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Q U I N T E S S E N C E I N T E R N AT I O N A L

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 aficts 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 rmer conclusions regarding the use of arginine-containing toothpastes for management of DH. Method and Materials: A protocol 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 controlled trials that assessed the efcacy 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 proler (version 3.6). Results: Fourteen randomized controlled studies with different risk of bias were included in the meta-analysis, all evaluated 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-containing 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 comparison 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 conrm the efcacy. (doi: 10.3290/j.qi.a30177)

Key words: arginine, dentin sensitivity, GRADE analysis, meta-analysis, systematic review, toothpaste

Research Student, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P.R. China.

Dentin hypersensitivity (DH) can be dened as short, sharp pain from exposed dentin in response to various stimuli, including thermal, evaporative, tactile, and osmotic irritation, 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 people with periodontal disease.1-3 Furthermore, the prevalence of DH is likely to increase as the adult population lives longer 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

Associate Professor, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P.R. China.

Lecturer, Chinese Evidence-Based Medicine Centre/ Chinese Cochrane Centre, West China Hospital of Sichuan University, Chengdu, P.R. China.

Professor, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P.R. China.

Correspondence: Dr Yu Li, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd section of Renmin South Road, Chengdu, 610041 P.R. China. Email: yuli@scu.edu.cn Supplementary material (Appendix 1 to 4) is included in the online version, available at http://qi.quintessenz.de

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Fig 1 Clinical image of sensitive anterior tooth without apparent gingival recession.

Fig 2 Clinical image of sensitive anterior teeth with extensive gingival recession.

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 uid movement within the dentin tubules, which induces sharp pain responses in the nerve bers.8-10 To date, a variety of interventions have been put into practice for managing the condition, but DH continues to be a problem. It seemed that oral care professionals felt condent diagnosing DH, but not treating it, and there was considerable uncertainty in the treatment, due to a shortage of effective methods against DH. 11,12 Most treatments were based on two primary approaches. One was to interfere with the nerve transmission, for instance, by applying potassium ion. The other was to occlude the dentinal tubules, for example by using oxalates and stannous uoride.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-containing toothpastes were rst reported to have an anti-sensitivity effect in 2002. The explanation was that the combination of arginine bicarbonate and calcium carbonate was able to mimic natural desensitizing processes of the saliva, and could be deposited 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 challenge.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 efcacy, and a rigorous systematic evaluation of the existing studies has yet to be reported. Clinical data on the efcacy 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 relative effect of arginine-containing toothpastes compared to other types of toothpastes for relieving the pain of DH through the meta-analysis of qualied randomized controlled trials.

METHOD AND MATERIALS


This review was planned, conducted, and reported in adherence to PRISMA (Preferred 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 review


Trials that met the following criteria were included:

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Types of studies Randomized controlled trial (RCT). The phase 1 stages of also included. randomized cross-over studies were

Identication

CENTRAL: 251 MEDLINE: 118 EMBASE: 92 Title/abstract: 156 Duplicates: 305

Types of participants People with selfreported tooth hypersensitivity, conrmed in the clinical evaluation. Post-restorative hypersensitivity studies were excluded.

Types of intervention Arginine-containing toothpastes. Primary outcomes Changes or nal scores in intensity of pain using quantitative pain scale. Secondary outcomes Adverse outcomes including any unexpected or unpredicted events related to the intervention, especially the serious uation of the treatment. adverse events leading to discontinTypes of outcome measurements:

Screening

From reference list: 3

Excluded: 129 -83 From MEDLINE/CENTRAL -46 From EMBASE

Eligibility

Potentially relevant articles: 30

Search methods for identi cation of studies


After the development of a protocol, paper citations were obtained through an electronic search of databases including MEDLibrary), EMBASE (via OVID), and China National Knowledge Infrastructure (CNKI) (all terminated by October 14, 2012), without language limitation. Hand-searching of bibliographic reference lists of published primary and review studies was also performed (Fig 3). The search strategy included MeSH terms and free-text words: dentin sensitivity (MeSH Term), toothpastes (MeSH Term), dentin hypersensitivity, dentifrice*, and toothpast*. The Cochrane Highly Sensitive Search Strategy (sensitivity- and precision-maximizing version) was adopted.19 Two reviewers assessed independently the titles and abstracts of studies identied 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 eligibility criteria were excluded. LINE (via OVID), CENTRAL (via Cochrane

Qualitative synthesis: 18 Included

Excluded: 12 -review, letter, opinion: 8 -animal or basic research: 3 -without appropriate comparison: 1

Included in the meta-analysis: 14

Fig 3 Flow diagram of the literature search and selection process.

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 outcome data, and selective outcome reporting.19 Conicts between reviewers were resolved by discussion or turning to a third person for judgment.

Data extraction Assessment of risk of bias in included studies


Two reviewers assessed the included studies independently following the domainA 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

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of participants, intervention and comparison, duration of the trials, and outcome measurement.

might change the estimate; one of the domains was not fullled. Low quality further research is likely to have an important impact on our condence in the estimate of effect and is likely to change the estimate; two of the domains were not fullled. Very low quality we are uncertain about the estimate; three of the domains were not fullled. GRADEproler (version 3.6) was adopted for the assessment.25

Data synthesis
Data 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 heterogeneity was deemed as high if I2 > 50% and P < .10. Funnel plots and the Beggs rank correlation test, the generic means of displaying 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 suggest a publication bias.20,21 Sensitivity analysis 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 consecutively from the analysis, and examined whether there were changes to the combined effects.

RESULTS
Results of the search
Electronic searches from all sources retrieved 156 unique citations. By screening titles and abstracts, 129 unrelated citations were excluded. Three articles not previously found through electronic search were discovered in the references of citations.26-28 We pared the remaining 30 citations 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 qualied studies26-34,37-39,42,43 were included in the metaanalysis according to the inclusion criteria (Fig 3).

Grading of the evidence


The GRADE approach (Grading of Recommendations 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 ve 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 denitions of quality of the evidence24: High quality further research is unlikely to change our condence in the estimate of effect. There are no known or suspected reporting biases; all domains fullled. Moderate quality further research is likely to have an important impact on our condence in the estimate of effect and

Study description
All 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 study 41 assessed 4% arginine-containing toothpastes and 17 studies evaluated 8% arginine-containing toothpastes. Two studies33,39 evaluated both the high cleaning calcium carbonate type and the conventional type, while other studies evaluated the conventional type. The comparative interventions were diverse, including placebo, potassium salt-, stannous uoride-, and strontium- con-

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Table 1

Studies included in the qualitative synthesis Number of participants 46/42 34/40 50/50/50 Outcome measurement Tactile, air blast Tactile, air blast Tactile, air blast

Study Kakar et al42 Kakar et al43 Docimo et al27

Method RCT RCT RCT

Age 1853 2556 2069

Country India India Italy

Intervention/comparison 8% arginine, calcium carbonate/2% potassium ion 8%arginine, calcium carbonate/ uoride 8% arginine, calcium carbonate/8% strontium acetate/ uoride Stannous uoride/8% arginine, calcium carbonate Stannous uoride/8% arginine, calcium carbonate 8% strontium acetate/ uoride/8% arginine, calcium carbonate 8% arginine, calcium carbonate/8% strontium acetate 8% strontium acetate/8% arginine, calcium carbonate *8% arginine, calcium carbonate/calcium carbonate + uoride 8% arginine, calcium carbonate/2% potassium ion 8% arginine, calcium carbonate/2% potassium ion/uoride 4% arginine, calcium carbonate/calcium carbonate + uoride 8% arginine, calcium carbonate/2% potassium ion 8% arginine, calcium carbonate/2% potassium ion *8% arginine, calcium carbonate/ calcium carbonate + uoride 8% arginine, calcium carbonate/2% potassium ion/uoride 8% arginine, calcium carbonate/uoride 8% arginine, calcium carbonate/uoride

Duration 8 weeks 8 weeks 8 weeks

He et al36 He et al35 Li et al28

RCT RCT RCT

2062 1856 1861

Canada China USA

40/41 40/38 50/50/50

3 days 2 weeks 7 days

Air blast Air blast Tactile, air blast

Schiff et al26 Hughes et al37 Que et al39

Crossover RCT RCT

1960 26.6 10.72 26.3 9.57 3578

USA Ireland China

61/60 39/39 40/40/41

16 weeks 8 weeks 8 weeks

Tactile, air blast Tactile, air blast Tactile, air blast

Ayad et al30 Ayad et al29 Cummins41

RCT RCT RCT

1866 1866 NR

Canada Canada USA

38/39 41/40/39 35/35

8 weeks 3 days 2 weeks

Tactile, air blast Tactile, air blast Tactile, air blast

Docimo et al31 Docimo et al32 Fu et al33

RCT RCT RCT

42.2 10.6 1970 2570

Italy Italy China

40/40 40/40 41/41/40

8 weeks 8 weeks 3 days

Tactile, air blast Tactile, air blast Tactile, air blast

Nathoo et al38 Hamlin et al34 Schiff et al40

RCT RCT RCT

1874 2766 1960

USA USA USA

42/41/42 22/23 32/36

3 days Instant 12 weeks

Tactile, air blast Tactile, air blast Tactile, air blast

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

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-

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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 brushing 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 studies35,36 measured the pain by air blast assessment with the Schiff scale and Visual Analog Scale (VAS). No adverse events were observed (Table 1).

measure of blinding, only two studies28,37 clearly described the procedure to secure the blinding of both participants and outcome 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 analysis to deal with the missing data, while the other two studies did not mention the methods to manage the missing data. Two studies 42,43 just reported the number of participants who completed the trial, but did not mention whether there was lost follow-up. Because of limited number of included studies, funnel plots were not performed. The other elds of risk of bias were acceptable (Table 2).

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 concealment, for no study no documented study the

Effects of the intervention


Arginine-containing toothpastes versus placebo toothpastes. Eight studies27-29,33,34,38,39,43 involving 645 participants evaluated the difference between the effect of arginine-containing toothpastes and pla-

sequence.

And

adequately

described the method of randomization. All studies found no signicant difference in the baseline characteristics between groups. Though every study mentioned the

Table 2

Risk of bias of included studies Domain

Study Kakar et al42 Kakar et al43 Docimo et al He et al36 He et al35 Li et al


28 27

Sequence generation Un Un Un Un Un Un Un Un Un Un Un
41

Allocation concealment N N N N N N N N N N N N N N N N N N

Blinding participants Y Y Y N N Y Y Y Un Y Y Y Y Y Y Y Un Y

Blinding assessors Un Un Un Y Y Y Un Y Un Un Un Un Un Un Un Un Un Un

Free of incomplete data bias Un Un Y Y Un Y Un Y Y Y Y Y Y Y Y Y Y Y

Free of selective reporting Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Schiff et al26 Hughes et al37 Que et al


39

Ayad et al30 Ayad et al29 Cummins et al Docimo et al31 Docimo et al32 Fu et al


33

Un Un Un Un Un Un Un

Nathoo et al38 Hamlin et al


34

Schiff et al40

N, high risk of bias; Un, unclear risk of bias; Y, low risk of bias.

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cebo toothpastes. Five studies28,29,33,34,38 involving 390 participants in the instant assessment, three studies
29,33,38

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 follow-up (tactile assessment: mean difference, 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).

involving

245 participants in the 3-day follow-up, and three studies27,39,43 involving 255 participants 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 better effect in the instant assessment (tactile assessment: mean difference, 18.98; 95% CI, 15.48 to 22.48; P < .05; I2 = 71.5%; air

Study ID Arginine vs Placebo: instant Ayad (2009) Fu (2009) Hamlin (2009) Li (2011) Nathoo (2009) Subtotal (I-squared = 71.5%, p = .007) Arginine vs Placebo: 3-day Ayad (2009) Fu (2009) Nathoo (2009) Subtotal (I-squared = 80.0%, p = .007) Arginine vs Placebo: 8-week Que (2010) Docimo (2011) Kakar (2012) Subtotal (I-squared = 92.7%, p = .000) Arginine vs Potassium: 3-day Ayad (2009) Nathoo (2009) Subtotal (I-squared = 61.2%, p =.108) Arginine vs Potassium: 8-week Ayad (2009) Docimo (2009) Docimo (2009) Kakar (2012) Subtotal (I-squared = 87.5%, p = .000) Arginine vs Strontium: 8-week Hughes (2010) Docimo (2011) Schi (2011) Subtotal (I-squared = 86.2%, p = .001)
NOTE: Weights are from random eects analysis

Tactile assessment IV, Random

WMD (95% Cl) 19.32 (14.64, 24.00) 13.14 (8.47, 17.81) 22.10 (16.69, 27.51) 17.20 (13.40, 21.00) 22.74 (19.78, 25.70) 18.98 (15.48, 22.48) 19.19 (14.50, 23.88) 17.41 (13.01, 21.81) 25.24 (22.23, 28.25) 20.84 (15.67, 26.00) 17.88 (13.74, 22.02) 27.70 (26.10, 29.30) 23.04 (21.36, 24.72) 23.23 (18.64, 27.82) 18.79 (14.07, 23.51) 23.32 (20.45, 26.19) 21.46 (17.09, 25.83) 8.34 (6.84, 9.84) 4.75 (2.73, 6.77) 4.93 (2.61, 7.25) 9.84 (8.50, 11.18) 7.09 (4.64, 9.54) -7.10 (-16.51, 2.31) 10.30 (8.02, 12.58) 11.68 (9.43, 13.93) 7.75 (2.61, 12.90)

% Weight 18.92 18.96 17.00 21.38 23.74 100.00 31.15 32.16 36.69 100.00 28.66 35.74 35.59 100.00 41.08 58.92 100.00 26.14 24.21 22.99 26.66 100.00 17.90 41.01 41.09 100.00

-30

Favor Control

Favor Arginine

30

Fig 4 Forest plot of pooled mean dierence for tactile assessment associated with arginine-containing toothpastes versus other toothpastes. WMD, weighted mean dierence.

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Tactile assessment Study ID IV, Random Arginine vs Placebo: instant Ayad (2009) Fu (2009) Hamlin (2009) Li (2011) Nathoo (2009) Subtotal (I-squared = 59.1%, p = .044) Argininie vs Placebo: 3-day Ayad (2009) Fu (2009) Nathoo (2009) Subtotal (I-squared = 71.6%, p = .030) Arginine vs Placebo: 8-week Que (2010) Docimo (2011) Kakar (2012) Subtotal (I-squared = 48.6%, p = .143) Arginine vs Potassium: 3-day Ayad (2009) Nathoo (2009) Subtotal (I-squared = 83.6%, p = .014) Arginine vs Potassium: 8-week Ayad (2009) Docimo (2009) Docimo (2009) Kakar (2012) Subtotal (I-squared = 83.5%, p = .000) Arginine vs Strontium: 8-week Hughes (2010) Docimo (2011) Schi (2011) Subtotal (I-squared = 85.9%, p = .001)
NOTE: Weights are from random eects analysis

WMD (95% Cl) -1.24 (-1.51, -0.97) -0.88 (-1.09, -0.67) -0.91 (-1.25, -0.57) -0.94 (-1.20, -0.68) -1.27 (-1.49, -1.05) -1.05 (-1.23, -0.88) -1.33 (-1.58, -1.08) -1.10 (-1.29, -0.91) -1.46 (-1.65, -1.27) -1.29 (-1.52, -1.07) -1.34 (-1.55, -1.13) -1.57 (-1.71, -1.43) -1.65 (-1.96, -1.34) -1.54 (-1.68, -1.34) -0.98 (-1.26, -0.70) -1.41 (-1.61, -1.21) -1.21 (-1.63, -0.78) -0.59 (-0.77, -0.41) -0.23 (-0.37, -0.09) -0.20 (-0.37, -0.03) -0.50 (-0.61, -0.39) -0.38 (-0.56, -0.20) -0.10 (-0.35, 0.15) -0.54 (-0.68, -0.40) -0.65 (-0.79, -0.51) -0.45 (-0.71, -0.19)

% Weight 19.02 23.35 15.20 19.69 22.75 100.00 29.54 35.48 34.98 100.00 32.57 46.62 20.80 100.00 47.55 52.45 100.00 23.60 25.49 23.86 27.04 100.00 29.18 35.38 35.43 100.00

-6

Favor Arginine

Favor Control

Fig 5 Forest plot of pooled mean dierence for air blast assessment associated with arginine-containing toothpastes versus other toothpastes. WMD, weighted mean dierence.

Arginine-containing toothpastes versus potassium salt-containing toothpastes. Six studies29-32,38,42 with a total of 489 participants 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 studies 29,38 involving 164 participants were pooled for analysis in the 3-day follow-up, and four studies
30-32,42

low-up. The combined results indicated that arginine-containing toothpastes had better effect in the 3-day follow-up (tactile assessment: 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).

involving 325 participants

were pooled for analysis in the 8-week fol-

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Table 3

Summary table of Participants; follow-up 390 (5 studies), instant

ndings Inconsistency No Indirectness No Imprecision No Publication bias Undetected Overall quality of the evidence +/+/+/-; moderate due to risk of bias +/+/+/-; moderate due to risk of bias +/+/+/-; moderate due to risk of bias +/+/+/-; moderate due to risk of bias +/+/+/-; moderate due to risk of bias +/+/-/-; low due to risk of bias and inconsistency

Outcomes

Limitations in the design Serious

Arginine vs placebo

245 (3 studies), 3 days 255 (3 studies); 8 weeks 164 (2 studies); 3 days 325 (4 studies); 8 weeks

Serious

No

No

No

Undetected

Serious

No

No

No

Undetected

Arginine vs potassium

Serious

No

No

No

Undetected

Serious

No

No

No

Undetected

Arginine vs strontium

299 (3 studies); 8 weeks

Serious

Serious

No

No

Undetected

Arginine-containing toothpastes versus strontium-containing toothpastes. Three studies 26,27,37 involving 299 participants were pooled for analysis with a randomeffect model. The combined result indicated 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).

assessment.

When

Schiff

et

al 26

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 sensitivity analysis. The details of the sensitivity analysis are presented in the Appendix (available as supplementary material online).

GRADE analysis
Quality 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 allocation 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 limitations in the design and inconsistency

Sensitivity analysis
Sensitivity analysis showed that there was a change in just one combined result when arginine-containing toothpastes were compared to strontium-containing toothpastes. We excluded Hughes et al37 rst, and the pooled mean difference was 11.00 (95% CI, 9.4 to 12; P < .05; I2 = 0) by tactile assessment and -0.6 (95% CI, -0.7 to 0.49; P < .05; I2 = 12.3%) by air blast assessment. 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

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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 summary table of ndings (Table 3).

Though comparisons were separated into several sections according to the methodologic 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-unidentied factors still exist. The heterogeneity could be attributed 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 weakness 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 uoride acquired desensitizing effects, and placebo effect needs to be considered.48,49 Third, there was a wide range in participants age across the studies and the trial settings were in various countries, and age, gender, psychological aspects, and even religion could be factors inuencing the sensation of pain.50 Sensitivity analysis revealed unstable results when argininecontaining toothpastes were compared to strontium-containing toothpastes. It seemed that Hughes et al37 was the trial causing heterogeneity, because I2 dropped signicantly when this trial was excluded. The heterogeneity in this comparison may be attributed to the fact that Hughes and colleagues measured the outcome by the mean change from baseline. Both arginine-containing toothpastes and strontium-containing toothpastes were based on the mechanism of occluding opened dentinal tubules, therefore 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 toothpastes 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 inuence on the blinding sequence. The double dummy design may be more appropriate. As all the trials included in this review were

DISCUSSION
This systematic review indicates that arginine-containing toothpastes have a superior desensitizing effect for reducing DH in contrast with placebo toothpastes and potassium 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 potassium salt-containing toothpastes in reducing DH, while laser therapy and oxalates-containing toothpastes failed to be associated with the reduction of DH.44-46 Arginine-containing 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 demonstration of clinical efcacy of any treatment difficult.11 Therefore, the placebo effects may have contributed partially to the desensitizing efcacy. 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 toothpastes in short-term trials may just act as placebo comparisons. The outcomes of DH involve measuring a subjective phenomenon as pain either by tactile or air blast assessment, which may be inuenced 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.

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sponsored by the manufacturers, conicts of interest may need to be taken into consideration, which could contribute to publication bias. Also, most of the trials included in this systematic review were real world research, which means that the compliance of the participants could vary and may inuence the nal results.51

effects than arginine-containing toothpastes for relieving DH. The clinical trials comparing arginine-containing toothpastes with another novel desensitizing toothpaste containing calcium sodium phosphosilicate were not found through the literature search. It was reported that calcium sodium phosphosilicate-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.

Limitations of the review


Because no study reported a cost-effect analysis, this issue could not be assessed. However, arginine-containing toothpastes are often more expensive than other marketed toothpastes, therefore the use of this toothpaste for DH therapy may need to be supported by a better quality of evidence.

CONCLUSION
Overall, the currently available evidence suggests that arginine-containing toothpastes are able to reduce DH. However, they may not have a superior desensitizing effect compared to toothpastes with a similar mechanism, and it was not possible to reach rm conclusions based on current studies. More well-designed clinical trials, especially independent studies without commercial involvement, are needed to conrm their effect.

Implication for research


The GRADE analysis suggested that the strength of evidence was moderate when arginine-containing toothpastes were compared to placebo toothpastes, which illustrated 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 potassium salt-containing toothpastes, which have been the standard dentifrice when dealing with DH. Thus, arginine-containing toothpastes could become a rst-line choice for DH treatment. Further trials to compare arginine-containing toothpastes with placebo toothpastes seem unnecessary, and more attention should be focused on the comparison between arginine-containing toothpastes and other positive control toothpastes. Since there is a risk of bias in the design, especially in the domain of allocation concealment, which was the main weakness causing the downgraded level of evidence, design of future trials should pay attention to this limitation. Through the literature search, we found two studies35,36 comparing arginine-containing toothpastes with stannous uoride-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 uoridecontaining toothpastes might acquire better

ACKNOWLEDGMENTS
The authors thank Professor Taixiang Wu and Professor Guanjian Liu from Chinese Evidence-based Centre/Chinese Cochrane Centre for the methodologic and statistical guidance, and Dr Xiaoxia Feng from West China School of Stomatology for critical review of this article. This systematic review was supported by Sichuan University Innovating Training Project 2012 (no. 20120248).

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32. Docimo R, Montesani L, Maturo P, et al. Comparing the ecacy in reducing dentin hypersensitivity of a new toothpaste containing 8.0% arginine, calcium carbonate, and 1450 ppm uoride to a benchmark commercial desensitizing toothpaste containing 2% potassium ion: an eight-week clinical study in Rome, Italy. J Clin Dent 2009;20:137143. 33. Fu Y, Li X, Que K, et al. Instant dentin hypersensitivity relief of a new desensitizing dentifrice containing 8.0% arginine, a high cleaning calcium carbonate system and 1450 ppm uoride: a 3-day clinical study in Chengdu, China. Am J Dent 2010;23(Spec No A):20A27A. 34. Hamlin D, Williams KP, Delgado E, Zhang YP, DeVizio W, Mateo LR. Clinical evaluation of the ecacy of a desensitizing paste containing 8% arginine and calcium carbonate for the in-oce relief of dentin hypersensitivity associated with dental prophylaxis. Am J Dent 2009;22(Spec No A):16A20A. 35. He T, Chang J, Cheng R, Li X, Sun L, Biesbrock AR. Clinical evaluation of the fast onset and sustained sensitivity relief of a 0.454% stannous uoride dentifrice compared to an 8.0% arginine-calcium carbonate-sodium monouorophosphate dentifrice. Am J Dent 2011;24:336340. 36. He T, Cheng R, Biesbrock AR, Chang A, Sun L. Rapid desensitizing ecacy of a stannous-containing sodium uoride dentifrice. J Clin Dent 2011;22: 4045. 37. Hughes N, Mason S, Jeery P, et al. A comparative clinical study investigating the ecacy of a test dentifrice containing 8% strontium acetate and 1040 ppm sodium uoride versus a marketed control dentifrice containing 8% arginine, calcium carbonate, and 1450 ppm sodium monouorophosphate in reducing dentinal hypersensitivity. J Clin Dent 2010;21:4955. 38. Nathoo S, Delgado E, Zhang YP, DeVizio W, Cummins D, Mateo LR. Comparing the ecacy in providing instant relief of dentin hypersensitivity of a new toothpaste containing 8.0% arginine, calcium carbonate, and 1450 ppm uoride relative to a benchmark desensitizing toothpaste containing 2% potassium ion and 1450 ppm uoride, and to a control toothpaste with 1450 ppm uoride: a threeday clinical study in New Jersey, USA. J Clin Dent 2009;20:123130. 39. Que K, Fu Y, Lin L, et al. Dentin hypersensitivity reduction of a new toothpaste containing 8.0% arginine and 1450 ppm uoride: an 8-week clinical study on Chinese adults. Am J Dent 2010;23(Spec No A):28A35A. 40. Schi T, Delgado E, Zhang YP, Cummins D, DeVizio W, Mateo LR. Clinical evaluation of the ecacy of an in-oce desensitizing paste containing 8% arginine and calcium carbonate in providing instant and lasting relief of dentin hypersensitivity. Am J Dent 2009;22(Spec No A):8A15A. 41. Cummins D. Dentin hypersensitivity: from diagnosis to a breakthrough therapy for everyday sensitivity relief. J Clin Dent 2009;20:19.

42. Kakar A, Kakar K, Sreenivasan PK, DeVizio W, Kohli R. Comparison of the clinical ecacy of a new dentifrice containing 8.0% arginine, calcium carbonate, and 1000 ppm uoride to a commercially available sensitive toothpaste containing 2% potassium ion on dentin hypersensitivity: a randomized clinical trial. J Clin Dent 2012;23:4047. 43. Kakar A, Kakar K, Sreenivasan PK, DeVizio W, Kohli R. Comparison of the clinical ecacy in reducing dentin hypersensitivity of a new dentifrice containing 8.0% arginine, calcium carbonate, and 1000 ppm sodium monouorophosphate to a commercially available toothpaste containing 1000 ppm sodium monouorophosphate: an eight-week clinical trial on adults in New Delhi, India. J Clin Dent 2012;23: 3339. 44. Poulsen S, Errboe M, Lescay Mevil Y, Glenny AM. Potassium containing toothpastes for dentine hypersensitivity. Cochrane Database Syst Rev 2006:CD001476. 45. Sgolastra F, Petrucci A, Gatto R, Monaco A. Eectiveness of laser in dentinal hypersensitivity treatment: a systematic review. J Endod 2011;37:297303. 46. Cunha-Cruz J, Stout JR, Heaton LJ, Wataha JC. Dentin hypersensitivity and oxalates: a systematic review. J Dent Res 2011;90:304310. 47. Dixon KE, Thorn BE, Ward LC. An evaluation of sex dierences in psychological and physiological responses to experimentally-induced pain: a path analytic description. Pain 2004;112:188196. 48. Lutins ND, Greco GW, McFall WT Jr. Eectiveness of sodium uoride on tooth hypersensitivity with and without iontophoresis. J Periodontol 1984;55:285 288. 49. McBride MA, Gilpatrick RO, Fowler WL. The eectiveness of sodium uoride iontophoresis in patients with sensitive teeth. Quintessence Int 1991;22:637640. 50. Wandner LD, Scipio CD, Hirsh AT, Torres CA, Robinson ME. The perception of pain in others: how gender, race, and age inuence pain expectations. J Pain 2012;13:220227. 51. Knottnerus JA, Tugwell P. Real world research. J Clin Epidemiol 2010;63:10511052. 52. Pradeep AR, Sharma A. Comparison of clinical ecacy of a dentifrice containing calcium sodium phosphosilicate to a dentifrice containing potassium nitrate and to a placebo on dentinal hypersensitivity: a randomized clinical trial. J Periodontol 2010;81:11671173. 53. Sharma N, Roy S, Kakar A, Greenspan DC, Scott R. A clinical study comparing oral formulations containing 7.5% calcium sodium phosphosilicate (NovaMin), 5% potassium nitrate, and 0.4% stannous uoride for the management of dentin hypersensitivity. J Clin Dent 2010;21:8892. 54. Wefel JS. NovaMin: likely clinical success. Adv Dent Res 2009;21:4043.

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Appendix 1

Modi ed search strategy in Medline (via OVID, 1996 to October 2012) Results 247660 40401 201383 94333 81780 137670 76098 558895 1689956 509602 1181 1373 1605 2032 1370 1605 2937 244 118

Search strategy #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14 #15 #16 #17 #18 #19 randomized controlled trial.pt. controlled clinical trial.pt. randomized.ab. placebo.ab. clinical trials as topic.sh. randomly.ab. trial.ti. 1 or 2 or 3 or 4 or 5 or 6 or 7 exp animals/not humans.sh. 8 not 9 exp dentin sensitivity/ exp toothpastes/ ((dentin$ or tooth or teeth) adj5 (sensitiv$ or hypersensitiv$ or hyper-sensitiv$)).mp. toothpast$.mp. dentifrice$.mp. 11 or 13 12 or 14 or 15 16 and 17 8 and 18

.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 Tactile assessment Mean difference (95% CI) 18.98 (15.07 to 23.80) 18.87 (14.46 to 23.28) 20.39 (17.60 to 23.19) 18.31 (14.19 to 22.42) 19.43 (15.07 to 23.80) 17.77 (14.33 to 21.21)
33 29

Item Original estimate Exclude Ayad et al29 Exclude Fu et al33 Exclude Hamlin et al34 Exclude Li et al28 Exclude Nathoo et al38 Exclude Ayad et al and Fu et al Exclude Ayad et al29 and Hamlin et al34 Exclude Ayad et al29 and Li et al28 Exclude Ayad et al29 and Nathoo et al38 Exclude Fu et al33 and Hamlin et al34 Exclude Fu et al33 and Li et al28 Exclude Fu et al33 and Nathoo et al38 Exclude Hamlin et al34 and Li et al28 Exclude Hamlin et al34 and Nathoo et al38 Exclude Li et al28 and Nathoo et al38 Combine Ayad et al29 and Fu et al33 Combine Ayad et al29 and Hamlin et al34

Air blast assessment Mean difference (95% CI) -1.05 (-1.23 to -0.88) -1.01 (-1.21 to -0.81) -1.11 (-1.30 to -0.92) -1.08 (-1.28 to -0.87) -1.08 (-1.30 to -0.86) -0.99 (-1.15 to -0.82) -1.06 (-1.31 to -0.82) -1.03 (-1.28 to -0.78) -1.03 (-1.30 to -0.76) -0.90 (-1.05 to -0.75) -1.16 (-1.36 to -0.95) -1.17 (-1.37 to -0.97) -1.04 (-1.25 to -0.83) -1.12 (-1.38 to -0.86) -1.01 (-1.22 to -0.80) -1.01 (-1.24 to -0.77) -1.05 (-1.40 to -0.70) -1.09 (-1.41 to -0.77)

20.67 (16.96 to 24.38) 17.92 (12.37 to 23.46) 19.42 (13.25 to 25.49) 17.31 (12.70 to 21.92) 19.95 (16.41 to 23.50) 21.82 (19.55 to 24.09) 19.01 (16.32 to 21.70) 18.60 (12.94 to 24.27) 16.60 (13.27 to 19.93) 18.07 (12.90 to 23.24) 16.23 (10.17 to 22.28) 20.51 (16.97 to 24.05) continued on next page

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continuation from previous page Combine Ayad et al29 and Li et al28 Combine Ayad et al29 and Nathoo et al38 Combine Fu et al33 and Hamlin et al34 Combine Fu et al33 and Li et al28 Combine Fu et al33 and Nathoo et al38 Combine Hamlin et al34 and Li et al28 Combine Hamlin et al34 and Nathoo et al38 Combine Li et al28 and Nathoo et al38 18.04 (15.09 to 21.00) 21.53 (18.33 to 24.74) 17.51 (8.72 to 27.52) 15.40 (11.45 to 19.36) 18.12 (8.72 to 27.52) 19.26 (14.52 to 24.00) 22.59 (19.99 to 25.19) 20.10 (14.68 to 25.53) -1.09 (-1.38 to -0.79) -1.26 (-1.43 to -1.09) -0.88 (-1.09 to -0.67) -0.90 (-1.07 to -0.74) -0.89 (-1.07 to -0.71) -0.93 (-1.14 to -0.72) -1.11 (-1.46 to -0.77) -1.11 (-1.44 to -0.79)

Appendix 3

Sensitivity analysis: arginine vs placebo: 3-day and 8-week follow-up Tactile assessment Mean difference (95% CI) Air blast assessment Mean difference (95% CI) 3-day -1.29 (-1.52 to -1.07) -1.28 (-1.63 to -0.93) -1.41 (-1.57 to -1.26) -1.20 (-1.42 to -0.98) 8-week -1.51 (-1.68 to -1.34) -1.58 (-1.71 to -1.46) -1.47 (-1.78 to -1.17) -1.47 (-1.69 to -1.25)

Item Original estimate Exclude Ayad et al29 Exclude Fu et al33 Exclude Nathoo et al38 Exclude Que et al39 Exclude Docimo et al27 Exclude Kakar et al43

3-day 20.84 (15.67 to 26.00) 21.50 (13.83 to 29.16) 22.49 (16.59 to 28.40) 18.24 (15.03 to 21.45) -

8-week 23.23 (18.64 to 27.82) 25.38 (20.81 to 29.94) 20.82 (15.81 to 25.83) 22.98 (13.37 to 32.60)

Appendix 4

Sensitivity analysis: arginine vs potassium: 8-week follow-up Tactile assessment Mean difference (95% CI) 7.09 (4.64 to 9.54) 6.59 (2.90 to 10.28) 7.87 (5.42 to 10.32) 7.74 (5.06 to 10.42) 6.11 (3.57 to 8.65) 6.61 (3.10 to 10.13) 6.76 (3.42 to 10.09) 9.13 (7.66 to 10.60) 4.83 (3.30 to 6.35) 7.35 (2.37 to 12.34) 7.48 (2.67 to 12.29) Air blast assessment Mean difference (95% CI) -0.38 (-0.58 to -0.20) -0.32 (-0.52 to -0.11) -0.43 (-0.64 to -0.22) -0.44 (-0.64 to -0.23) -0.34 (-0.57 to -0.10) -0.41 (-0.76 to -0.05) -0.39 (-0.78 to -0.01) -0.53 (-0.02 to -0.43) -0.22 (-0.33 to -0.11) -0.37 (-0.63 to -0.10) -0.36 (-0.65 to -0.06)

Item Original estimate Exclude Ayad et al30 Exclude Docimo et al32 Exclude Docimo et al31 Exclude Kakar et al42 Combine Ayad et al30 and Docimo et al32 Combine Ayad et al30 and Docimo et al31 Combine Ayad et al and Kakar et al
30 42

Combine Docimo et al32 and Docimo et al31 Combine Docimo et al32 and Kakar et al42 Combine Docimo et al31 and Kakar et al42

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