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Transcript of Arginine containing toothpastes for dentin hypersensitivity systematic review and meta analysis.pdf
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONAL
1
GENERAL DENTISTRY
Arginine-containing toothpastes for dentin hypersensitivity: systematic review and meta-analysis
Boxi Yan, BDS1/Jianru Yi, DDS1/Yu Li, DDS, PhD2/Yin Chen, MS, DMSc3/Zongdao Shi, MD4
Objective: Arginine-containing toothpastes are a promising new treatment for dentin hypersensitivity (DH), which afflicts a considerable number of patients. However, there have to date been only individual studies. We aim to present an overview of the clinical evidence in order to determine trends and establish firmer conclusions regarding the use of arginine-containing toothpastes for management of DH. Method and Materials: A pro-tocol was developed based on the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0), including: search strategy, selection criteria, data extraction, and risk of bias assessment. We searched electronic databases (up to October 2012) without language limitation, and reference lists of relevant papers for randomized con-trolled trials that assessed the efficacy of arginine-containing toothpastes for DH treatment. Data extraction and domain-based risk of bias assessment were independently performed by two reviewers. The meta-analysis was performed in STATA (version 12.0). The GRADE analysis was conducted in GRADE profiler (version 3.6). Results: Fourteen randomized controlled studies with different risk of bias were included in the meta-analysis, all evaluat-ed by tactile and air blast assessment. The mean differences and standard deviations for each treatment group were pooled for analysis using a random-effect model. We found that arginine-containing toothpastes had better overall effects in comparison with placebo toothpastes (P < .05), potassium salt-containing toothpastes (P < .05), and strontium-con-taining toothpastes (P < .05). The GRADE analysis showed that quality of the evidence was moderate when arginine-containing toothpastes were compared to placebo and potassium salt-containing toothpastes, and quality of the evidence was low with compari-son to strontium-containing toothpastes. Conclusion: Current available clinical evidence suggests that arginine-containing toothpastes are associated with the reduction of DH compared to both placebo and positive control toothpastes. However, there are limitations to the current studies, and more well-designed trials are needed to confirm the efficacy. (doi: 10.3290/j.qi.a30177)
Key words: arginine, dentin sensitivity, GRADE analysis, meta-analysis, systematic review, toothpaste
1Research Student, State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
P.R. China.
2Associate Professor, State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
P.R. China.
3Lecturer, Chinese Evidence-Based Medicine Centre/ Chinese
Cochrane Centre, West China Hospital of Sichuan University,
Chengdu, P.R. China.
4Professor, State Key Laboratory of Oral Diseases, West China Hos-
pital of Stomatology, Sichuan University, Chengdu, P.R. China.
Correspondence: Dr Yu Li, State Key Laboratory of Oral Dis-
eases, West China Hospital of Stomatology, Sichuan University,
No.14, 3rd section of Renmin South Road, Chengdu, 610041 P.R.
China. Email: [email protected]
Supplementary material (Appendix 1 to 4) is included in the
online version, available at http://qi.quintessenz.de
Dentin hypersensitivity (DH) can be defined
as short, sharp pain from exposed dentin in
response to various stimuli, including ther-
mal, evaporative, tactile, and osmotic irrita-
tion, and the pain cannot be explained by
any other form of dental defect or disease.1
The prevalence of DH ranges from 8% to
74% among the adult population (Fig 1),
and can reach as high as 98% among peo-
ple with periodontal disease.1-3 Further-
more, the prevalence of DH is likely to
increase as the adult population lives lon-
ger and retains their teeth later in life, as a
result of gingival recession, which is an
important factor in inducing DH (Fig 2).4,5
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
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DH can cause considerable pain to patients
and affect oral health-related quality of life
(OHRQoL).6,7
The commonly accepted hydrodynamic
theory may explain DH. It assumed that
stimuli cause fluid movement within the
dentin tubules, which induces sharp pain
responses in the nerve fibers.8-10
To date, a variety of interventions have
been put into practice for managing the
condition, but DH continues to be a prob-
lem. It seemed that oral care professionals
felt confident diagnosing DH, but not treat-
ing it, and there was considerable uncer-
tainty in the treatment, due to a shortage of
effective methods against DH.11,12 Most
treatments were based on two primary ap-
proaches. One was to interfere with the
nerve transmission, for instance, by apply-
ing potassium ion. The other was to
occlude the dentinal tubules, for example
by using oxalates and stannous fluoride.1,13
Arginine-containing toothpastes, mainly
based on the latter approach, offered a new
therapeutic option and had the advantage
of being a convenient method for patients
to deal with DH at home. Arginine-contain-
ing toothpastes were first reported to have
an anti-sensitivity effect in 2002. The expla-
nation was that the combination of arginine
bicarbonate and calcium carbonate was
able to mimic natural desensitizing pro-
cesses of the saliva, and could be depos-
ited on the exposed dentin surfaces to form
a plug that physically blocked and sealed
the opened dentinal tubules so as to
reduce DH.14 In vitro studies revealed that
the use of arginine-containing toothpastes
was capable of occluding dentinal tubules,
and that the formed plug was resistant to
normal pulpal pressures and to acid chal-
lenge.15,16 A recent review also indicated
that arginine-based mouthwash was able to
reduce DH effectively.17
Though arginine-containing toothpastes
seemed to be a promising method against
DH, only a few clinical trials were carried
out to determine its efficacy, and a rigorous
systematic evaluation of the existing studies
has yet to be reported. Clinical data on the
efficacy of arginine-containing toothpastes
are essential to guide both dental practice
and further research in the treatment of DH.
Our objective is therefore to assess the rel-
ative effect of arginine-containing tooth-
pastes compared to other types of tooth-
pastes for relieving the pain of DH through
the meta-analysis of qualified randomized
controlled trials.
METHOD AND MATERIALS
This review was planned, conducted, and
reported in adherence to PRISMA (Pre-
ferred Reporting Items for Systematic
Reviews and Meta-Analyses) standards of
quality for reporting meta-analyses.18 The
“PICO” principle (participants, intervention,
comparison, and outcomes) was applied to
form the clinical question.
Criteria for considering studies for this reviewTrials that met the following criteria were
included:
Fig 1 Clinical image of sensitive anterior tooth without apparent gingival recession.
Fig 2 Clinical image of sensitive anterior teeth with extensive gingival recession.
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QUINTESSENCE INTERNATIONALYan et al
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• Types of studies – Randomized con-
trolled trial (RCT). The phase 1 stages of
randomized cross-over studies were
also included.
• Types of participants – People with self-
reported tooth hypersensitivity, confirmed
in the clinical evaluation. Post-restorative
hypersensitivity studies were excluded.
• Types of intervention – Arginine-contain-
ing toothpastes.
• Types of outcome measurements:
• Primary outcomes – Changes or final
scores in intensity of pain using
quantitative pain scale.
• Secondary outcomes – Adverse out-
comes including any unexpected or
unpredicted events related to the
intervention, especially the serious
adverse events leading to discontin-
uation of the treatment.
Search methods for identi!cation of studiesAfter the development of a protocol, paper
citations were obtained through an elec-
tronic search of databases including MED-
LINE (via OVID), CENTRAL (via Cochrane
Library), EMBASE (via OVID), and China
National Knowledge Infrastructure (CNKI)
(all terminated by October 14, 2012), without
language limitation. Hand-searching of
biblio graphic reference lists of published pri-
mary and review studies was also performed
(Fig 3). The search strategy included MeSH
terms and free-text words: “dentin sensitiv-
ity” (MeSH Term), “toothpastes” (MeSH
Term), “dentin hypersensitivity”, “dentifrice*”,
and “toothpast*”. The Cochrane Highly Sen-
sitive Search Strategy (sensitivity- and preci-
sion-maximizing version) was adopted.19
Two reviewers assessed independently the
titles and abstracts of studies identified in
the search. Full copies of all relevant and
potentially relevant trials were obtained for
further consideration. Any disagreement on
the eligibility of trials was resolved through
discussion and consensus. All potentially
relevant studies that failed to meet the eligi-
bility criteria were excluded.
Assessment of risk of bias in included studiesTwo reviewers assessed the included stud-
ies independently following the domain-
based evaluation described in Chapter 8 of
the Cochrane Handbook for Systematic
Reviews of Interventions (version 5.1.0),
including sequence generation, allocation
concealment, blinding of participants,
blinding of care providers, incomplete out-
come data, and selective outcome report-
ing.19 Conflicts between reviewers were
resolved by discussion or turning to a third
person for judgment.
Data extractionA customized data extraction form was
developed. The following items were
included: method of the design, age of the
participants, setting of the trial, the number
CENTRAL:251
Iden
tifica
tion
Scre
enin
g El
igib
ility
Incl
uded
MEDLINE: 118
EMBASE: 92
Duplicates: 305
Excluded: 129 -83 From MEDLINE/CENTRAL -46 From EMBASE
Excluded: 12 -review, letter, opinion: 8 -animal or basic research: 3 -without appropriate comparison: 1
From reference list:
3
Title/abstract: 156
Potentially relevant articles:
30
Qualitative synthesis: 18
Included in the meta-analysis:
14
Fig 3 Flow diagram of the literature search and selection process.
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
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of participants, intervention and compari-
son, duration of the trials, and outcome
measurement.
Data synthesisData were pooled for analysis in STATA
(version 12.0; StataCorp). For continuous
data, the mean difference and standard
deviation of this mean for each treatment
group were estimated by random-effects
model. We assessed the heterogeneity
across trials by calculating the I2 statistic
(describing the percentage of total variation
across trials that was due to heterogeneity
rather than chance). The value of I2 ranged
from 0 to 100%. The statistical heterogene-
ity was deemed as high if I2 > 50% and
P < .10. Funnel plots and the Begg’s rank
correlation test, the generic means of dis-
playing small-study effects, were chosen to
detect publication bias if the number of
included studies exceeded ten. Asymmetry
of the funnel plot and P < .10 would sug-
gest a publication bias.20,21 Sensitivity analy-
sis was conducted for the robustness of the
combined results with three or more pooled
studies. It compared the treatment effects
obtained with each trial removed consecu-
tively from the analysis, and examined
whether there were changes to the com-
bined effects.
Grading of the evidenceThe GRADE approach (Grading of Recom-
mendations Assessment, Development,
and Evaluation) was adopted to evaluate
overall quality of the evidence.22,23 Quality of
the evidence was downgraded by one or
two levels for each of the five factors we
encountered: limitations in the design,
inconsistency of results, indirectness,
imprecision, and publication bias. Two
reviewers judged whether these factors
were present for each outcome. We applied
the following definitions of quality of the evi-
dence24:
• High quality – further research is unlikely
to change our confidence in the esti-
mate of effect. There are no known or
suspected reporting biases; all domains
fulfilled.
• Moderate quality – further research is
likely to have an important impact on our
confidence in the estimate of effect and
might change the estimate; one of the
domains was not fulfilled.
• Low quality – further research is likely to
have an important impact on our confi-
dence in the estimate of effect and is
likely to change the estimate; two of the
domains were not fulfilled.
• Very low quality – we are uncertain
about the estimate; three of the domains
were not fulfilled.
GRADEprofiler (version 3.6) was adopted
for the assessment.25
RESULTS
Results of the searchElectronic searches from all sources
retrieved 156 unique citations. By screening
titles and abstracts, 129 unrelated citations
were excluded. Three articles not previ-
ously found through electronic search were
discovered in the references of cita-
tions.26-28 We pared the remaining 30 cita-
tions to 18 by scanning full article contents.
Eighteen studies26-43 were included in the
qualitative analysis. Two studies40,41 were
not included in the meta-analysis due to the
different duration. Two studies35,36 were
excluded because of different follow-up
and control groups. Fourteen qualified stud-
ies26-34,37-39,42,43 were included in the meta-
analysis according to the inclusion criteria
(Fig 3).
Study descriptionAll the 18 studies included in this review
were funded by the product manufacturers
and published in English between 2009 and
2012. Most studies were conducted in North
America and Europe (USA, Canada, Italy,
and Ireland), and the remaining in Asia
(India and China). Among the 18 studies, 17
trials were parallel studies, and one trial26
was a cross-over study. One study41
assessed 4% arginine-containing tooth-
pastes and 17 studies evaluated 8% argi-
nine-containing toothpastes. Two studies33,39
evaluated both the high cleaning calcium
carbonate type and the conventional type,
while other studies evaluated the conven-
tional type. The comparative interventions
were diverse, including placebo, potassium
salt-, stannous fluoride-, and strontium- con-
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
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taining toothpastes. The follow-up intervals
varied, ranging from instant measurement to
16 weeks follow-up. The pain was evaluated
immediately after a focused application of
the product to the sensitive teeth in instant
measurement. There was also a focused
product application in the 3-day and 7-day
follow-up studies, four28,29,33,34 of which pro-
Table 1 Studies included in the qualitative synthesis
Study Method Age CountryNumber of participants Intervention/comparison Duration
Outcome measurement
Kakar et al42 RCT 18–53 India 46/42 8% arginine, calcium carbon-ate/2% potassium ion
8 weeks Tactile, air blast
Kakar et al43 RCT 25–56 India 34/40 8%arginine, calcium carbonate/fluoride
8 weeks Tactile, air blast
Docimo et al27 RCT 20–69 Italy 50/50/50 8% arginine, calcium carbon-ate/8% strontium acetate/fluoride
8 weeks Tactile, air blast
He et al36 RCT 20–62 Canada 40/41 Stannous fluoride/8% arginine, calcium carbonate
3 days Air blast
He et al35 RCT 18–56 China 40/38 Stannous fluoride/8% arginine, calcium carbonate
2 weeks Air blast
Li et al28 RCT 18–61 USA 50/50/50 8% strontium acetate/fluoride/8% arginine, calcium carbonate
7 days Tactile, air blast
Schiff et al26 Cross-over
19–60 USA 61/60 8% arginine, calcium carbon-ate/8% strontium acetate
16 weeks Tactile, air blast
Hughes et al37 RCT 26.6 ± 10.72 26.3 ± 9.57
Ireland 39/39 8% strontium acetate/8% argi-nine, calcium carbonate
8 weeks Tactile, air blast
Que et al39 RCT 35–78 China 40/40/41 *8% arginine, calcium carbon-ate/calcium carbonate + fluoride
8 weeks Tactile, air blast
Ayad et al30 RCT 18–66 Canada 38/39 8% arginine, calcium carbon-ate/2% potassium ion
8 weeks Tactile, air blast
Ayad et al29 RCT 18–66 Canada 41/40/39 8% arginine, calcium carbon-ate/2% potassium ion/fluoride
3 days Tactile, air blast
Cummins41 RCT NR USA 35/35 4% arginine, calcium carbon-ate/calcium carbonate + fluoride
2 weeks Tactile, air blast
Docimo et al31 RCT 42.2 ± 10.6 Italy 40/40 8% arginine, calcium carbon-ate/2% potassium ion
8 weeks Tactile, air blast
Docimo et al32 RCT 19–70 Italy 40/40 8% arginine, calcium carbon-ate/2% potassium ion
8 weeks Tactile, air blast
Fu et al33 RCT 25–70 China 41/41/40 *8% arginine, calcium carbon-ate/ calcium carbonate + fluoride
3 days Tactile, air blast
Nathoo et al38 RCT 18–74 USA 42/41/42 8% arginine, calcium carbon-ate/2% potassium ion/fluoride
3 days Tactile, air blast
Hamlin et al34 RCT 27–66 USA 22/23 8% arginine, calcium carbon-ate/fluoride
Instant Tactile, air blast
Schiff et al40 RCT 19–60 USA 32/36 8% arginine, calcium carbon-ate/fluoride
12 weeks Tactile, air blast
NR, not reported; *One of the arginine-containing toothpastes was the high cleaning calcium carbonate type.
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
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vided the data of instant relief assessment.
It was followed by routine application for the
remainder of the study. Twice daily brush-
ing was the means of product application in
the rest of studies. Most studies evaluated
the pain by both tactile assessment using
electronic force sensing probe and air blast
assessment with the Schiff scale. Two stud-
ies35,36 measured the pain by air blast
assessment with the Schiff scale and Visual
Analog Scale (VAS). No adverse events
were observed (Table 1).
Risk of bias in included studies Only one study35 reported sample size and
statistical power calculation. All studies did
not do well in the allocation (selection bias)
domain, especially the allocation conceal-
ment, for no study documented the
sequence. And no study adequately
described the method of randomization. All
studies found no significant difference in
the baseline characteristics between
groups. Though every study mentioned the
measure of blinding, only two studies28,37
clearly described the procedure to secure
the blinding of both participants and out-
come assessors (performance bias and
detection bias). Lost follow-up occurred in
three studies.26,35,37 Only Hughes et al37
reported the use of intention-to-treat analy-
sis to deal with the missing data, while the
other two studies did not mention the meth-
ods to manage the missing data. Two stud-
ies42,43 just reported the number of
participants who completed the trial, but
did not mention whether there was lost fol-
low-up. Because of limited number of
included studies, funnel plots were not per-
formed. The other fields of risk of bias were
acceptable (Table 2).
Effects of the interventionArginine-containing toothpastes versus placebo toothpastes. Eight stud-
ies27-29,33,34,38,39,43 involving 645 participants
evaluated the difference between the effect
of arginine-containing toothpastes and pla-
Table 2 Risk of bias of included studies
Study
Domain
Sequence generation
Allocation concealment
Blinding participants
Blinding assessors
Free of incom-plete data bias
Free of selec-tive reporting
Kakar et al42 Un N Y Un Un Y
Kakar et al43 Un N Y Un Un Y
Docimo et al27 Un N Y Un Y Y
He et al36 Un N N Y Y Y
He et al35 Un N N Y Un Y
Li et al28 Un N Y Y Y Y
Schiff et al26 Un N Y Un Un Y
Hughes et al37 Un N Y Y Y Y
Que et al39 Un N Un Un Y Y
Ayad et al30 Un N Y Un Y Y
Ayad et al29 Un N Y Un Y Y
Cummins et al41 Un N Y Un Y Y
Docimo et al31 Un N Y Un Y Y
Docimo et al32 Un N Y Un Y Y
Fu et al33 Un N Y Un Y Y
Nathoo et al38 Un N Y Un Y Y
Hamlin et al34 Un N Un Un Y Y
Schiff et al40 Un N Y Un Y Y
N, high risk of bias; Un, unclear risk of bias; Y, low risk of bias.
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
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cebo toothpastes. Five studies28,29,33,34,38
involving 390 participants in the instant
assessment, three studies29,33,38 involving
245 participants in the 3-day follow-up, and
three studies27,39,43 involving 255 partici-
pants in the 8-week follow-up were pooled
for analysis separately with a random-effect
model. The combined results indicated that
arginine-containing toothpastes had a bet-
ter effect in the instant assessment (tactile
assessment: mean difference, 18.98; 95%
CI, 15.48 to 22.48; P < .05; I2 = 71.5%; air
blast assessment: mean difference, -1.05;
95% CI, -1.23 to -0.88; P < .05; I2 = 59.1%),
3-day follow-up (tactile assessment: mean
difference, 20.84; 95% CI, 15.67 to 26.00;
P < .05; I2 = 80.0%; air blast assessment:
mean difference, -1.29; 95% CI, -1.52 to
-1.07; P < .05; I2 = 71.6%), and 8-week fol-
low-up (tactile assessment: mean differ-
ence, 23.23; 95% CI, 18.64 to 27.82;
P < .05; I2 = 92.7%; air blast assessment:
mean difference, -1.51; 95% CI, -1.68 to
-1.34; P < .05; I2 = 48.6%) (Figs 4 and 5).
Study IDTactile assessment
IV, Random WMD (95% Cl) % WeightArginine vs Placebo: instantAyad (2009) 19.32 (14.64, 24.00) 18.92Fu (2009) 13.14 (8.47, 17.81) 18.96Hamlin (2009) 22.10 (16.69, 27.51) 17.00Li (2011) 17.20 (13.40, 21.00) 21.38Nathoo (2009) 22.74 (19.78, 25.70) 23.74Subtotal (I-squared = 71.5%, p = .007) 18.98 (15.48, 22.48) 100.00
Arginine vs Placebo: 3-dayAyad (2009) 19.19 (14.50, 23.88) 31.15Fu (2009) 17.41 (13.01, 21.81) 32.16Nathoo (2009) 25.24 (22.23, 28.25) 36.69Subtotal (I-squared = 80.0%, p = .007) 20.84 (15.67, 26.00) 100.00
Arginine vs Placebo: 8-weekQue (2010) 17.88 (13.74, 22.02) 28.66Docimo (2011) 27.70 (26.10, 29.30) 35.74Kakar (2012) 23.04 (21.36, 24.72) 35.59Subtotal (I-squared = 92.7%, p = .000) 23.23 (18.64, 27.82) 100.00
Arginine vs Potassium: 3-dayAyad (2009) 18.79 (14.07, 23.51) 41.08Nathoo (2009) 23.32 (20.45, 26.19) 58.92Subtotal (I-squared = 61.2%, p =.108) 21.46 (17.09, 25.83) 100.00
Arginine vs Potassium: 8-weekAyad (2009) 8.34 (6.84, 9.84) 26.14Docimo (2009) 4.75 (2.73, 6.77) 24.21Docimo (2009) 4.93 (2.61, 7.25) 22.99Kakar (2012) 9.84 (8.50, 11.18) 26.66Subtotal (I-squared = 87.5%, p = .000) 7.09 (4.64, 9.54) 100.00
Arginine vs Strontium: 8-weekHughes (2010) -7.10 (-16.51, 2.31) 17.90Docimo (2011) 10.30 (8.02, 12.58) 41.01Schi! (2011) 11.68 (9.43, 13.93) 41.09Subtotal (I-squared = 86.2%, p = .001) 7.75 (2.61, 12.90) 100.00NOTE: Weights are from random e!ects analysis
-30 Favor Control
Favor Arginine
0 30
Fig 4 Forest plot of pooled mean di!erence for tactile assessment associated with arginine-containing toothpastes versus other toothpastes. WMD, weighted mean di!erence.
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QUINTESSENCE INTERNATIONALYan et al
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Arginine-containing toothpastes versus potassium salt-containing toothpastes. Six
studies29-32,38,42 with a total of 489 partici-
pants evaluated the differences in effect
between arginine-containing toothpastes
and potassium salt-containing toothpastes.
The studies were pooled for analysis with a
random-effect model. Two studies29,38
involving 164 participants were pooled for
analysis in the 3-day follow-up, and four
studies30-32,42 involving 325 participants
were pooled for analysis in the 8-week fol-
low-up. The combined results indicated that
arginine-containing toothpastes had better
effect in the 3-day follow-up (tactile assess-
ment: mean difference, 21.46; 95% CI,
17.09 to 25.83; P < .05; I2 = 92.7%; air blast
assessment: mean difference, -1.21; 95%
CI, -1.63 to -0.78; P < .05; I2 = 83.6%) and
8-week follow-up (tactile assessment: mean
difference, 7.09; 95% CI, 4.64 to 9.54;
P < .05; I2 = 87.5%; air blast assessment:
mean difference, -0.38; 95% CI, -0.56 to
-0.20; P < .05; I2 = 83.5%) (Figs 4 and 5).
Study IDTactile assessment
IV, Random WMD (95% Cl) % WeightArginine vs Placebo: instantAyad (2009) -1.24 (-1.51, -0.97) 19.02Fu (2009) -0.88 (-1.09, -0.67) 23.35Hamlin (2009) -0.91 (-1.25, -0.57) 15.20Li (2011) -0.94 (-1.20, -0.68) 19.69Nathoo (2009) -1.27 (-1.49, -1.05) 22.75Subtotal (I-squared = 59.1%, p = .044) -1.05 (-1.23, -0.88) 100.00
Argininie vs Placebo: 3-dayAyad (2009) -1.33 (-1.58, -1.08) 29.54Fu (2009) -1.10 (-1.29, -0.91) 35.48Nathoo (2009) -1.46 (-1.65, -1.27) 34.98Subtotal (I-squared = 71.6%, p = .030) -1.29 (-1.52, -1.07) 100.00
Arginine vs Placebo: 8-weekQue (2010) -1.34 (-1.55, -1.13) 32.57Docimo (2011) -1.57 (-1.71, -1.43) 46.62Kakar (2012) -1.65 (-1.96, -1.34) 20.80Subtotal (I-squared = 48.6%, p = .143) -1.54 (-1.68, -1.34) 100.00
Arginine vs Potassium: 3-dayAyad (2009) -0.98 (-1.26, -0.70) 47.55Nathoo (2009) -1.41 (-1.61, -1.21) 52.45Subtotal (I-squared = 83.6%, p = .014) -1.21 (-1.63, -0.78) 100.00
Arginine vs Potassium: 8-weekAyad (2009) -0.59 (-0.77, -0.41) 23.60Docimo (2009) -0.23 (-0.37, -0.09) 25.49Docimo (2009) -0.20 (-0.37, -0.03) 23.86Kakar (2012) -0.50 (-0.61, -0.39) 27.04Subtotal (I-squared = 83.5%, p = .000) -0.38 (-0.56, -0.20) 100.00
Arginine vs Strontium: 8-weekHughes (2010) -0.10 (-0.35, 0.15) 29.18Docimo (2011) -0.54 (-0.68, -0.40) 35.38Schi! (2011) -0.65 (-0.79, -0.51) 35.43Subtotal (I-squared = 85.9%, p = .001) -0.45 (-0.71, -0.19) 100.00NOTE: Weights are from random e!ects analysis
-6 Favor Arginine
Favor Control
0
Fig 5 Forest plot of pooled mean di!erence for air blast assessment associated with arginine-containing toothpastes versus other toothpastes. WMD, weighted mean di!erence.
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QUINTESSENCE INTERNATIONALYan et al
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Arginine-containing toothpastes versus strontium-containing toothpastes. Three
studies26,27,37 involving 299 participants
were pooled for analysis with a random-
effect model. The combined result indi-
cated that arginine-containing toothpastes
had better effect in the 8-week follow-up
(tactile assessment: mean difference, 7.75;
95% CI, 2.61 to 12.90; P < .05; I2 = 86.2%;
air blast assessment: mean difference,
-0.45; 95% CI, -0.71 to -0.19; P < .05;
I2 = 85.9%) (Figs 4 and 5).
Sensitivity analysisSensitivity analysis showed that there was a
change in just one combined result when
arginine-containing toothpastes were com-
pared to strontium-containing toothpastes.
We excluded Hughes et al37 first, and the
pooled mean difference was 11.00 (95% CI,
9.4 to 12; P < .05; I2 = 0) by tactile assess-
ment and -0.6 (95% CI, -0.7 to 0.49;
P < .05; I2 = 12.3%) by air blast assess-
ment. When Docimo et al27 was excluded,
the pooled mean difference was 2.87 (95%
CI, -15.50 to 21.24; P > .05; I2 = 93.1%) by
tactile assessment and -0.38 (95% CI, -0.92
to 0.45; P > .05; I2 = 92.9%) by air blast
assessment. When Schiff et al26 was
excluded, the pooled mean difference was
2.22 (95% CI, -14.79 to 19.23; P > .05;
I2 = 91.9%) by tactile assessment and -0.33
(95% CI, -0.76 to 0.40; P > .05; I2 = 88.9%)
by air blast assessment. The outcomes of
other comparisons were stable in the sensi-
tivity analysis. The details of the sensitivity
analysis are presented in the Appendix
(available as supplementary material online).
GRADE analysisQuality of the evidence was downgraded
by one level and deemed as moderate
when arginine-containing toothpastes were
compared to placebo toothpastes and
potassium salt-containing toothpastes, for
the domain of “limitations in the design”
was considered as serious, owing to the
presence of high risk of bias in the alloca-
tion concealment domains in all studies and
suspected risk of bias in some other
domains. Quality of the evidence was
downgraded by two levels and deemed as
low when arginine-containing toothpastes
were compared to strontium-containing
toothpastes, since the domains of “limita-
tions in the design” and “inconsistency”
Table 3 Summary table of !ndings
OutcomesParticipants; follow-up
Limitations in the design
Incon-sistency
Indirect-ness
Impre-cision
Publication bias
Overall quality of the evidence
Arginine vs placebo
390 (5 studies), instant
Serious No No No Undetected+/+/+/-; moder-ate due to risk of bias
245 (3 studies), 3 days
Serious No No No Undetected+/+/+/-; moder-ate due to risk of bias
255 (3 studies); 8 weeks
Serious No No No Undetected+/+/+/-; moder-ate due to risk of bias
Arginine vs potassium
164 (2 studies); 3 days
Serious No No No Undetected+/+/+/-; moder-ate due to risk of bias
325 (4 studies); 8 weeks
Serious No No No Undetected+/+/+/-; moder-ate due to risk of bias
Arginine vs strontium
299 (3 studies); 8 weeks
Serious Serious No No Undetected
+/+/-/-; low due to risk of bias and inconsis-tency
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
10
were considered as serious, due to high
risk of bias in the allocation concealment
domain and suspected risk of bias in some
other domains and the unstable sensitivity
analysis. The result is presented in a sum-
mary table of findings (Table 3).
DISCUSSION
This systematic review indicates that argi-
nine-containing toothpastes have a superior
desensitizing effect for reducing DH in con-
trast with placebo toothpastes and potas-
sium salt-containing toothpastes, but may
not be better than strontium-containing
toothpastes owing to the inconsistent
results. Previously published systematic
reviews only supported the use of potas-
sium salt-containing toothpastes in reducing
DH, while laser therapy and oxalates-con-
taining toothpastes failed to be associated
with the reduction of DH.44-46 Arginine-con-
taining toothpastes seem to be an effective
option for clinicians to manage DH.
It can be observed that the participants
in the placebo toothpastes groups also had
better scores compared to the baseline
data in measuring the pain of DH, and it
has been reported that strong placebo
effects could be observed that made dem-
onstration of clinical efficacy of any treat-
ment difficult.11 Therefore, the placebo
effects may have contributed partially to the
desensitizing efficacy. It should be noted
that potassium salt-containing toothpastes
acquired a desensitizing effect after 4 to 8
weeks of application.40 Thus, the control
groups of potassium salt-containing tooth-
pastes in short-term trials may just act as
placebo comparisons. The outcomes of DH
involve measuring a subjective phenome-
non as pain either by tactile or air blast
assessment, which may be influenced by
many factors.47 It seemed that tactile
assessment could provide more accurate
data than the air blast assessment, as in the
tactile assessment the force exerted on the
testing tooth began at 10 g and increased
by 10 g increments until the participants
reported pain sensation. However, in the air
blast assessment, the measurement relied
heavily on the participants’ perception of
pain, which was apparently more objective.
Though comparisons were separated
into several sections according to the meth-
odologic and clinical aspects of this review,
the statistical heterogeneity was still high in
most of the combined results, which may
imply that some as-yet-unidentified factors
still exist. The heterogeneity could be attrib-
uted to the following reasons: First, the risk
of bias in the included studies varied
between studies, especially in the domain of
allocation concealment, which was a weak-
ness of all included studies. Second, the
ingredients of the comparative toothpastes
may differ from each other due to different
manufacturers and the types of products,
because it was reported that even sodium
fluoride acquired desensitizing effects, and
placebo effect needs to be considered.48,49
Third, there was a wide range in partici-
pants’ age across the studies and the trial
settings were in various countries, and age,
gender, psychological aspects, and even
religion could be factors influencing the
sensation of pain.50 Sensitivity analysis
revealed unstable results when arginine-
containing toothpastes were compared to
strontium-containing toothpastes. It seemed
that Hughes et al37 was the trial causing het-
erogeneity, because I2 dropped significantly
when this trial was excluded. The heteroge-
neity in this comparison may be attributed to
the fact that Hughes and colleagues mea-
sured the outcome by the mean change
from baseline. Both arginine-containing
toothpastes and strontium-containing tooth-
pastes were based on the mechanism of
occluding opened dentinal tubules, there-
fore similar desensitizing effects seemed
reasonable. The GRADE analysis showed
that the strength of evidence was low in this
comparison, thus both clinical and basic
research is needed to illustrate which tooth-
pastes perform better.
In addition, we noticed that most studies
reported participants’ and investigators’
unawareness of study-group status, but in
fact arginine-containing toothpastes had a
faintly yellow color, which differed slightly
from that of the control groups, a difference
that might be observed by the participants
or investigators and could have some influ-
ence on the blinding sequence. The double
dummy design may be more appropriate.
As all the trials included in this review were
doi: 10.3290/j.qi.a30177
QUINTESSENCE INTERNATIONALYan et al
11
sponsored by the manufacturers, conflicts
of interest may need to be taken into con-
sideration, which could contribute to publi-
cation bias. Also, most of the trials included
in this systematic review were “real world
research”, which means that the compli-
ance of the participants could vary and may
influence the final results.51
Limitations of the reviewBecause no study reported a cost-effect
analysis, this issue could not be assessed.
However, arginine-containing toothpastes
are often more expensive than other mar-
keted toothpastes, therefore the use of this
toothpaste for DH therapy may need to be
supported by a better quality of evidence.
Implication for researchThe GRADE analysis suggested that the
strength of evidence was moderate when
arginine-containing toothpastes were com-
pared to placebo toothpastes, which illus-
trated that the reduction of DH by
arginine-containing toothpastes was likely
beyond a placebo effect. The strength of
evidence was moderate when comparing
arginine-containing toothpastes to potas-
sium salt-containing toothpastes, which
have been the standard dentifrice when
dealing with DH. Thus, arginine-containing
toothpastes could become a first-line choice
for DH treatment. Further trials to compare
arginine-containing toothpastes with pla-
cebo toothpastes seem unnecessary, and
more attention should be focused on the
comparison between arginine-containing
toothpastes and other positive control tooth-
pastes. Since there is a risk of bias in the
design, especially in the domain of alloca-
tion concealment, which was the main
weakness causing the downgraded level of
evidence, design of future trials should pay
attention to this limitation. Through the litera-
ture search, we found two studies35,36 com-
paring arginine-containing toothpastes with
stannous fluoride-containing toothpastes,
the outcomes of which were measured by
air blast assessment with Schiff scale and
VAS. Because of different duration of the
follow-up, they cannot be combined in the
meta-analysis. However, the results of these
two studies showed that stannous fluoride-
containing toothpastes might acquire better
effects than arginine-containing toothpastes
for relieving DH. The clinical trials compar-
ing arginine-containing toothpastes with
another novel desensitizing toothpaste con-
taining calcium sodium phosphosilicate
were not found through the literature search.
It was reported that calcium sodium phos-
phosilicate-containing toothpastes could
also mimic the natural process of the saliva
and were effective in dealing with DH,52-54
thus future trials are needed to ascertain
which types of toothpastes are better.
CONCLUSION
Overall, the currently available evidence
suggests that arginine-containing tooth-
pastes are able to reduce DH. However,
they may not have a superior desensitizing
effect compared to toothpastes with a simi-
lar mechanism, and it was not possible to
reach firm conclusions based on current
studies. More well-designed clinical trials,
especially independent studies without
commercial involvement, are needed to
confirm their effect.
ACKNOWLEDGMENTS
The authors thank Professor Taixiang Wu and Professor Guanjian Liu from Chinese Evidence-based Centre/Chi-nese Cochrane Centre for the methodologic and statis-tical guidance, and Dr Xiaoxia Feng from West China School of Stomatology for critical review of this article. This systematic review was supported by Sichuan Uni-versity Innovating Training Project 2012 (no. 20120248).
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Appendix 1 Modi!ed search strategy in Medline (via OVID, 1996 to October 2012)
Search strategy Results
#1 randomized controlled trial.pt. 247660
#2 controlled clinical trial.pt. 40401
#3 randomized.ab. 201383
#4 placebo.ab. 94333
#5 clinical trials as topic.sh. 81780
#6 randomly.ab. 137670
#7 trial.ti. 76098
#8 1 or 2 or 3 or 4 or 5 or 6 or 7 558895
#9 exp animals/not humans.sh. 1689956
#10 8 not 9 509602
#11 exp dentin sensitivity/ 1181
#12 exp toothpastes/ 1373
#13 ((dentin$ or tooth or teeth) adj5 (sensitiv$ or hypersensitiv$ or hyper-sensitiv$)).mp. 1605
#14 toothpast$.mp. 2032
#15 dentifrice$.mp. 1370
#16 11 or 13 1605
#17 12 or 14 or 15 2937
#18 16 and 17 244
#19 8 and 18 118
.ab., a word in an abstract; .mpm, a search of title, original title, name of substance word, and subject heading word;
.pt., a Publication Type term; .sh., a Medical Subject Heading (MeSH) term.
Appendix 2 Sensitivity analysis: arginine vs placebo: instant assessment
ItemTactile assessmentMean difference (95% CI)
Air blast assessmentMean difference (95% CI)
Original estimate 18.98 (15.07 to 23.80) -1.05 (-1.23 to -0.88)
Exclude Ayad et al29 18.87 (14.46 to 23.28) -1.01 (-1.21 to -0.81)
Exclude Fu et al33 20.39 (17.60 to 23.19) -1.11 (-1.30 to -0.92)
Exclude Hamlin et al34 18.31 (14.19 to 22.42) -1.08 (-1.28 to -0.87)
Exclude Li et al28 19.43 (15.07 to 23.80) -1.08 (-1.30 to -0.86)
Exclude Nathoo et al38 17.77 (14.33 to 21.21) -0.99 (-1.15 to -0.82)
Exclude Ayad et al29 and Fu et al33 20.67 (16.96 to 24.38) -1.06 (-1.31 to -0.82)
Exclude Ayad et al29 and Hamlin et al34 17.92 (12.37 to 23.46) -1.03 (-1.28 to -0.78)
Exclude Ayad et al29 and Li et al28 19.42 (13.25 to 25.49) -1.03 (-1.30 to -0.76)
Exclude Ayad et al29 and Nathoo et al38 17.31 (12.70 to 21.92) -0.90 (-1.05 to -0.75)
Exclude Fu et al33 and Hamlin et al34 19.95 (16.41 to 23.50) -1.16 (-1.36 to -0.95)
Exclude Fu et al33 and Li et al28 21.82 (19.55 to 24.09) -1.17 (-1.37 to -0.97)
Exclude Fu et al33 and Nathoo et al38 19.01 (16.32 to 21.70) -1.04 (-1.25 to -0.83)
Exclude Hamlin et al34 and Li et al28 18.60 (12.94 to 24.27) -1.12 (-1.38 to -0.86)
Exclude Hamlin et al34 and Nathoo et al38 16.60 (13.27 to 19.93) -1.01 (-1.22 to -0.80)
Exclude Li et al28 and Nathoo et al38 18.07 (12.90 to 23.24) -1.01 (-1.24 to -0.77)
Combine Ayad et al29 and Fu et al33 16.23 (10.17 to 22.28) -1.05 (-1.40 to -0.70)
Combine Ayad et al29 and Hamlin et al34 20.51 (16.97 to 24.05) -1.09 (-1.41 to -0.77)
continued on next page
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Appendix 4 Sensitivity analysis: arginine vs potassium: 8-week follow-up
ItemTactile assessmentMean difference (95% CI)
Air blast assessmentMean difference (95% CI)
Original estimate 7.09 (4.64 to 9.54) -0.38 (-0.58 to -0.20)
Exclude Ayad et al30 6.59 (2.90 to 10.28) -0.32 (-0.52 to -0.11)
Exclude Docimo et al32 7.87 (5.42 to 10.32) -0.43 (-0.64 to -0.22)
Exclude Docimo et al31 7.74 (5.06 to 10.42) -0.44 (-0.64 to -0.23)
Exclude Kakar et al42 6.11 (3.57 to 8.65) -0.34 (-0.57 to -0.10)
Combine Ayad et al30 and Docimo et al32 6.61 (3.10 to 10.13) -0.41 (-0.76 to -0.05)
Combine Ayad et al30 and Docimo et al31 6.76 (3.42 to 10.09) -0.39 (-0.78 to -0.01)
Combine Ayad et al30 and Kakar et al42 9.13 (7.66 to 10.60) -0.53 (-0.02 to -0.43)
Combine Docimo et al32 and Docimo et al31 4.83 (3.30 to 6.35) -0.22 (-0.33 to -0.11)
Combine Docimo et al32 and Kakar et al42 7.35 (2.37 to 12.34) -0.37 (-0.63 to -0.10)
Combine Docimo et al31 and Kakar et al42 7.48 (2.67 to 12.29) -0.36 (-0.65 to -0.06)
Appendix 3 Sensitivity analysis: arginine vs placebo: 3-day and 8-week follow-up
Item
Tactile assessment Mean difference (95% CI)
Air blast assessment Mean difference (95% CI)
3-day 8-week 3-day 8-week
Original estimate 20.84 (15.67 to 26.00)
23.23 (18.64 to 27.82)
-1.29 (-1.52 to -1.07)
-1.51 (-1.68 to -1.34)
Exclude Ayad et al29 21.50 (13.83 to 29.16)
- -1.28 (-1.63 to -0.93)
-
Exclude Fu et al33 22.49 (16.59 to 28.40)
- -1.41 (-1.57 to -1.26)
-
Exclude Nathoo et al38 18.24 (15.03 to 21.45)
- -1.20 (-1.42 to -0.98)
-
Exclude Que et al39 - 25.38 (20.81 to 29.94)
- -1.58 (-1.71 to -1.46)
Exclude Docimo et al27 - 20.82 (15.81 to 25.83)
- -1.47 (-1.78 to -1.17)
Exclude Kakar et al43 - 22.98 (13.37 to 32.60)
- -1.47 (-1.69 to -1.25)
Combine Ayad et al29 and Li et al28 18.04 (15.09 to 21.00) -1.09 (-1.38 to -0.79)
Combine Ayad et al29 and Nathoo et al38 21.53 (18.33 to 24.74) -1.26 (-1.43 to -1.09)
Combine Fu et al33 and Hamlin et al34 17.51 (8.72 to 27.52) -0.88 (-1.09 to -0.67)
Combine Fu et al33 and Li et al28 15.40 (11.45 to 19.36) -0.90 (-1.07 to -0.74)
Combine Fu et al33 and Nathoo et al38 18.12 (8.72 to 27.52) -0.89 (-1.07 to -0.71)
Combine Hamlin et al34 and Li et al28 19.26 (14.52 to 24.00) -0.93 (-1.14 to -0.72)
Combine Hamlin et al34 and Nathoo et al38 22.59 (19.99 to 25.19) -1.11 (-1.46 to -0.77)
Combine Li et al28 and Nathoo et al38 20.10 (14.68 to 25.53) -1.11 (-1.44 to -0.79)
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