J Clin Periodontol 2015; 42 (Suppl. 16): S139S151 doi: 10.1111/jcpe.

12340

Are anti-inflammatory agents

effective in treating gingivitis as
solo or adjunct therapies? A
systematic review

David Polak1, Conchita Martin2, Igna
nchez3, Nurit Beyth4 and

cio Sanz-Sa
Lior Shapira1
1

Department of Periodontology, Hebrew

University-Hadassah Faculty of Dental
Medicine, Jerusalem, Israel; 2Department of
Stomatology IV, Area of Orthodontics,
Complutense University of Madrid, Madrid,
Spain; 3Department of Stomatology, Area of
Periodontics, Complutense University of
Madrid, Madrid, Spain; 4Department of
Prosthodontics, Hebrew University-Hadassah
Faculty of Dental Medicine, Jerusalem, Isreal

Polak D, Martin C, Sanz-S

anchez I, Beyth N, Shapira L. Are anti-inflammatory
agents effective in treating gingivitis as solo or adjunct therapies? A systematic review.
J Clin Periodontol 2015; 42 (Suppl. 16): S139S151. doi: 10.1111/jcpe.12340.

Abstract
Objective: Systematically review the scientific evidence for efficiency of antiinflammatory agents against gingivitis, either as solo treatments or adjunctive
therapies.
Methods: A protocol was developed aimed to answer the following focused question: Are anti-inflammatory agents effective in treating gingivitis as solo or
adjunct therapies? RCTs and cohort studies on anti-inflammatory agents against
gingivitis studies were searched electronically. Screening, data extraction and
quality assessment were conducted. The primary outcome measures were indices
of gingival inflammation. A sub-analysis was performed dividing the active agents
into anti-inflammatory and other drugs.
Results: The search identified 3188 studies, of which 14 RCTs met the inclusion
criteria. The use of anti-inflammatory or other agents, in general showed a higher
reduction in the test than in the control in terms of gingival indexes and bleeding
scores. Only two RCTs on inflammatory drugs could be meta-analysed, showing
a statistically significant reduction in the GI in the experimental group
[WMD = 0.090; 95% CI ( 0.105; 0.074); p = 0.000]. However, the contribution of both studies to the global result was unbalanced (% weight: 99.88 and
0.12 respectively).
Conclusions: Most of the tested material showed beneficial effect as anti-inflammatory agents against gingivitis, either as a single treatment modality or as an
adjunctive therapy.

Gingivitis is the most common form

of periodontal disease affecting 50%
to 90% of adults worldwide (Albandar & Rams 2002). Although gingiConflict of interest and source of
funding
The authors declare that there is no
conflict of interest in this study. The
study was self-funded.

vitis does not lead to irreversible

tissue damage or significant impairment of well-being, it is considered a
risk for the development of graver
forms of periodontal disease, such as
chronic periodontitis (Burt 2005).
Therefore, gingivitis treatment and
prevention, in the individual patient
or in populations, is considered one
of the first steps towards preventing
periodontitis.

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Key words: gingival inflammation; antiinflammatory; adjunctive therapy; gingival

index
Accepted for publication 25 November 2014

The most common way of gingivitis development is related to the accumulation of dental plaque adjacent to
the gingival margin (Loe et al. 1965).
The accumulation of plaque leads to
direct and indirect changes in the gingiva which can be broadly defined as
distinct phases (Page & Schroeder
1976). The first stage is characterized
as an acute inflammatory response
dominated by neutrophils, followed

S139

S140

Polak et al.

by T lymphocytes accumulation at
the inflammatory sites along with
changes in collagen homoeostasis and
robust pro-inflammatory cytokine
expression profile. Thereafter, the
chronicity of plaque insult leads to
chronic inflammation consisting of
innate and adaptive immune components. Clinically, these dramatic
inflammatory processes which occur
during the first days from plaque
accumulation are mildly evident.
Clinical signs of inflammation of the
gingiva become apparent at more
advanced stages of the inflammatory
processes, and include redness and
oedema of the gingival tissue, bleeding upon probing, changes in contour
and consistency and increasing gingival crevicular fluid (GCF) flow (AAP
parameter of care position paper
2000).
In the classical model of experimental gingivitis in man, L
oe and
coworkers found that elimination of
plaque deposits from the tooth surfaces, and establishment of clean
surfaces for extended time by meticulous oral hygiene, leads to the eradication of clinical signs of gingivitis
(Loe et al. 1965). This data validate
the fundamental role of plaque in
the development of gingivitis. Consequently, the most common treatment
modality for gingivitis consists of
mechanical dental plaque debridement and proper oral hygiene practice instructions. However, from an
epidemiological point of view, the
ability of patients to maintain appropriate oral hygiene is sometimes limited (Artnik et al. 2008). Physical
disability or lack of proper hand
coordination may limit the ability of
some patients to clean their teeth
properly (Bizarra & Ribeiro 2009).
Also, plaque retentive factors, such
as caries lesions, fillings or poorly fitting crowns may present obstacles
that reduce accessibility and proper
cleaning (Litonjua et al. 2011).
Over the past decades, there have
been pursuits for additional tools
that will assist in treating gingival
inflammation, besides mechanical
removal of dental plaque. Such tools
can be easily divided into two main
subcategories: (a) anti-plaque agents,
and (b) anti-inflammatory agents.
These chemical agents are available
in toothpastes or mouth rinse selfadministered by patients or used as
professional treatment protocols.

Substantial evidence demonstrates

an additional effect of anti-plaque or
anti-inflammatory agents to mechanical plaque removal.
The current systematic review
looks into the existing scientific evidence that shows a clinical effect of
primarily anti-inflammatory agents
on gingival inflammation as a solo
or an adjunctive treatment focusing
on subjects with plaque-induced gingivitis.
Materials and Methods
Protocol development and PICO question

A protocol was developed covering

all aspects of systematic reviews
methodology according to the Prisma guidelines (Moher et al. 2009).
The following focused question
was proposed (Needleman 2002):
Are anti-inflammatory agents effective in treating gingivitis as solo or
adjunct therapies?
To answer this question, PICO
descriptors were defined as follows:
Population: Healthy individuals,
age above 18, generally healthy
(specifically not suffering from
diabetes, immune deficiency disorders,
autoimmune
disorders,
inflammatory diseases, such as
inflammatory bowel disease, psoriasis etc.), who did not consume
antibiotics at least 4 weeks before
study enrolment, over 16 teeth
present, and not suffering from
any form of periodontitis.
Intervention: Any known antiinflammatory drugs: NSAID, steroids, anti-IL1, Anti-TNF; any
drugs with possible anti- inflammatory mechanism (statins, etc.);
innovative drugs with anti-inflammatory properties; natural substances with anti-inflammatory
claims - given either systemically
or locally.
Comparison: Anti-inflammatory
agents with and without mechanical debridement versus mechanical
debridement. Specifically, the following comparisons were considered:

Anti-inflammatory agents with

mechanical debridement versus
mechanical debridement alone.
Anti-inflammatory agents without with mechanical debridement

versus mechanical debridement

alone.
Anti-inflammatory agents with
mechanical debridement and
anti-inflammatory agents without
mechanical debridement.Eventually, subgroup analysis was
undertaken considering:
Type of gingival or other index
used.
Type of study.
Type of drugs used.
Outcomes: The primary outcome
was gingival inflammation, measured as gingival index, sulcus
bleeding index, BOP etc. (Loe
et al. 1965, Muhlemann & Son
1971, Cowell et al. 1975, Talbott
et al. 1977, Lobene et al. 1986,
Mombelli et al. 1987).
Plaque Index (Quigley & Hein
1962, Silness & Loe 1964, Lange
et al. 1977), periodontal probing
depth (PPD) and clinical attachment loss (CAL) were considered
as secondary outcome variable.

Selection of studies

This systematic review included randomized controlled trials (RCTs)

and prospective cohort studies.
Studies needed to be conducted
in human subjects with gingivitis,
older than 18 years and in good general health, who did not suffer from
any form of periodontitis.
A minimum sample size (10 subjects per group) was established in
an attempt to minimize publication
bias.
Search strategy

Three electronic sources were be

used to search for studies that satisfied the inclusion criteria. They
included (1) The National Library of
Medicine (MEDLINE via Pubmed);
(2) Embase; and (3) Cochrane Central Register of Controlled Trials.
All databases were searched for
studies published until February
2011. The search was limited to
human subjects. Additionally, a
hand-search was performed reviewing the following journals: Journal
of Clinical Periodontology, Journal
of Periodontology, Journal of Periodontal Research and International

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Anti-inflammatory agents against gingivitis

Journal of Periodontics and Restorative Dentistry.
The following search terms were
used:
Population
(<[text words] gingivitis OR gingival inflammation OR GCF
OR gingival crevicular fluid OR
inflammatory markers OR gingival bleeding OR gingival
index OR bleeding index OR
gingivitis treatment OR gingivitis therapy> OR <[MeSH terms/
all subheadings] Gingivitis
OR Periodontal Index>)

Population AND Intervention

There were no language restrictions.
All reference lists of the selected
studies were checked for cross-references. The following journals were
hand-searched for this review: Journal of Clinical Periodontology, Journal of Periodontology, Journal of
Periodontal Research, Journal of
Dental Research, Clinical Oral
Implants
Research,
International
Journal of Oral & Maxillofacial
Implants.
Review methodology

Screening and selection

Intervention
(<[text words] (anti-inflammatory AND (drug* OR therapy
OR agent)) OR NSAID* OR
non steroidal anti-inflammatory
OR steroids OR dexamethasone
OR prednisone OR anti-IL1
OR anti-interleukin OR antiTNF OR anti-tumor necrosis
factor OR statins OR ((IL-1
OR TNF OR interleukine OR
tumor necrosis factor) AND
inhibitor)) OR ((natural OR
herbal OR extract) AND (antiinflammatory OR inflammation)) OR low dose doxycycline
OR periostat OR ldd OR LDD
OR resolvin* OR aspirin OR
acetylsalicylic acid OR acetaminophen OR paracetamol OR
omega-3 OR fish oil OR biologicals OR biological agents OR
antioxidant OR inos inhibitor
OR anti-neutrophil OR anti
cyclogenase OR anti prostaglandins OR anti chemokine OR
vitamin e OR ((cyclogenase OR
cyclooxygenase-2 OR cox-2 OR
prostaglandins OR chemokine)
AND inhibitor)) OR celecoxib
OR rofecoxib OR meloxicam
OR lumiracoxib OR valdecoxib
OR parecoxib OR etoricoxib
OR diclofenac OR ibuprofen
OR naproxen OR piroxicam
OR indomethacin OR indometacin OR azapropazone OR etodolac OR fenbufen OR
fenoprofen OR flurbiprofen OR
ketoprofen OR ketorolac OR
mefenamic acid OR nabumetone OR sulindac OR tenoxicam OR tiaprofenic acid)> OR
<[MeSH terms] anti-inflammatory agents>)

Two reviewers (DP and NB) did the

search and screened titles and
abstracts of all retrieved studies
independently. Studies were selected
when appearing to meet the inclusion criteria, or when there were
insufficient data in the title and
abstract to make a clear decision.
The full manuscripts from these references were obtained and independently assessed by two reviewers
(DP and LS) to determine their final
inclusion or exclusion. The reasons
for rejecting studies at this or at subsequent stages were recorded. Any
disagreement was solved by consulting a third reviewer (IS). In an
attempt to avoid the selection bias,
the reviewers were blind to the name
of the authors, institutions and journal titles. Studies meeting the inclusion criteria underwent validity
assessment. Special attention was
paid to duplicate publications to
avoid a likely bigger impact of the
same data in the global result.
Data extraction
Three reviewers (DP, NB and IS)
independently extracted the data
using specially designed data extraction forms. Authors of studies were
contacted for further information
when data were incomplete or missing. When the results of a study were
published more than once or if the
results were presented in different
publications, the most complete data
set was included only once.
Inter-reviewer reliability
After screening of titles and
abstracts, using four possible categories
(0 = Exclude;
1 = Include;
2 = Doubt; 9 = No abstract), the

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

S141

percentage of agreement was determined using Kappa analysis. Once

the full text was assessed, another
Kappa analysis was calculated.
Quality assessment

The quality assessment of the

included studies was undertaken
independently by three reviewers
(DP, NB and IS) who were blind to
the name of the authors, institutions
and journal titles. Data were revised
by a forth reviewer (CM), who also
solved any disagreement in the previous decisions. Quality assessment
was carried out following the recommendations by Cochrane for assessing risk of bias (Higgins et al. 2009)
and evaluating six criteria. RevMan
software (Review Manager, version
5.2.,
Cochrane
Collaboration,
Copenhagen, Denmark) was used to
obtain the risk of bias figures. Studies were defined as low risk of bias if
these six criteria were clearly met in
the study: random sequence allocation (selection bias), allocation concealment (selection bias), blinding of
participants and personnel (performance bias), bias of outcome assessment (detection bias), incomplete
outcome data (attrition bias), selective reporting (reporting bias) and
other bias. When missing one of
these criteria, the study was classified
as moderate potential risk of bias.
Missing two or more of these criteria
resulted in a high potential risk of
bias (Ten Heggeler et al. 2011).
Data analysis

To compare the selected studies, the

data on the primary outcome (gingival index) were pooled and analysed
using weighted mean differences
(WMDs) and 95% CI.
The
statistical
heterogeneity
among studies was assessed using
the Q-test according to DerSimonian
and Laird (DerSimonian & Laird
1986). As a complement to the Qtest, the I2 index (Higgins et al.
2003) was performed to identify the
percentage of variation in the global
estimate that was attributable to hetlow;
erogeneity
(I2 = 25%:
I2 = 50%: moderate; I2 = 75%: high
heterogeneity).
The study-specific estimates were
pooled using both the fixed effect
model (MantelHaenzelPeto test)

S142

Polak et al.

and the random effect model (DersimonianLaird test). If a significant

heterogeneity was found, the random
effect model results were presented.
Forest Plots were created to illustrate the effects in the meta-analysis
of the global estimation and the different sub-analysis. STATA 11.1
(StataCorp LP, Lakeway Drive, College Station, TX, USA) intercooled
software was used to perform all
analyses. Statistical significance was
defined as a p value <0.05.

p < 0.001). At the end, 33 articles

were included in the qualitative synthesis and 19 in the quantitative synthesis. Since five publications had to
be excluded after contacting the
authors due to the lack of numeric
data or its expression in medians
(Campan et al. 1997, Eberhard et al.
2002, Soukoulis & Hirsch 2004, Sekino et al. 2005, Grbic et al. 2011), 14
studies were included at the end. The
manual search didnt add any additional publication for the review.

Results

Study design

Search results

Idencaon

Figure 1 depicts the study flow

chart. The electronic search delivered
3188 titles. After the evaluation of
the titles and abstracts, 3023 studies
were
discarded
(agreement = 73.94%;
kappa = 0.508;
p < 0.001) resulting in 165 studies.
After reviewing the full-text articles,
109 were excluded and 56 were
assessed
for
eligibility
(agreement = 85.19%;
kappa = 0.73;

The methodological characteristics

of the selected studies are shown in
Table 1. All the included investigations were randomized controlled trials. From the 14 publications, all
except two had a parallel design, one
with a split-mouth design (Chandra
et al. 2007) and another with a
cross-over design (Rosin et al. 2005).
Among the studies, one study had
more than one experimental group
that met the inclusion criteria, so the
data were divided for the compari-

Records idened through

database searching
(n = 3188 )

sons with the same control group

(Khosravi Samani et al. 2011). The
most common control group used
was a placebo, except for one study
in which no treatment was performed (Pistorius et al. 2005), one
study in which a conventional mouth
rinse was used (Pistorius et al. 2003)
and two studies in which a conventional toothpaste was used (He et al.
2013, Hellstrom & Ramberg 2014).
Two different periodontal conditions
were studied: periodontally healthy
(Vogel et al. 1986, Twetman et al.
2009, Hiremath et al. 2013, Hellstrom & Ramberg 2014) and gingivitis/experimental gingivitis (Johnson
et al. 1990, Heasman et al. 1994,
Pistorius et al. 2003, 2005, Rosin
et al. 2005, Samuels et al. 2012).
When reported, all the studies except
one (Heasman et al. 1993) were
funded by the industry.
Study population

This systematic review pooled data

of 942 patients at baseline, 529 in
the experimental group and 413 in

Addional records idened

through other sources
(n = 0)

Eligibility

Screening

Records aer duplicates removed

(n = 3188)

Records screened
(n = 165)

Records excluded
(n = 3023)

Full-text arcles assessed

for eligibility
(n = 56)

Full-text arcles excluded,

with reasons
(n = 109)

Included

Studies included in
qualitave synthesis
(n = 33)

Studies included in
quantave synthesis
(meta-analysis)
(n = 14)

Fig. 1. Flow diagram (PRISMA format) of the screening and selection process.
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

J Clin Periodontol 2015; 42 (Suppl. 16): S139S151 doi: 10.1111/jcpe.12340

Are anti-inflammatory agents

effective in treating gingivitis as
solo or adjunct therapies? A
systematic review

David Polak1, Conchita Martin2, Igna
nchez3, Nurit Beyth4 and

cio Sanz-Sa
Lior Shapira1
1

Department of Periodontology, Hebrew

University-Hadassah Faculty of Dental
Medicine, Jerusalem, Israel; 2Department of
Stomatology IV, Area of Orthodontics,
Complutense University of Madrid, Madrid,
Spain; 3Department of Stomatology, Area of
Periodontics, Complutense University of
Madrid, Madrid, Spain; 4Department of
Prosthodontics, Hebrew University-Hadassah
Faculty of Dental Medicine, Jerusalem, Isreal

Polak D, Martin C, Sanz-S

anchez I, Beyth N, Shapira L. Are anti-inflammatory
agents effective in treating gingivitis as solo or adjunct therapies? A systematic review.
J Clin Periodontol 2015; 42 (Suppl. 16): S139S151. doi: 10.1111/jcpe.12340.

Abstract
Objective: Systematically review the scientific evidence for efficiency of antiinflammatory agents against gingivitis, either as solo treatments or adjunctive
therapies.
Methods: A protocol was developed aimed to answer the following focused question: Are anti-inflammatory agents effective in treating gingivitis as solo or
adjunct therapies? RCTs and cohort studies on anti-inflammatory agents against
gingivitis studies were searched electronically. Screening, data extraction and
quality assessment were conducted. The primary outcome measures were indices
of gingival inflammation. A sub-analysis was performed dividing the active agents
into anti-inflammatory and other drugs.
Results: The search identified 3188 studies, of which 14 RCTs met the inclusion
criteria. The use of anti-inflammatory or other agents, in general showed a higher
reduction in the test than in the control in terms of gingival indexes and bleeding
scores. Only two RCTs on inflammatory drugs could be meta-analysed, showing
a statistically significant reduction in the GI in the experimental group
[WMD = 0.090; 95% CI ( 0.105; 0.074); p = 0.000]. However, the contribution of both studies to the global result was unbalanced (% weight: 99.88 and
0.12 respectively).
Conclusions: Most of the tested material showed beneficial effect as anti-inflammatory agents against gingivitis, either as a single treatment modality or as an
adjunctive therapy.

Gingivitis is the most common form

of periodontal disease affecting 50%
to 90% of adults worldwide (Albandar & Rams 2002). Although gingiConflict of interest and source of
funding
The authors declare that there is no
conflict of interest in this study. The
study was self-funded.

vitis does not lead to irreversible

tissue damage or significant impairment of well-being, it is considered a
risk for the development of graver
forms of periodontal disease, such as
chronic periodontitis (Burt 2005).
Therefore, gingivitis treatment and
prevention, in the individual patient
or in populations, is considered one
of the first steps towards preventing
periodontitis.

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Key words: gingival inflammation; antiinflammatory; adjunctive therapy; gingival

index
Accepted for publication 25 November 2014

The most common way of gingivitis development is related to the accumulation of dental plaque adjacent to
the gingival margin (Loe et al. 1965).
The accumulation of plaque leads to
direct and indirect changes in the gingiva which can be broadly defined as
distinct phases (Page & Schroeder
1976). The first stage is characterized
as an acute inflammatory response
dominated by neutrophils, followed

S139

(0.12)

(0.19)
(0.3)
(0.6406)
(0.6406)
(0.6406)

(0.5736)
(0.4602)
(0.092)
(0.16)

(0.23)
(0.34)

(0.19)
(0.16)
(0.6125)
(0.6125)
(0.6125)
(0.086)
(0.13)
2000 IU
1000 IU
500 IU

Articles, numbers are assigned according to Table 1, and divided into (a) anti-inflammatory agents, and (b) all other materials. nr, not reported/missing data; ns, not significant. *Standard
error values.

p
p
p
p
p
ns
ns
ns
nr
ns

(1.23)
(0.39)
(0.6046)
(0.6615)
(0.9859)
(0.121)
(0.13)

(0.14)
(0.14)
(0.14)
(0.13)
(0.21)
(0.26)
(0.2)
(0.19)
With prophylaxis
Without prophylaxis

12
29
nr
10
10
nr
74
16
24
24
24
75
48
Loe & Silness (1963)
Loe & Silness (1963)
nr
Lobene et al. (1986)
Lobene et al. (1986)
nr
Loe & Silness (1963)
Loe & Silness (1963)
Loe & Silness (1963)
Loe & Silness (1963)
Loe & Silness (1963)
Lobene et al. (1986)
Loe & Silness (1963)
5
6
7
8
8
9
10
11
12
12
12
13
14

11
34
nr
10
10
nr
74
15
24
24
24
75
46

0.05
1.79
nr
1.156
1.04
nr
1.4
0.682
2.238
2.238
2.238
2.03
1.3

(0.02*)
(0.05)

0.06
1.8
nr
1.03
1.25
nr
1.51
0.83
2.4127(0.5435)
2.3973
2.2423
2.04
1.34

(0.03*)
(0.04)

0.42
1.68
nr
0.42
0.56
nr
1.1
0.895
1.8973
1.8973
1.8973
1.86(0.106)
1.19

(0.09*)
(0.04)

0.46
1.56
nr
0.12
0.3
nr
0.78
0.804
0.3405
0.5532
0.8832
1.81
1.08

(0.05*)
(0.04)

nr
nr
nr
ns
ns
nr
p < 0.001

p
p

nr
0.046
nr
< 0.01
< 0.01
nr
< 0.001
0.007
< 0.0001
< 0.0001
< 0.0001
< 0.001
< 0.001

nr
nr
0.05
0.240
nr
nr
0.05
1.37 (0.04)
nr
nr
0.927 (0.337)
1.46 (0.04)
nr
nr
0.984 (0.286)
1.8 (0.02)
nr
0.93 (0.24)
1.205 (0.164)
1.79 (0.02)
nr
0.89 (0.23)
1216 (0.262)
49
nr
24
21
Loe & Silness (1963)
Nr
Loe & Silness (1963)
Talbott et al. (1977)
1
2
3
4
(b)

53
nr
23
21

Baseline
Control
Test
Control
Test

Remarks
Type of index

All the studies except three

(Heasman et al. 1993, Pistorius et al.
2005, Twetman et al. 2009) reported
the changes in the gingival index.
The most commonly used index was
the gingival index by L
oe & Silness
(Loe et al. 1965). One study (Rosin

No.

Gingival index

Table 2. Data of gingival indices in the included articles

The groups were defined according

to the type of agent used. Table 1
depicts the definition of each group.
Anti-inflammatory drugs were used
in four studies (Johnson et al. 1990,
Heasman et al. 1993, 1994, Rosin
et al. 2005), whereas the remaining
10 publications studied different
compounds. There was a high heterogeneity between the study groups
and the type of vehicles used.
Changes in gingival inflammation
were studied in terms of the reduction in the gingival index (Table 2)
or the bleeding on probing (Table 3).
Additionally, the plaque index and
the changes in PPD were registered
in some of the studies.

Number of
subjects

Interventions

Control

Baseline; mean (SD)

Final; mean (SD)

Test

Intergroup p value

the control. The minimal study

length was 7 days and the maximal
was 6 months. At the end of the
study, 898 patients were followed
(501 in the test and 397 in the control). The study with the smallest
sample followed 12 patients per
group (Vogel et al. 1986) while the
one with the largest sample studied
75 patients per group (He et al.
2013).
The age data were presented for
the test and the control groups in
eight studies, whereas in six studies
it was presented for the whole study
population. Similarly the gender distribution was mostly reported for
the total sample, except in one study
(Hiremath et al. 2013). With regard
to smoking, eight studies did not
report the smoking status of the participants (Vogel et al. 1986, Johnson
et al. 1990, Heasman et al. 1993,
Rosin et al. 2005, Khosravi Samani
et al. 2011, He et al. 2013, Hiremath
et al. 2013, Hellstrom & Ramberg
2014), five studies included nonsmokers patients (Heasman et al.
1994, Pistorius et al. 2005, Chandra
et al. 2007, Twetman et al. 2009,
Samuels et al. 2012) and one study
included smokers and non-smokers
(Pistorius et al. 2003).

Final

Polak et al.

(a)

S144

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

12
13
14

10
11

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Articles numbers are assigned according to Table 1, and divided into (a) anti-inflammatory agents, and (b) all other materials. nr, not reported/missing data; ns, not significant. *Standard
error values.

nr
p < 0.001
nr
nr
nr
nr
nr
4.96 (5.478)
nr
nr
6.47 (5.573)
nr
nr
10.48 (6.431)
nr
nr
75
nr

nr
75
nr

nr
11.41 (8.97)
nr

p < 0.001
0.035
p < 0.001
1.14 (0.038)
12.8 (8.6)
74
16

74
15

1.53 (0.41)
20.6 (18.4)

0.73 (0.41)
22.3 (15.7)

0.52 (0.33)
20.8 (20.6)

ns
ns
15
64
68
12

13

58

p < 0.01
ns
1.03 (0.42)
0.28 (0.1)
1 (0.45)
Without prophylaxis
8

Gingival bleeding index

Sulcus Bleeding index (Not specified)
Sulcus Bleeding index
(Muhlemann & Son 1971)
Modified sulcular bleeding
index (Mombelli et al. 1987)
Modified sulcular bleeding
index (Mombelli et al. 1987)
Full mouth bleeding score
(Ainamo & Bay 1975)
Cowell et al. (1975)
Sulcus Bleeding index
(Muhlemann & Son 1971)
nr
Number of bleeding sites
nr
5
6
7

2
3
4
(b)

Sulcular bleeding index

(Muhlemann & Son 1971)
% of BOP sites
nr
nr
1

(a)

10

10

1.73 (0.46)

p < 0.01
ns
0.61 (0.34)
0.16 (0.1)
1.27 (0.31)
With prophylaxis

10

10

1.74 (0.39)

nr
0.001
p < 0.0001
nr
nr
p > 0.05
0.27 (0.05*)
2.13 (0.06)
40.7 (23)
0.25 (0.05*)
2.44 (0.06)
61.4 (20.6)
0.05 (0.02*)
2.45 (0.07)
68 (21.9)
12
29
20

11
34
40

0.1 (0.03*)
2.51 (0.06)
72.9 (20)

p < 0.01
nr
nr
nr
nr
nr
1.43 (0.4*)
nr
nr
12 (1.1*)
nr
nr
2.6 (0.0*)
nr
nr
7
nr
nr

7
nr
nr

4.3 (0.6*)
nr
nr

nr
nr
nr
nr
nr
53

49

nr

Final
Baseline
Test
Control
Test
Control
Test
Control

Remarks
Type of index
No.

Table 3. Data of bleeding indices in the included articles

Number of
subjects

Baseline; mean (SD)

Final; mean (SD)

Intergroup p value

Anti-inflammatory agents against gingivitis

S145

et al. 2005) used the modification of

the L
oe and Silness by Talbott et al.
1977 (Talbott et al. 1977) and two
studies (Chandra et al. 2007, He
et al. 2013) used the modified gingival index by Lobene et al. (1986).
Two publications using antiinflammatory agents showed reduction in gingival index in the test
group compared with the control
group (Johnson et al. 1990, Heasman et al. 1994), whereas one publication failed to show significant
differences between groups (Rosin
et al. 2005). Meta-analysis was performed using the studies that presented complete data (Johnson et al.
1990, Rosin et al. 2005). The analysis revealed a greater reduction in
gingival inflammation following the
use of anti-inflammatory drugs, with
a weight mean difference of 0.09 and
the study of Johnson et al. 1990 representing 99.88% of the weight
(Table 4 and Fig. 2).
On the other hand, when using
different agents than the anti-inflammatory drugs, all the studies except
one (Vogel et al. 1986) showed a
benefit in terms of gingival index
reduction in the test group compared
to the control. Due to the discrepancy between the agents used, no
subgrouping could be performed.
The reductions varied from 0.09 to
1.56, as it is represented in Fig. 3.
Bleeding on probing
All the studies except 5 (Johnson
et al. 1990, Heasman et al. 1994,
Rosin et al. 2005, Hiremath et al.
2013, Hellstrom & Ramberg 2014)
reported the changes in bleeding on
probing. The percentage of bleeding
sites was reported in three studies
(Heasman et al. 1993, Twetman
et al. 2009, He et al. 2013), the sulcular bleeding index by Muhlemann
& Son (1971) in two studies (Pistorius et al. 2005, Samuels et al. 2012),
the modified sulcular bleeding index
by Mombelli et al. (1987) in one
study (Chandra et al. 2007), the
bleeding index by Cowell et al. 1975
(Cowell et al. 1975) in one study
(Khosravi Samani et al. 2011). One
study did not specify the type of
index used (Pistorius et al. 2003).
When analysing the results of each
study individually, the publication
using an anti-inflammatory agent
showed a higher reduction in the
percentage of bleeding sites in the

S146

Polak et al.

Table 4. Meta-analysis of the two studies that used anti-inflammatory drugs

Study
Johnson et al. (1990)
Rosin et al. (2005)
I
V pooled WMD
D + L pooled WMD

WMD
0.090
0.057
0.090
0.090

95% Conf. Interval

% Weight

0.106
0.502
0.105
0.105

99.88
0.12
100.00
100.00

0.074
0.388
0.074
0.074

Heterogeneity v2 = 0.02 (d.f. = 1), p = 0.884. I2 (variation in WMD attributable to heterogeneity) = 0.0%. Test of WMD = 0: z = 11.36, p = 0.000.
WMD, weighted mean differences; I
V pooled WMD, fixed effect model; D + L pooled
WMD, random effect model.

test group (reduction of 2.87% in

the test and increase of 9.4% in the
control) (Heasman et al. 1993). For
non-anti-inflammatory agents, two
studies showed an increase in the
bleeding index for both control and
test groups (Vogel et al. 1986, Samuels et al. 2012), whereas six studies
showed a higher reduction in the test
(Pistorius et al. 2003, 2005, Chandra
et al. 2007, Twetman et al. 2009,
Khosravi Samani et al. 2011, He
et al. 2013). One study showed
higher reductions in the control
group when a dental prophylaxis
was provided to the patients (Chan-

dra et al. 2007). Again, due to the

discrepancy between the agents used,
no subgrouping could be performed.
Plaque index
The plaque index was registered in
all the included studies except three
(Twetman et al. 2009, He et al.
2013, Hiremath et al. 2013). The plaque index by Silness & Loe (1964)
was used in five studies (Vogel et al.
1986, Johnson et al. 1990, Heasman
et al. 1993, 1994, Khosravi Samani
et al. 2011), the modification by
Turesky et al. (1970) of the Quigley
& Hein 1962 plaque index (Quigley

& Hein 1962) in four studies (Pistorius et al. 2003, Rosin et al. 2005,
Chandra et al. 2007, Hellstrom &
Ramberg 2014) the modified proximal plaque index (Lange et al. 1977)
in one study (Pistorius et al. 2005).
One study did not specify which plaque index was used (Samuels et al.
2012).
Using the Silness & L
oe plaque
index, two studies found a reduction
in the plaque levels that varied from
1.031.42 in the test group to 0.321
in the control (Johnson et al. 1990,
Khosravi Samani et al. 2011),
whereas two other studies found an
increase, varying from 1.38 in the
test to 1.45 in the control (Vogel
et al. 1986, Heasman et al. 1993).
For the individual studies, only one
study found differences favouring
the test group, with a statistical significant reduction in plaque levels
(Khosravi Samani et al. 2011).
Using the Quigley & Hein index,
three studies found a reduction in
the plaque levels that varied from
0.251.13 in the test to 0.090.5 in
the control (Pistorius et al. 2003,

Fig. 2. Forest Plot and Meta-analysis of the two studies that used anti-inflammatory drugs.
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Anti-inflammatory agents against gingivitis

S147

Fig. 3. Forest Plot without meta-analysis of other studies that other drugs.

Chandra et al. 2007, Hellstrom &

Ramberg 2014), whereas one study
showed no changes in the test group
and an increase of 0.2 in the control
(Rosin et al. 2005). For the individual studies, one study found differences favouring the test group, with
a statistical significant reduction in
plaque levels (Hellstrom & Ramberg
2014).
For the other two indexes, no significant changes were found in the
test or control groups (Pistorius
et al. 2005, Samuels et al. 2012).
Probing pocket depth
The changes in PPD were registered
only in two studies (Pistorius et al.
2003, Khosravi Samani et al. 2011).
In the study by Pistorius et al., there
was a mean reduction of 0.2 mm,
both in the test and the control,
whereas Khosravi Samani et al.
showed reduction that varied from
0.260.56 in the test to 0.42 in the

control. None of the comparisons

showed significant differences.
Clinical attachment levels were not
analysed since none of the included
articles evaluated this outcome.
Quality assessment

Table 5 represents the risk of bias of

each individual study. From the 14
investigations, only one was considered to have a low risk of bias
(Rosin et al. 2005) and three a moderate risk of bias (Chandra et al.
2007, Twetman et al. 2009, Hellstrom & Ramberg 2014). The
remaining articles were at a high risk
of bias. Figure 4(a) represents the
review authors judgments about
each risk of bias item presented as
percentages across all included studies and Fig. 4(b) the summery of
review authors judgments about
each risk of bias item for every
included study.

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Discussion

The current systematic review examines the effect of anti-inflammatory

agents against gingivitis, either as a
solo treatment or as an adjunctive
therapy to conventional mechanical
treatment.
Although the literature search
resulted in a large number of studies,
only 14 studies were compatible with
the inclusion criteria. The included
studies were divided into two
groups: (a) anti-inflammatory drugs,
and (b) all other materials, due to
the fact that the materials used in
the studies varied greatly.
There were four included studies
that used known anti-inflammatory
drugs, and all of which used non-steroidal
anti-inflammatory
agents
(Johnson et al. 1990, Heasman et al.
1993, 1994, Rosin et al. 2005, Sekino
et al. 2005). Heasman et al. (1993)
studied the effect of flurbiprofen both

Moderate
High
High
High
Moderate
High
High
High
High
High
Low
High
Moderate
High
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
risk
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low
Low risk
High risk
Low risk
Low risk
Low risk
Low risk
Low risk
High risk
Low risk
Low risk
Low risk
High risk
Low risk
High risk
Low risk
Low risk
Unclear risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
Low risk
High risk
Low risk
Low risk
Low risk
Low risk
Low risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Low risk
Unclear risk
Unclear risk
High risk
2007
2013
1993
1994
2014
2013
1990
2011
2005
2003
2005
2012
2009
1986
Chandra
He
Heasman
Heasman
Hellstrom
Hiremath
Johnson
Khosravi
Pistorius
Pistorius
Rosin
Samuels
Twetman
Vogel

Low risk
Unclear risk
Unclear risk
Unclear risk
Low risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Unclear risk
Low risk
Low risk
Low risk
High risk

Year
Auhtor

Random
sequence
generation

Allocation
sequence
concealment

Blinding
of participants/
personnel

Blinding of
outcome
assessment

Incomplete
outcome
data

Selective
reporting

Other
potential
risk

Risk of
bias

Polak et al.

Table 5. Quality assessment of the articles included

S148

on the development and treatment of

gingivitis. It was shown that flurbiprofen as a solo treatment (without
mechanical treatment or tooth-brushing) reduced inflammatory signs
(bleeding and redness) during plaque
accumulation. A reduction of approximately 50% in bleeding sites was
reported compared with the control
placebo group (4.3  0.6 compared
with 2.6  0.7). Interestingly, the
flurbiprofen treatment reduced the
percentage of bleeding sites in established gingivitis by approximately
90% (1.43  0.4 compared with
12.0  1.1). In another study by
Heasman et al. (1994) subjects with
experimental gingivitis received flurbiprofen alongside tooth-brushing.
Although there was no significant difference in plaque deposits between
the groups, there was a significant
reduction in gingival inflammation in
the test group that received flurbiprofen compared with a placebo group.
These studies show that flurbiprofen
has a significant effect on gingival
inflammation both as a solo treatment and as an adjunctive treatment
to the mechanical treatment. Johnson
et al. (1990) looked at naproxen treatment both as a solo treatment or as
an adjunctive to the mechanical treatment. While the naproxen treatment
as a solo treatment did not result in
significant change in gingival inflammation, the use of naproxen as an
adjunctive therapy to mechanical
treatment resulted in a significant
reduction in gingival inflammation
(compared with placebo control).
Overall, the above results suggest that
NSIADs as a solo treatment or as
adjunctive therapy to conventional
treatment against gingivitis have the
potential to decreases inflammatory
signs. Rosin et al. (2005) looked at
the local effect of dexibuprofen in a
mouth wash product. Remarkably, it
was found that while the dexibuprofen mouthwash did not reduce gingival inflammation, it did manage to
reduce plaque accumulation.
In other studies mostly natural
products were used, and the majority
of materials were applied topically (as
mouthwash, toothpaste, chewing
gum etc.). Although most of the topical applied materials showed a beneficial effect on gingival inflammation,
it is very difficult to attribute this
effect to an anti-inflammatory ability,
since their biological mechanisms are
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Anti-inflammatory agents against gingivitis

S149

(a)

(b)

Fig. 4. Risk of bias analysis. (a) Review authors judgments about each risk of bias item presented as percentages across all
included studies, (b) summery of review authors judgments about each risk of bias item for every included study.
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

S150

Polak et al.

poorly defined. In four studies the

tested materials were systemically
administered. These studies included
ascorbic acid (Vogel et al. 1986), fatty
acid (Campan et al. 1997), lycopene
(Chandra et al. 2007) and vitamin D
(Hiremath et al. 2013). While systemically administrated ascorbic acid and
fatty acid did not show a significant
effect on gingival inflammation, the
systemic use of lycopene or vitamin D
showed significant anti-inflammatory
affect. The effect of vitamin D was
found to be dose dependent (Hiremath et al. 2013). Emerging evidence
showed that vitamin D has antiinflammatory properties (Hypponen
et al. 2010, Ashraf et al. 2012, Mellenthin et al. 2014). Similarly, lycopene was shown to possess antiinflammatory properties, due to its
antioxidant properties. It may be suggested that these properties of vitamin D and lycopene, are probably
the reason for the observed anti-gingivitis effect.
In addition to the human studies,
there are some animal studies that
investigated the effect of anti-inflammatory agents on gingival inflammation. Using a beagle dog model,
administration of the non-steroidal
anti-inflammatory drug piroxicam
significantly reduced gingival inflammation and the percentage of bleeding sites compared with a placebo
group (Howell et al. 1991). This
effect was regardless of plaque accumulation, which remained high in all
groups. In another study with beagle
dogs, Paquette et al. (2006) studied
the anti-gingivitis effect of the inflammatory component iNOS (inducible
nitric oxide synthase) inhibitors. It
was found that gingival indices (gingival index and bleeding on probing)
remained low in the test groups, while
the placebo control group showed
increases signs of gingival inflammation. Similarly to the previous study,
there was no difference in plaque levels between test and control groups,
indicating that the effect was solely
due to anti-inflammatory effect and
not anti-plaque effect.
There is also a body of evidence
on the effect of anti-inflammatory
agents upon measures of gingival
inflammation while treating patients
with chronic periodontitis. The
analysis of these studies is beyond
the scope of this systematic review,
but the data may be applicable to

gingival inflammation in general.

Taiyeb and Waite showed that the
use of ibuprofen in addition to scaling and root planning resulted in
reduction in gingival inflammation
(gingival bleeding and colour) compared with placebo treatment (Taiyeb Ali & Waite 1993). Gurkan
et al. (2005) showed that the adjunctive sub-antimicrobial dose doxycycline to the mechanical treatment led
to significant reduction in gingival
inflammation (full-mouth papilla
bleeding index) alongside elevation
in anti-inflammatory cytokine TGFb
(Transforming growth factor beta).
The above animal and periodontitis
data may lend support to the conclusion that anti-inflammatory agents
may reduce gingival inflammation in
the presence of plaque.
Overall, there is abundant evidence showing a beneficial effect of
anti-inflammatory agents against
gingivitis, either as a single treatment
modality or as an adjunctive therapy. Due to the fact that gingivitis
precedes the development of periodontitis, the use of such drugs or
natural products may be beneficial
by individual risk reduction. Still,
since the effectiveness of conventional mechanical treatment against
gingivitis is clear, the use of chemical
treatment should be carefully considered according to the patients general and oral health and compliance
to treatment. This is especially
important, when systemic drug
administration is considered that
may be accompanied by known or
yet unknown side effects.
Limitations

In the current study, in addition to

well established anti-inflammatory
agents (such as NSAIDs), we
included other agents that show antigingival inflammatory effects, but are
not considered as classical antiinflammatory agents. We included
them in a separate analysis since there
is some scientific evidence that these
materials possess anti-inflammatory
properties either from in vitro studies
or animal models. Nevertheless,
according to the currently available
literature, we cannot dismiss the possibility that the observed anti-inflammatory effects of these agents may be
attributed to an indirect effect (such
as anti-plaque properties). We did not

specifically include studies employing

Triclosan, as these are dealt with separately in another paper in this volume (Serrano et al. 2015).
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and they may benefit from adjunct

therapy using agents with antiinflammatory properties.
Principal findings: Material with
anti-inflammatory properties, particularly NSAID, showed beneficial
effects in resolving gingivitis, either
as a single treatment modality or as
an adjunctive therapy. However, this
conclusion relies on limited studies.
Practical implications: Due to the
limited available data, it is not yet
recommended for professionals to

consider the use of non-steroidal

anti-inflammatory agents for the
prevention of gingivitis, even in
patients with limited ability for plaque control, mainly due to their
side effects. Although some topically applied natural products
showed a beneficial effect on gingival inflammation, it is very difficult
to attribute this effect to an antiinflammatory ability, since their
biological mechanisms are still
poorly defined.

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Address:
Lior Shapira
Department of Periodontology
The Hebrew University-Hadassah Medical
Center
P.O.Box 12272, Jerusalem 91120, Israel
E-mail: lior.shapira@ekmd.huji.ac.il