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Drug-induced gingival enlargement

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 Review Article

Drug-induced gingival enlargement

K. Archana1, M. Dhanraj1, Ashish R. Jain1*, T. Nirosa2

ABSTRACT

Gingival enlargement is an increase in the size or inflammation of the gingiva. Gingival overgrowth, hypertrophic gingivitis,
gingival hyperplasia, or gingival hypertrophy is the other names of gingival enlargement. Gingival enlargement occurs due to certain
inflammatory conditions and the side effects of certain medications. The etiology should be known for deciding a proper treatment
plan. A closely related term is epulis, denoting a localized tumor-like lump on the gingiva. Drug-induced gingival overgrowth or
enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction in patients treated with anticonvulsants,
immunosuppressants, and calcium channel blockers. Drug-induced gingival enlargement occurs on intake of three types of drugs:
Anticonvulsants, immunosuppressants, and calcium channel blockers. Patients develop complications due to these drugs. The extent
and severity of the gingival disease increase in these patients. This article throws light on respective drugs and their association with
gingival overgrowth and approaches to treatment based on current knowledge and investigative observations.

KEY WORDS: Calcium channel blockers, Cyclosporin, Gingival enlargement, Phenytoin

INTRODUCTION • Periodontal pocket depth

Drug-induced gingival overgrowth or enlargement occurs
in case of systemic drug use in particular drugs used for
non-dental treatments.[1] Age, genetic predisposition,
presence of preexisting plaque, and gingival inflammation
are the factors influencing the relationship between the
drugs and gingival tissue.[2] There is a variable gingival
response in patients taking drugs. Furthermore, within
the group of patients that develop this unwanted effect,
there appears to be variability in the extent and severity
of the gingival changes.[3]
CAUSES
Drug-induced gingival enlargement is one of the most
common causes for gingival hyperplasia. Congenital
gingival enlargement is also a cause which can be
hereditary or may be due to metabolic disorders, such
as the fetal valproate syndrome.[1]
There are several risk factors for drug-induced
gingival overgrowth such as
• Poor oral hygiene
• Periodontal disease
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• Gingival inflammation
• Degree of dental plaque
• Duration and dose of cyclosporine.
CLASSIFICATION
Based on etiology, gingival enlargement is classified
into five groups: [1]
• Inflammatory enlargement
• Drug-induced enlargement
• Enlargement associated with systemic diseases or
conditions
• Neoplastic enlargement
• False enlargement.
INFLAMMATORY ENLARGEMENT
The cause of gingival enlargement is multifactorial.
In chronic inflammatory gingival enlargement, due
to edema and plaque-induced cellular infiltration, the
gingiva becomes soft and discolored. This condition being
common can be is with scaling and root planing.[1] Mouth
breathers are commonly affected by gingivitis and
gingival enlargement,[4] due to surface dehydration
causing irritation.[1] The major cause of inflammatory
gingival enlargement is plaque accumulation and
retention. Poor oral hygiene[5] and improper restorative
and orthodontic appliances causing irritation of the

Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha University, Chennai, Tamil Nadu, India,
1

Department of Public Health Dentistry,Saveetha Dental College and Hospital, Saveetha University, Chennai, Tamil Nadu, India.
2

*Corresponding author: Dr. Ashish R. Jain, Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha University,
Ponamalle High Road, Chennai - 600 127, Tamil Nadu, India. Phone: +91-9884233423. E-mail: dr.ashishjain_r@yahoo.com

Received on: 09-02-2018; Revised on: 06-04-2018; Accepted on: 17-05-2018

1292 Drug Invention Today | Vol 10 • Issue 7 • 2018

 K. Archana, et al.
gingiva are the common risk factors of inflammatory
gingival enlargement.[1]
Enlargement associated with systemic factors. Many
systemic diseases can develop oral manifestations
that may include gingival enlargement, some that are
related to conditions, and others that are related to
disease: [4]
• Conditioned enlargement
• Pregnancy
• Puberty
• Vitamin C deficiency
• Non-specific, such as a pyogenic granuloma
• Systemic disease causing enlargement
• Leukemia
• Granulomatous diseases such as Wegener’s
granulomatosis, sarcoidosis, or orofacial
granulomatosis.[5]
• Neoplasm benign neoplasm such as fibromas,
papillomas, and giant cell granulomas. Malignant
neoplasms, such as a carcinoma or malignant
melanoma.
• False gingival enlargements, such as when there is
an underlying bony or dental tissue lesion.
DRUG-INDUCED ENLARGEMENT
Drug-induced gingival enlargement or otherwise
called drug-influenced gingival enlargement[6] or “drug
induce gingival overgrowth” abbreviated as “DIGO.”[7]
Gingival enlargement is mostly associated with
administration of three different classes of drugs
producing almost similar response which are phenytoin,
cyclosporine, and dihydropyridines.[8] “Phenytoin-
induced gingival overgrowth” is a most common
side effect of phenytoin[9] observed in epileptic
patients in taking phenytoin affecting 50% of patients.
Cyclosporine is an immunosuppressant causing gingival
enlargement in 25–80% of patients. The calcium
channel antagonist, in particular, dihydropyridines
(e.g.  nifedipine, felodipine, and amlodipine) is also
commonly associated with gingival enlargement.
• Anticonvulsants (such as phenytoin, phenobarbital,
lamotrigine, valproate, vigabatrin, ethosuximide,
topiramate, and primidone).[10]
• Calcium channel blockers, such as nifedipine,
amlodipine, and verapamil. The dihydropyridine
derivative is radipidine can replace nifedipine and
does not induce gingival overgrowth.[10]
• Cyclosporine, an immunosuppressant.[10]
Almost all cases of drug-induced gingival enlargement
are due to phenytoin, cyclosporine, and calcium channel
blockers. Cyclosporine is an immunosuppressant
which is used in organ transplant recipients and for
treating psoriasis. Other calcium channel blocker
agents such as nifedipine and amlodipine also induce
gingival enlargement.[11,12]
Drug Invention Today | Vol 10 • Issue 7 • 2018
Nifedipine tends to have an additive effect when
used in combination with cyclosporine in transplant
recipients with hypertension.[13] Not all patients on
phenytoin, cyclosporine, and calcium channel blockers
develop gingival enlargement.[14] The etiology of drug-
induced gingival enlargement is multifactorial. The
pathogenesis and etiology of gingival enlargement are
not clearly known.[15]
CLINICAL PRESENTATION
Gingival enlargement develops in a few months of
starting the medication.[16] Drug-induced gingival
enlargement develops in a few months of medication
in which soft-tissue growth begins between the teeth
which rapidly increases. Drug-induced gingival
enlargement develops in a few months of medication
in
which soft-tissue growth begins between the
teeth
which rapidly increases, becomes thickened
and lobulated and it partially or completely cover the
occlusal surfaces of teeth and sulcus. In cyclosporine-
induced enlargement, the epithelial surface is usually
smooth and fibrotic. In case of underlying periodontal
disease, the tissues become inflamed, appear red
or purplish in color, and highly vascularized, with a
tendency to bleed profusely.[17] Gingival enlargement
is prominent in areas, plaque accumulated areas, and
around orthodontic appliances rarely in edentulous
areas. Gingival enlargement causes plaque or food
accumulation, producing halitosis or suppuration.
The anterior teeth are more severely affected than the
posterior teeth.[18]
DIFFERENTIAL DIAGNOSIS
A differential diagnosis requires thorough medical
and dental histories, a careful evaluation of nature
of enlargement, and an identification of the etiologic
factors. A biopsy specimen may be required to confirm
diagnosis.[19]
Drug-induced gingival overgrowth must be
differentiated from inflammatory enlargement: Acute
inflammatory enlargement appears as a localized
gingival swelling characterized by acute pain of rapid
onset suggesting an abscess. Chronic inflammatory
enlargement appears as deep red or bluish red and
soft, friable with smooth, shiny surface along with
bleeding tendency. Inflammatory enlargements
usually are a secondary complication to any of the
other types of enlargement, creating a combined
gingival enlargement.[20]
Idiopathic or familial or hereditary gingival
enlargement: It affects the attached gingiva, as well
as the gingival margin and interdental papillae. The
facial and lingual surfaces of the mandible and maxilla
are generally affected, but the involvement may be
limited to either jaw. The color of enlarged gingiva
1293
 K. Archana, et al.
is pink with firm and leathery in consistency. The
etiology is unknown.[20]
Conditioned enlargement: It occurs when the systemic
condition of the patient exaggerates or distorts the
usual gingival response to dental plaque. It includes
hormonal-like pregnancy, puberty, nutritional
conditions like associated with Vitamin C deficiency,
and allergic conditions like plasma cell gingivitis.
The gingiva shows features of chronic inflammatory
enlargement, especially interproximally. Plasma cell
gingivitis consists of lesion located in the oral aspect
of attached gingiva.[20]
Systemic diseases induced gingival enlargement:
Several systemic diseases, namely, leukemia,
sarcoidosis, tuberculosis, and other granulomatous
diseases can result in gingival enlargement.
Hematological investigations as in leukemia and
histopathological examination such as leukemic
infiltrate in leukemia, foreign body giant cell in
sarcoidosis, tuberculosis are useful in establishing the
diagnosis.[20]
Neoplastic enlargement or gingival tumors: It may
appear as slowly growing spherical mass that tends to
be firm and nodular or hard and wart-like protuberance
from gingival surface.[20]
False enlargement: These are not true enlargements of
the gingival tissues but appear as such. These result
due to increase in size of the underlying osseous or
dental tissues. The gingiva usually presents with no
abnormal clinical features except the massive increase
in size of area.[20]
Gingival overgrowth induced by various drugs is
differentiated from one another as:
In phenobarbitone treated patients, gingival
overgrowth occurs without lobulations of the
interdental papillae. The lesions develop often in
posteriors than in anteriors.[19]
In individuals, immunosuppressed with cyclosporin,
sometimes pebbly or papillary lesions appear on
the surface of larger lobulations, which have been
associated with the presence of Candida hyphae
invading the gingival epithelium. In phenytoin-
induced gingival overgrowth, gingival tends to bleed
rapidly whereas in cyclosporine-induced gingival
overgrowth, tissues become hyperemic.[19]
RISK FACTORS
Poor oral hygiene is the major risk factor for gingival
overgrowth. Dental plaque serves as a reservoir for
the accumulation of phenytoin or cyclosporine. In
patients undergoing orthodontic treatment, gingival
1294
enlargement occurs due to accumulation of nickel and
proliferation of epithelium.[15,16]
Fibroblasts, keratinocytes, and Langerhans cells
present in oral epithelium are risk factors for gingival
enlargement.[17]
PLAQUE CONTROL
Gingival enlargement can be prevented by effective
plaque control and proper tooth brushing technique.
Removal of plaque and calculus reduces gingival
enlargement. In case of severe gingival enlargement,
surgical gingival resection is indicated. Chlorhexidine
0.1% should be rinsed two or three times daily for the
first few postoperative days, with careful mechanical
cleaning introduced gradually as it becomes more
comfortable. Areas that are not included in the surgery
can be cleaned as usual. The efficacy of chlorhexidine
may be reduced by toothpaste because of a chemical
interaction. The interval between tooth brushing and
rinsing should, therefore, be at least 30 min.[18]
In drug-induced gingival enlargement excess gingival
growth occurs between the teeth and thickening of the
gums occurs on brushing the soft tissue or inadequate
cleaning of the crown of the tooth close to the gingival
margin. Flossing and using interproximal brushes
and wood sticks are difficult in case of often out of
the gingival enlargement. Plaque can be removed
by cleaning each tooth separately, holding the brush
in line with the long axis of the tooth. The narrower
dimension of the head of the brush then fits in between
the papillae. Another option is to use an electric
toothbrush with a round head to clean the teeth in the
same longitudinal fashion. Plaque removal can be
done with proper brushing and flossing at least once
daily.
MANAGEMENT
Proper oral hygiene maintenance and plaque control
help in treating gingival overgrowth. Chronic
inflammatory gingival enlargements which do not
respond to scaling and root planing are treated with
gingivectomy.[19]
Plaque control and proper oral hygiene maintenance
reduce inflammation. Drug-induced gingival
enlargement can be controlled by ceasing drug therapy
or substituting to another drug. For example, tacrolimus
can be used as a substitute for cyclosporine.[16] The
dihydropyridine derivative is radipidine can be used
as a subtitute for nifedipine.[17]
In addition to plaque control, periodontal surgical
treatment can also be needed in case of severe gingival
enlargement.[21]
Drug Invention Today | Vol 10 • Issue 7 • 2018
 K. Archana, et al.
In case of mild gingival enlargement, proper oral
hygiene maintenance and teeth cleaning can reduce
inflammation. Periodontitis with gingival enlargement
is more complex. Periodontitis can be treated
using conventional clinical care, whereas gingival
enlargement requires drug substitution, periodontal
surgery to remove excess tissue, or a combination of
the two.[22]
TREATMENT NON-SURGICAL
Effective oral hygiene measures, professional tooth
cleaning, scaling, and root planning are used to control
plaque accumulation and thereby avoid the need
for surgery.[23] In addition, in case of patients with
immunosuppression have been reported to resolve
using topical antifungal are used to treat papillary
lesions on the enlarged gingiva.[24] These possibilities
should be consulted with the patient’s physician.
Simple discontinuation of the offending agent is
usually not a practical option but replacing it with
another medication might be. Alternative medications
to pulmonary hypertension include carbamazepine
and valproic acid, both of which have been reported
to have a lesser impact in inducing gingival
enlargement.[25] Recently, the feasibility of pulmonary
hypertension substitution has increased with the
addition of a new generation of anticonvulsants such as
lamotrigine, gabapentin, sulthiame, and topiramate.[21]
Drug substitution options for cyclosporin are more
limited due to the fact that few of these options exist.
Earlier, it was said that cyclosporin-induced gingival
enlargement can spontaneously resolve if the drug
is substituted by tacrolimus.[26] Mycophenolic acid
and azathioprine are proved to prevent gingival
hyperplasia in renal transplant patients. Azathioprine
is an antiproliferative and anti-inflammatory drug.[27]
The dihydropyridine derivative is radipine which can
replace nifedipine in some cases and does not induce
gingival overgrowth.[28] Consideration may be given to
the use of another class of antihypertensive medications
than calcium channel blockers, none of which are
known to induce gingival enlargement.[26] If any drug
substitution is attempted, it is important to allow for
6–12 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.[26]
SURGICAL
Gingival enlargement may persist, despite drug
substitution attempts and good plaque control. These
cases need to be treated by periodontal surgery. Before
any surgical procedure, precautions and consultations
with physician regarding underlying systemic disease
should be taken into consideration. The surgical
management of drug-induced gingival overgrowth
Drug Invention Today | Vol 10 • Issue 7 • 2018
includes the scalpel gingivectomy, periodontal
flap surgery, electrosurgery, and laser excision.[29]
The clinician’s decision to choose gingivectomy or
periodontal flap surgical techniques must be made on
a case-by-case basis and should take into consideration
the extent of area to be involved in surgery, the presence
of periodontitis, the presence of osseous defects
combined with the gingival enlargement lesions, and
the position of the bases of the pockets in relation to
the existing mucogingival junction. Nevertheless,
surgical intervention using conventional means using
scalpel may sometimes be technically difficult and/
or impractical for example in children or mentally
handicapped or in patients suffering from impaired
hemostasis. In these situations, the use of electrosurgery
may be advantageous. The use of lasers has shown
some utility for reducing gingival enlargement.[30]
MAINTENANCE
Chlorhexidine gluconate rinse and scaling can lower
the rate and the degree of recurrence of gingival
enlargement. A hard, natural rubber, fitted bite guard
worn at night also helps in the control of recurrence.
Recurrence may occur as early as 3–6 months after the
surgical treatment, but in general, surgical results are
maintained for at least 12 months.[31]
CONCLUSION
Gingival enlargement occurs on intake of
cyclosporine, phenytoin, and calcium channel
blockers. Drug-induced gingival overgrowth also
results in periodontal disease. It is necessary to advise
patients of the possibility of this effect and emphasize
the importance of maintaining good oral hygiene as a
preventive measure. Hence, it would be pertinent to
identify and explore possible risk factors relating to
both prevalence and severity of drug-induced gingival
overgrowth. Several new therapeutic modalities
are needed to establish the pathogenesis of gingival
enlargement and to create awareness for the future.
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Source of support: Nil; Conflict of interest: None Declared
Drug Invention Today | Vol 10 • Issue 7 • 2018