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

2

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.

doi: 10.3290/j.qi.a30177


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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


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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


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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


Docimo et al27 RCT 20–69 Italy 50/50/50 8% arginine, calcium carbon-ate/8% strontium acetate/fluoride


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


Hughes et al37 RCT 26.6 ± 10.72 26.3 ± 9.57

Ireland 39/39 8% strontium acetate/8% argi-nine, calcium carbonate


Que et al39 RCT 35–78 China 40/40/41 *8% arginine, calcium carbon-ate/calcium carbonate + fluoride


Ayad et al30 RCT 18–66 Canada 38/39 8% arginine, calcium carbon-ate/2% potassium ion


Ayad et al29 RCT 18–66 Canada 41/40/39 8% arginine, calcium carbon-ate/2% potassium ion/fluoride


Cummins41 RCT NR USA 35/35 4% arginine, calcium carbon-ate/calcium carbonate + fluoride


Docimo et al31 RCT 42.2 ± 10.6 Italy 40/40 8% arginine, calcium carbon-ate/2% potassium ion


Docimo et al32 RCT 19–70 Italy 40/40 8% arginine, calcium carbon-ate/2% potassium ion


Fu et al33 RCT 25–70 China 41/41/40 *8% arginine, calcium carbon-ate/ calcium carbonate + fluoride


Nathoo et al38 RCT 18–74 USA 42/41/42 8% arginine, calcium carbon-ate/2% potassium ion/fluoride


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


NR, not reported; *One of the arginine-containing toothpastes was the high cleaning calcium carbonate type.

doi: 10.3290/j.qi.a30177


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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



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


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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;



-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.

doi: 10.3290/j.qi.a30177


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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;



-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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9

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


255 (3 studies); 8 weeks


Arginine vs potassium

164 (2 studies); 3 days




Arginine vs strontium


Serious Serious No No Undetected

+/+/-/-; low due to risk of bias and inconsis-tency

doi: 10.3290/j.qi.a30177


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


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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doi: 10.3290/j.qi.a30177


14

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

doi: 10.3290/j.qi.a30177


15

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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arginine containing toothpastes for dentin hypersensitivity systematic review and meta analysis.pdf

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