3. Introduction
Gingival hyperplasia (GH) is a benign enlargement of the gingiva characterized by increase in
size and volume.
The reported causes of gingival hyperplasia varied, and included plaque accumulation, genetic
predisposition, hormonal changes as well as a secondary to the use of specific medications. 1
Multiple medications have been linked to medication-induced gingival hyperplasia (MIGH)
including (nifedipine, cyclosporine (CsA), and phenytoin.) 2), 3
However, the exact pathogenesis is not well understood and likely to be multifactorial.
Several underlying mechanisms have been proposed including decrease in gingival matrix
metalloproteinases leading to decrease in collagen degradation, in addition to increase in pro-
inflammatory cytokines and collagen synthesis. 3
Factors such as plaque accumulation in the surrounding tissues and hormonal imbalance may
boost this particular process and accelerate the hyperplastic transformation of gingival tissues.4
3
4. Even with MIGH being a benign condition, it imposes a significant impact on patients’ life quality
through compromised aesthetics and daily function more often in advanced cases.
Several management options have been reported including medical referral to consider
switching the medication in question if deemed feasible and safe, scaling and root planning
(SC/RP), oral hygiene instructions and use of antimicrobial mouth rinses.
Patients with more severe disease, no response to treatment or relapse may require surgical
resection of the fibrotic enlarged gingival tissue.
In order to better understand MIGH, the aim of this study was to systematically review the
treatment options offered to MIGH patients in addition to estimating recurrence rate and time
to relapse reported in the literature.
4
5. Material and Methods:
Electronic literature search was conducted via Pub Med and Web of science search engines up to
December 2019.
The search followed pre-determined PICO questions.(EBDM)
*P=patients with medication-induced gingival hyperplasia
*I=surgical and/or non-surgical treatment options
*C=no control is required
*O= partial or complete resolution and recurrence
.
5
6. Published studies with focus on non-medications induced gingival hyperplasia as well as animal
studies were excluded.
The systematic review search terms included the following:
(((medications induced gingival hyperplasia) OR(medications induced gingival overgrowth) OR
(medications induced gingival enlargement))
AND ((non surgical management) OR (surgical management))
AND ((relapse) OR (healing) OR (recurrence) OR (decrease signs and symptoms) OR (reduce
size))).
Due to limited available literature on MIGH, inclusion of studies with lower level of evidence
such as case reports and case series was permitted.
6
7. Results:
The literature search yielded a total of 28 articles, in which 22 articles met the
inclusion criteria and were included in this analysis (published from 1988 to 2017).
In total, there were six cohort studies, four randomized clinical trials (RCTs), two case
series and ten case reports.
The reported classes of medications associated with MIGH included :
1. anticonvulsant (phenytoin and phenobarbital),
2. calcium-channel blockers (CCBs; nifedipine, amlodipine and diltiazem)
3. immunosuppressive medications (CsA and tacrolimus).
7
9. 1.1 Non-surgical approach (Table 1):
A study was conducted by Aimetti et al. to assess the effect of non-surgical periodontal treatment
alone on liver transplant patients who received CsA therapy and developed MIGH. 8
The study included 21 patients compared to control group of 18 systemically healthy subjects
who were indicated to receive crown lengthening procedure for different reasons.
For all participants, gingival hyperplasia index (HI) was used as a primary outcome to measure
changes in gingival tissue volumes.
MIGH patients underwent supra and sup-gingival SC/RP and were instructed to perform daily
plaque control measures and follow a strict recall program every 2 months for oral hygiene
instructions (OHI) at 12-months follow up.
9
10. persistent gingival overgrown tissues were excised, and sent for histopathological analysis
combined with crown lengthening procedure excised gingival tissues obtained from control
group.
Histologically, there was significant reduction in the total number of inflammatory cell infiltrate
including plasma cells, lymphocytes and macrophage-like cells together with blood vessels in
lamina propria following non- surgical therapy in MIGH group.
This finding was similar to gingival samples obtained at baseline from the control group.
10
11. A case series included 11 patients with MIGH associated with CCBs (n=4), CsA (n=1) and
combination of both (n=6). 9
All patients received
*full mouth disinfection (FMD) proposed by Quirynen and coworkers which includes non-surgical
* SC/RP
*OHI followed by 1% chlorhexidine (CHX) gel for the tongue
*subgingival pocket irrigation with 0.12% CHX solution. 10
Patients were followed up for an average of 28 months and demonstrated improvement of all
periodontal parameters except for 6% of teeth which required further surgical intervention.
11
12. Multiple studies looking at the efficacy of azithromycin and/or metronidazole as a
management option for MIGH in organ transplant patients were reported.
A study by Wong et al. reported on 4 renal transplant patients with CsA-induced gingival
hyperplasia. 11
Patients were managed with metronidazole (400 mg/day) for 7 days and all showed total
resolution at the end of the study.
Furthermore, Hooda et al. reported on renal transplant patients who had symptomatic MIGH
related to CsA (n= 11) and amlodipine (n= 7).
13. All patients in this series received azithromycin (500 mg/day) on day 1 followed by 250 mg/day
on days 2 to 5.
At the end of the treatment course, there was a symptomatic relief with reduction in gingival
pain and bleeding.
Out of all, a single patient reported recurrence of MIGH requiring gingivectomy.
The measured level of gingival enlargement showed significant increase in crown height and
width ratio from 1.06 +/- 0.11 at baseline to 1.24 +/- 0.09 at 8 weeks following therapeutic
intervention
14. Using anti-microbial agents, Montebugnoli et al reported on the efficact of a locally delivered
metronidazole gel on 6 heart transplant patients with CsA-induced gingival hyperplasia in a double-
blinded split-mouth study design. 13
Initially, patients underwent conventional therapy including SC/RP for all 12 anterior teeth and OHI.
The maxillary and mandibular anterior sextant were divided into two groups to randomly receive either
placebo or metronidazole gel.
Clinical examination was conducted at baseline, 1, 2, 3- and 4-months intervals which included plaque
index (PI), bleeding on probing (BOP) and probing depth (PD).
There was no significant difference between placebo and metronidazole groups within 1 month follow up
interval.
However, at 4-months follow up time point, all gingival parameters for metronidazole gel and
conventional therapy groups had improved compared to placebo group.
15. Table 1. Characteristics of the included studies using the non-surgical approach.
Author Type
of
study
No. of
subjects
Underlyin
g medical
diagnosis
Offending
medication
Management of
MIGH
Follow-
up
duration
Conclusion Methodolo
gical
quality
assessmen
t score
Aufricht et
al. 1997
{Aufricht,
1997 #35}
Cohort
study
13
children
Kidney
transplant
CsA + nifedipine
(n=6) OR CsA +
verapamil (n=7)
Metronidazole
(10- 25
mg/kg/day for 7
days)
3
months
No improvement of
gingival hyperplasia or
gingival inflammation with
the use of Metronidazole
12/16
Hooda et
al. 2004
{AK
Hooda,
2004 #64}
Cohort
study
11 Kidney
transplant
CsA (n=4) and
combination of CsA
with amlodipine
(n=7)
Azithromycin
(500 mg) on the
first day
followed by 250
mg from days 2
to 5.
8 weeks Azithromycin help in
reducing the symptoms
(pain and bleeding) and
increasing the average
value of ratio of crown
height and width
increased from pre-
treatment baseline at 4
and 8 weeks
10/16
15
16. 16
Author Type of
study
No. of
subjects
Underlying
medical
diagnosis
Offending
medication
Management of
MIGH
Follow-up
duration
Conclusion Methodolo
gical quality
assessment
score
Aimetti et
al. 2008
{Aimetti,
2008 #72}
Controlled
cohort study
39
(21 with
MIGH and
18 healthy
control)
Liver
transplant
CsA SRP, OHI, frequent
recall visits (strict
recall maintenance
and full mouth
scaling every 2
months for 12
months)
12
months
There was significant reduction
in the total number of
inflammatory cell infiltrate
including plasma cells,
lymphocytes and macrophage-
like cells together with blood
vessels in lamina propria
following nonsurgical therapy in
MIGH group
10/24
Montebugn
o li et al.
2002.
{Montebug
n oli, 2002
#34}
RCT
(split mouth
design)
6 Cardiac
transplant
CsA SRP, OHI and
Metronidazole gel
(treatment group)
OR placebo gel
(control)
4 months Metronidazole and placebo are
equally effective in reducing
periodontal parameters and
MIGH when associated with
scaling and root planing.
11/15
17. 17
Author Type
of
study
No. of
subjects
Underlying
medical
diagnosis
Offending
medication
Management of MIGH Follow-up
duration
Conclusion Method
olo gical
quality
assessm
ent
score
Mesa et al.
2003
{Mesa,
2003 #37}
RCT 40 Kidney
transplant
CsA Metronidazole (250 mg, 3 times daily) OR
Azithromycin (500 mg, twice daily) for 7
days OR no treatment (control)
1 months A 7‐ day course of
Metronidazole or
Azithromycin does not
induce remission of
CsA‐ induced gingival
hyperplasia
11/15
Nafar et al.
2003
{Nafar,
2003 #39}
RCT 25 Kidney
transplant
CsA SPR and 2g of Amoxicillin + Group
1: Azithromycin (total of 6 capsules X
500mg/4 days), Group
2: Placebo capsules Group
3: 25% oral gel for one week Group 4:
Placebo gel
6 week Azithromycin capsules
and gel does not give
any benefits over SPR
for management of CsA
‐ induced gingival
hyperplasia
12/15
Chand et
al. 2004
{Chand,
2004 #38}
RCT 28 Steroidresistant
nephrotic
syndrome and
post organ
transplantation
CsA +
nifedipine
or
amlodipine
Group 1: Azithromycin (10 mg/kg at day 1
followed by a daily dose of 5 mg/kg for 4
days).
Group 2: Metronidazole (45 mg/kg/day
divided into three daily doses for total of 7
days).
6 month Both antibiotics showed
significant reduction in
the gingival overgrowth,
but Azithromycin was
superior
12/16
MIGH= Medication-induced gingival hyperplasia, RCT= Randomized clinical trial, CCB= calcium channel blockers,
CsA= Cyclosporine, OHI= Oral hygiene instruction, SRP= Scaling and root planning.
18. 1.2 Surgical approach (Table 2):
Several surgical interventions were reported as a potential treatment option for MIGH including
conventional scalpel gingivectomy, laser-assisted gingivectomy and electrosurgery.
Four cases of nifedipine-induced gingival hyperplasia were reported by Deen-Duggins et al.2 In
this case series, two patients received conventional gingivectomy (flap procedures) without
further details on outcome as patients failed to attend scheduled follow up visits.
The other two patients were managed with combination of gingivectomy in addition to
medication substitution which included combination of hydrochlorothiazide and fosinopril
sodium resulting in MIGH size reduction within 1-3 months.
However, a secondary surgical intervention was indicated for both cases for complete resolution
of MIGH.
18
19. Combination of non-surgical and surgical approaches was reported in several studies.
A cohort study by Fardal et al. included 103 patients currently on CCB who were followed up for
11.3 years. 18
Initially, all patients received conventional periodontal therapy including SC/RP, OHI and
selective antibiotic prescription for cases with acute periodontal abscess, significant swelling and
pus.
Afterward, pocket depths of >/=7 mm with BOP were surgical treated.
Next, all patients were placed on preset supportive periodontal and maintenance therapy.
Evaluation of gingival overgrowth was measured using vertical and horizontal gingival
overgrowth index proposed by Miranda & Brunet.19
19
20. At the end of the study, 86.4% (89/103) of patients developed MIGH which were managed with
SC/RP and surgical intervention if needed.
In total, 47.2% (42/103) of patients experienced recurrence of MIGH and needed re-treatment
including non-surgical treatment which was effective only in 2 patients.
The remaining sites underwent surgical treatment including gingivectomies and modified
Widman flap procedures, electro-surgery and laser-assisted surgery (no statistically significant
difference in healing parameters was reported).
In this report, the author reported replacement or discontinuation of CCB therapy to result in
significant decrease of MIGH without complete resolution (GOI: from 3.45 to 1.45).
20
21. Table 2. Characteristics of the included studies using the surgical approach.
21
Author Type of
study
No. of
subjects
Underlying medical
diagnosis
Offending
medication
Management of MIGH Time to recurrence /
duration of follow-up
Methodolog ical
quality assessment
score
Bowman et
al. 1988
{Bowman,
1988 #79}
Case
report
1 Cardiovascular
disease (not
specified)
Diltiazem (CCB) Electrosurgery No recurrence / 8
months
NA
Lawrence et
al. 1994
{Lawrence,
1994 #75}
Case
report
1 Hypertension Diltiazem (CCB),
spironolactone
(diuretic) and
hydrochlorothiaz
ide (diuretic)
SRP, OHI, frequent
recall visits, medication
substitution (first to
nifedipine then to
felodipine) and
gingivectomy.
Recurrence (3 times)
with diltiazem within
the 1 year Recurrence
with nifedipine after 1
year Recurrence with
felodipine after 18
months
NA
Gregoriou
et al. 1996
{Gregoriou,
1996 #77}
Case
report
2 Seizures Phenobarbital
(anti-convulsant)
SRP, OHI, dental
prophylaxis,
electrosurgery (1st
case) and scalpel
gingivectomy (2nd case)
No recurrence / 6
months (1st case) No
recurrence / 12
months (2nd case)
NA
22. Author Type of
study
No. of
subjects
Underlying medical
diagnosis
Offending
medication
Management of MIGH Time to recurrence /
duration of follow-up
Methodolog ical
quality assessment
score
Khocht &
Schneider
1997
{Khocht,
1997 #76}
Case
report
1 Cardiac transplant Phenobarbital
(anti-convulsant)
SRP, OHI, frequent recall
visits, CHX mouth wash
(0.12%) and
gingivectomy
Minor gingival
overgrowth /12
months
NA
Luvizuto et
al. 2012
{Luvizuto,
2012 #32}
Case
report
1 Epilepsy Phenytoin
(anti-convulsant)
SRP, OHI, CHX mouth
wash (0.12 %), dental
prophylaxis, frequent
recall visits, patient
education and
gingivectomy
No recurrence / 36
months
NA
D’Errico et
al. 2013
{D'Errico,
2013 #78}
Case
report
1 Hypertension Amlodipine (CCB) Medication substitution
(not specified),
professional dental
prophylaxis and diode
laser-assisted
gingivectomy
No follow-up was
reported
NA
23. Author Type of
study
No. of
subjects
Underlying medical
diagnosis
Offending
medication
Management of MIGH Time to recurrence /
duration of follow-up
Methodolog ical
quality
assessment
score
Aral et al.
2015 {Aral,
2015 #71}
Case
report
1 Kidney transplant,
hypertension
CsA
(immunosuppres
sants), nifedipine
(CCB
SRP, OHI, frequent recall
visits, medication
substitution (cyclosporine
to tacrolimus and
nifedipine to captopril) and
diode laser-assisted
gingivectomy
No recurrence /18
months
NA
Maddi et al.
2015
{Maddi,
2015 #70}
Case
report
1 Cardiac
transplant,
hypertension
CsA
(immunosuppres
sants)
SRP, OHI, frequent recall
visits, medication
substitution (CsA to
sirolimus) and diode laser-
assisted gingivectomy
No recurrence /12
months
NA
Gurgel, B.
C.et al.
2015
{Gurgel,
2015 #31}
Case
report
1 Epilepsy Phenytoin,
phenobarbital
(anti-convulsant)
SRP, OHI, frequent recall
visits, CHX mouth wash
(0.12%), patient education
and gingivectomy
No recurrence / 4
years
NA
24. Author Type of
study
No. of
subjects
Underlying medical
diagnosis
Offending
medication
Management of MIGH Time to recurrence /
duration of follow-up
Methodolog ical
quality assessment
score
Carty et al.
2015 {Carty,
2015 #67}
Case
report
1 Hypertension Amlodipine (CCB) SRP, OHI, frequent recall
visits and gingivectomy
No follow-up was
reported
NA
Deen-
Duggins et
al. 1996
{DeenDuggi
ns, 1996
#68}
Case
report
4 Hypertension Nifedipine (CCB) SRP, OHI, medication
substitution (nifedipine
replaced for 2 of the
patients) and
gingivectomy or flap
surgical procedures
No follow-up was
reported
NA
Dannewitz
et al. 2009
{Dannewitz,
2010 #73}
Case
report
11 N/A CCBs (no further
details were
included in the
article), CsA
(immunosuppres
sants)
FMD (OHI, professional
dental prophylaxis, SRP,
CHX gel (1%) and mouth
rinse (0.12%), antibiotic
for patients who were
on CsA) and surgical
intervention (only when
needed).
No recurrence / 28
months
NA
25. Author Type of
study
No. of
subjects
Underlying
medical diagnosis
Offending
medication
Management of MIGH Time to recurrence / duration
of follow-up
Methodolog ical
quality
assessment score
Fardal & Lygre
2015 {Fardal,
2015 #74}
Cohort
study
103 (89
showed
MIGH)
Hypertension +
diabetes
(16 patients)
or cardiovascular
diseases
(7 patients).
CCBs SRP, OHI, medication
substitution, frequent recall
visits and surgical intervention
(gingivectomies/ modified
Widman flap procedures,
electro-surgery and laser
assisted gingivectomy).
47.2% had recurrence during
SPT/Follow-up 11.30 ±8.06
years
9/16
Pernu et al.
1993 {Pernu,
1993 #81}
Cohort
study
27 Kidney transplant CsA,
dihydropyridine
(nifedipine and
felodipine) and
diltiazem
OHI, SRP, restoration of carious
teeth and defective restorations
and gingivectomy (for moderate
and severe MIGH in 10 patients)
13 out of 27 participants
had more overgrown gingiva
than initially or developed
score 2 MIGH after
gingivectomy. 5 out of 10
patients showed recurrence
of MIGH after gingivectomy /
Follow-up = 14.5±7.2 months
13/16
Ilgenli et al.
1999 {Ilgenli,
1999 #80}
Cohort
study
38 Kidney transplant,
cardiovascular
disease
(not specified)
Nifedipine, CsA OHI, SRP, amoxicillin (500 mg 3
times daily for 7 days),
flap with 90º gingivectomy and
maintenance recall program
3 out of 38 patients (34%)
had recurrence of MIGH
(6/22 patients on CsA and
7/16 patients on nifedipine)
/18 months
14/16
MIGH= Medication-induced gingival hyperplasia, RCT= Randomized clinical trial, CCB= calcium channel blockers, CsA=
Cyclosporine, SPT= Supportive periodontal therapy, OHI= Oral hygiene instruction, SRP= Scaling and root planning, CHX =
Chlorhexidine, FMD= Full mouth disinfection.
26. 2. Recurrence rate
Based on included RCTs and cohort studies, data on the recurrence rate of MIGH was limited and
varied based on type of delivered treatment.
Patients managed with non-surgical approach had mostly reduction in reported symptoms
without complete resolution of MIGH.
However, surgical management of MIGH had in a recurrence rate ranging between 34-47.2%
within a wide follow up duration of 1.5 to 19.9 years. 18, 27, 28
26
27. Discussion:
MIGH is a gingival tissues disorder linked to several medications, specifically the three main
classes of anti-hypertensives, immunosuppressants and anti-convulsants. 29
It has a common clinical presentation disregard the type of offending medication which include
enlargement of the interdental papillae and attached gingiva leading to gingival disfigurement
and aesthetic burden.
{Heasman, 2014 #82} Upon palpation, the consistency of enlarged tissue may vary, and ranges
between soft to more fibrotic one according to duration, dose and type of offending medication.
18 Based on the available literature, MIGH could appear as early as the first to third month after
medication administration.
27
28. Analysis of the available literature revealed two treatment approaches for MIGH: surgical and
non-surgical options.
In general, non-surgical therapy is offered to patients as a first line of treatments for mild to
moderate disease as a more conservative option with reduced cost. 3
It includes plaque control using anti-microbial mouth rinse (e.g. chlorhexidine gluconate) with
SC/RP to reduces the severity of tissue inflammation. 1, 5
Complete removal of plaque retentive areas (e.g. faulty restorations and badly constructed fixed
or removable prosthesis) is mandatory to achieve the best treatment outcomes. 2, 30
In addition, enforcing good oral hygiene and attending regular periodontal maintenance visits
may help to decrease MIGH severity as well.5, 18
28
29. Few studies reported promising outcome when combining locally-delivered or systemic antibiotics
with plaque-control. 18, 30
However, the exact mechanism of this approach wasn’t investigated in these studies and could be
related more to the antibiotic’s antimicrobial and anti-inflammatory effect rather than modifications in
fibrogenic component of gingival lamina propria. 11, 15
This observation should be investigated further with better control of factors such as level of gingival
overgrowth, concomitant synergistic effect of offending medications or serum levels. 14, 15
In addition, the variability in antibiotic dosage used should be accounted for when assessing treatment
outcome.
29
30. This was more evident in metronidazole as 10-25 mg/kg/day dosage had no effect on MIGH. 14, 16
However, significant improvement with higher dose of 45 mg/kg/day. 14, 16
Following the same approach, the application of FMD as a treatment modality for MIGH has
been reported in a single study which included 11 patients. 9
The proposed mechanism focuses on eradicating the inflammatory components from within the
gingival tissues and decrease the microbial load prior to triggering an immunological response.
The limited literature demonstrated promising FMD outcome and reduced the need for further
surgical therapy within average follow up of 28 months suggesting the need for further
investigation to confirm this data.
30
31. Patients with refractory or recurring MIGH may require referrals for medical consultation and
possible substitution of the offending medication if medically feasible. 3, 31
A systematic review concluded that medication substitution should be carried out only if the
new medication is anticipated to control the patient’s underlying medical condition, as well as
improving MIGH symptoms and clinical presentation. 30
Safe medications suggested as a substitution include carbamazepine, ethosuximide and sodium
valproate which have not been linked to MIGH so far. 30
The reported time to resolution of MIGH following drug substitution/cessation hoovers around
1-8 weeks. Therefore, it is considered as the most effective treatment for MIGH and accepted by
affected patients.
31
32. Incomplete resolution or relapse following conservative therapy may require gingivectomy using
a scalpel or laser-assisted therapy, flap surgery or electrosurgery. 30
In general, the surgical approach carries the advantage of providing an instant aesthetic
improvement to patients and expedite the resolution process. 20, 23
From all commercially available laser devices, two in particular have been reported for MIGH
management including CO2 and diode laser from which CO2 laser has demonstrated the least
risk for relapse.30 However, no clinical differences in treatment outcome have been noted
between conventional and laser-assisted surgeries.9, 18
Data on the role of newer laser devices (e.g. Nd;YAG) and potential benefit for MIGH is still
deficient. Furthermore, the impact of inter-provider clinical skills on these procedures is still
unclear and should be always considered.
32
33. The risk of MIGH recurrence following provided treatments varied as well, and has been linked
to multiple factors such as age, gingival inflammation and patient compliance with recall visits.
In addition, different classes of medications may pose higher risk of recurrence compared to
others.5
At the same time, frequent use of adjunctive therapy (e.g. chlorhexidine gluconate or folic acid
based-mouth rinses) may also reduce the risk for recurrence.1, 5, 20
The available literature demonstrated faster resolution of MIGH with less risk of recurrence
with the use of antiseptic mouth rinse which should be further investigated . 9
33
34. This systematic review has several limitations.
First, the quality of included literature may not provide the highest level of evidence as there were only
four RCTs and 6 cohort studies.
The majority of studies were case series/reports with either a small sample size or no control group.
As such, it would be hard to elucidate the best treatment approach for MIGH based on the current
literature.
Second, multiple studies reported no or short-term follow up period which may compromise the reported
outcomes.
Third, several studies failed to report recurrence rate data and associated risks.
Fourth, there was significant heterogeneity between reported parameters to evaluate MIGH among
included studies as well as the surgical techniques used.
34
35. Conclusion and Recommendations:
MIGH is a gingival disorder with potential impact on patients’ esthetics and functions.
The available literature on best management approach is limited and advice for both nonsurgical and
surgical treatment options without sufficient evidence to support one versus another.
Non-surgical therapy includes substitution of offending medication if medically safe, SC/RP, and/or
anti-microbial therapy in addition to use of adjunctive antibiotic therapy.
More severe cases or with frequent recurrence may benefit from resection of fibrotic gingival tissues
using scalpel or laser-assisted therapy.
Future larger randomized clinical trials, with longer follow ups are needed to better understand this
disease pathogenesis and best management approach.
In addition, controlling for potential confounding factors such as the class of medication, dose and
treatment duration would help to generate solid, unbiased conclusions.
However, recruiting sufficient number of participants for these studies could be a potential challenge
considering the overall low prevalence rate.
35
