy is commonly
associated with termination of taste/smell
dysfunction, but occasionally effects persist and
require specific therapy to alleviate symptoms.
According to Henkin,
sensory distortions requires reactivation
of biochemical inhibition at the receptor or
inactivation of an inappropriate stimulus receptor
binding and/or correction of other steps initiating
the causal pathology. These agents include
dopaminergic antagonists, gamma-aminobutyric
acid (GABA)-ergic agonists, calcium channel
blockers, some orally active local anaesthetics,
and antiarrhythmic drugs.
121treatment that inhibits
Halitosis
Halitosis or oral malodor is offensive breath
resulting from poor oral hygiene, dental or
oral infections, ingestion of certain foods, use
of tobacco, and some systemic diseases and
medications.
can cause halitosis. Drugs causing xerostomia,
which was discussed earlier, may indirectly cause
or aggravate this problem.
5 Table 20 shows a list of drugs that
Assessment of oral malodor is usually subjective
by simply smelling exhaled air (organoleptic
method) coming from the mouth and nose
and comparing the two. Odor originating in
the mouth but not detectable from the nose is
likely to be either oral or pharyngeal in origin.
Odor originating in the nose may come from the
sinuses or nasal passages.
122
Oral Infections
Many types of systemic drug therapy can alter
oral flora and, therefore, predispose the mouth
interfering with the chemical composition of
saliva, the flow of saliva, or by affecting either
taste receptor function or signal transduction.
Sulfhydryl compounds are a common cause of
taste disturbance.
affecting taste are listed in Tables 18 and 19.
98Drugs with the potential for
Penicillamine causes partial or total loss of taste
in many patients. There appears to be a marked
difference in the frequency of this effect between
patients being treated for Wilson’s disease
and those being treated for other conditions.
In patients treated for Wilson’s disease, the
frequency is much lower. Loss of taste has been
found to be dose related. Taste disturbance is
reversible within a period of eight to ten weeks,
whether or not penicillamine is discontinued.
119
Impaired salty taste is a frequent complaint
associated with captopril. The extent of captopril-
induced dysgeusia seems to be related to dose,
renal function, and can be compounded by
smoking. Taste disturbances tend to be self-
limiting and reversible in two to three months
even if the drug is continued. ACE inhibitors also
cause persistent chronic dry cough.
Systemic griseofulvin can render certain foods
profoundly tasteless, with the effect gradually
worsening for as long as the patient takes
the drug. Furthermore, the effect may take
some months to disappear after the drug is
withdrawn. Other drugs, especially those used for
gastrointestinal disorders such as tripotassium
dicitrato bismuthate chelate, clarithromycin,
lansoperazole, anti-HIV protease inhibitors,
terbinafine, intravenous pentamidine, and
isotretinoin may cause some degree of loss of
taste or altered taste.
98
History taking should always include the
assessment of the current and former medication
history. Conditions that interfere with access of
a tastant to the taste bud are differentiated from
conditions that either injure the receptor cell or
damage the gustatory afferent nerves and the
central pathways. Psychophysical taste evaluation
includes identification of taste quality using sprays
or taste strips and testing of the intensity of taste
perception by measuring the taste threshold using
the 3-drop technique. Moreover, measurement
of taste in localized areas can be performed

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the use of medication, the global tendency is
to carry out analgesic symptomatic treatment,
accompanied by antinflamatory treatment and
antibiotics. Some authors advise the placement
of antiseptic intra-alveolar pastes. These pastes,
according to their active ingredients, can be
classified into antimicrobial dressings, soothing
dressings, or dressings with local anesthetics.
125
Angioedema
Angioedema is a sudden occurrence of
subcutaneous or submucosal swelling. It is well
known and in cases where the pharynx or larynx
are involved it can be a potentially life-threatening
condition. These swellings occur under different
conditions and often remain unrecognized.
The majority of cases of angioedema are
due to allergic reactions. Some drugs like
penicillin and sulfa drugs can cause allergic
angioedema. Beside the well-known forms of
allergic angioedema, many forms of non-allergic
angioedema are known.
126
Some drugs have the potential to induce non-
allergic angioedema; among them the ACEIs are
the most important. Angioedema is an established
and potentially life threatening side effect of
ACEIs. Occurrence of angioedema following
the onset of ACEI treatment ranges from one
day to eight years with a median of six months
and reverses within hours of terminating the
use of the drug. The incidence of ACEI-induced
angioedema is 0.4–0.7%. The mortality worldwide
is 0.1% of these cases. Black people may have
an increased risk of developing angioedema.
It seems ACEI-induced angioedema arises as
a consequence of an alternation in bradykinin
metabolism in susceptible patients. Inhibitors of
angiotensin converting enzyme (ACE) inevitably
account for increased bradykinin plasma levels.
to bacterial or fungal infection. Drugs causing
xerostomia may also potentiate the initiation of
oral infections.
to cause oral candidiasis.
15 Table 21 lists drugs with potential
Superficial candidia infections usually have a
characteristic clinical appearance, and diagnosis
is often based on clinical findings. Subjective
complaints of localized oral burning are
sometimes empirically treated for candidiasis.
Objective assays in the diagnosis of oral
candidiasis include exfoliative cytology, imprint
culture, swab culture, salivary assays, and
mucosal biopsy. Topical and systemic antifungal
agents are used more frequently by dentists to
treat oral fungal infections.
123
Alveolar Osteitis
Alveolar osteitis, commonly referred to as “dry
socket”, is by far the most common complication
following dental extraction and has been defined
as an inflammation of the alveolus.
of oral contraceptives has been associated with
a significant increase in the frequency of dry
sockets after removal of impacted lower third
molars. The probability of dry sockets increases
with the estrogen dose in the oral contraceptive.
Estrogens and other drugs activate the fibrinolytic
system in an indirect way (increasing the factors
II, VII, VIII, X, and the plasminogen), contributing
to the premature destruction of the clot and the
development of dry socket.
minimized by performing extractions during days
23-28 of the contraceptive tablet cycle.
124,125The use
5
125 Dry sockets can be
Dry socket is clinically recognizable by the
existence of a naked alveolus without the
presence of a sanguine clot revealing the
exposed bony walls and separation of gingival
borders. Although suppuration is not evident, a
very profound sharp pain persists for days and
increases with mastication and sucking forces in
the mouth. Dry socket typically appears on the
second or third day following an extraction and
usually lasts about ten or 15 days regardless
of whether it is treated or not. The patient
experiences a slight initial uneasiness followed
by a slight improvement and then a sudden
worsening in the form of profound pain that is
difficult to control even with strong analgesics.
The goal of treatment is to control the pain during
the ten to 15 day period. Even though healing
occurs within this time period, with or without

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the skin. This is usually associated with fungal
infections and frequently occurs with drug-
induced xerostomia.
potential to cause cheilitis.
5Table 23 lists drugs with the
Conclusion
Since most drug reactions occur within one to
two weeks following initiation of therapy, reactions
seen after two weeks are less likely to be due to
medication use. Some reactions are dependent
on dosage or cumulative toxicity. The majority
of drug-induced oral reactions are moderate in
severity. However, severe reactions necessitate
rapid withdrawal of the suspected drug. In most
cases, the oral reaction will be resolved by
symptomatic treatment. Re-administration of the
offending drug helps to establish whether the oral
eruption is drug-induced. Reactions after such a
re-challenge may be more severe and, therefore,
a re-challenge should not be performed without
medical supervision.
Since many patients take multiple medications,
dentists must be aware of the issues related to
drug use including indications, interactions, and
adverse side effects. The ability to evaluate these
issues is necessary to accurately assess patient
status and prevent situations that compromise
client safety. Oral side effects interfere with
patient function and increase risks for infection,
pain, and possible tooth loss. It has been
reported the most frequent side-effects of drugs
are xerostomia, dysgeusia, and stomatitis.
130
As a final note, rapid progress in
pharmacotherapeutics requires clinicians to
constantly update their knowledge of drugs used
by their patients. Attention must be paid to their
toxic and unwanted effects that in many cases
may be similar to characteristics of common
diseases.
4,131
Bradykinin is a mediator of inflammation,
activates nociceptors, increases vascular
permeability, and causes endothelium-dependent
vasodilatation. High levels of bradykinin have
been demonstrated in plasma during an acute
episode of angioedema.
126,127
A variety of non-steroidal anti-inflammatory
drugs (NSAIDs) can cause angioedema. Aspirin
is the most common and the reaction is called
pseudoallergic angioedema. Only cyclooxygenase
(COX)-1 inhibitors cause pseudoallergic
angioedema, while COX-2 inhibitors are thought
to be inactive. Acetaminophen is generally
tolerated even by patients sensitive to aspirin,
most likely because of very weak COX-1
inhibition.
angioedema.
128Table 22 lists drugs that can cause
One of the most important steps in the diagnosis
of edema is to separate allergic from non-allergic
angioedema and then exclude other pathologies
such as infection, inflammation, tumors, and
diseases of large salivary glands. A physical
examination (preferably laryngoscopy), blood
studies (C1-esterase inhibitor and markers of
inflammation, e.g., C-reactive protein and the
leucocyte count), some imaging procedures,
family history, and a review of current medications
may help with the diagnosis of angioedema.
Angioedema is usually treated by a conservative
clinical approach using artificial ventilation,
glucocorticoids, and antihistamines. Today, a
plasma pool C1-esterase inhibitor (C1-INH)
concentrate is the therapy of choice in
some forms of angioedema. The current
pharmacotherapy of non-allergic angioedema is
unsatisfactory, thus, requiring the identification of
effective agents in clinical trials. Recently, several
new drugs such as a recombinant C1-INH, a
kallikrein inhibitor (ecallantide), and a specific
bradykinin-B2-receptor antagonist (icatibant)
have been developed.
available reports, these drugs may improve the
treatment of kinin-induced angioedema. Following
basic emergency treatment as described above, it
is important to break off any drug therapy known
to induce angioedema.
126 According to currently
127
Cheilitis
Cheilitis is an abnormal condition of the lips
characterized by inflammation and cracking of

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Table 1. List of subjects reviewed in 2003 by Abdollahi and Radfar.
5
Table 2. Drugs with potential to cause fixed drug eruption.
3,5-7
Table 3. Compounds with potential to cause oral contact allergic reactions.
3,5,8