arginine-containing desensitizing toothpaste for the

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Clinical, Cosmetic and Investigational Dentistry 2016:8 1–14

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Open access Full Text article

http://dx.doi.org/10.2147/CCIDE.S95660

arginine-containing desensitizing toothpaste for the treatment of dentin hypersensitivity: a meta-analysis

Zheng-yan Yang1,2

Fei Wang1,2

Keke lu1,2

Yue-heng li1,2

Zhi Zhou1,2

1Department of Preventive Dentistry, The College of stomatology, 2Department of Preventive Dentistry, The affiliated hospital of stomatology, Chongqing Medical University, Chongqing, People’s republic of China

Correspondence: Zhi Zhou The Affiliated Hospital of Stomatology, Chongqing Medical University, no 426, songshibei road, Yubei District, Chongqing 401147, People’s republic of China Tel +86 130 6238 1906 Fax +86 23 8886 0222 email [email protected]

Objective: To estimate the effect of arginine-containing desensitizing toothpaste on dentin

hypersensitivity (DH).

Methods: Databases including China National Knowledge Infrastructure, VIP Database for

Chinese Technical Periodicals, China Biology Medicine disc, Wangfang Data, PubMed, Web of

Science, and Cochrane Trials Register were searched, and Google was used as a supplementary

tool to search for information through February 2014. Randomized controlled trials (RCTs) of

the treatment of DH with arginine-containing toothpaste were included. Relevant information

was extracted, and a quality evaluation was performed. Meta-analyses were performed using

RevMan 5.2 software.

Results: Eighteen RCTs with 1,423 patients were included. The results of the meta-analyses

demonstrated that at days 0 and 3; weeks 2, 4, and 8; and more than 12 weeks, arginine-

containing toothpaste led to significantly improved results on the tactile sensitivity test

(standardized mean difference [SMD] =1.95, 95% confidence interval [CI] [1.14, 2.76]) and the

air-blast test (SMD =−1.60, 95% CI [−2.14, −1.05]) at 4 weeks and the tactile sensitivity test

(SMD =2.01, 95% CI [1.41, 2.61]) and the air-blast test (SMD =−1.41, 95% CI [−1.83, −0.98])

at 8 weeks compared to toothpastes containing other desensitizing components, thus indicating

a superior therapeutic effect of arginine-containing desensitizing toothpaste. However, no

significant differences between arginine-containing toothpaste and toothpastes containing other

desensitizing components were observed in the air-blast test at days 0 and 3 and week 2 and in

the tactile sensitivity and air-blast tests at more than 12 weeks.

Conclusion: The current evidence indicates that arginine-containing toothpaste is effective for

DH. However, further high-quality, large-sample RCTs are needed.

Keywords: arginine-containing toothpastes, dentin hypersensitivity, meta-analysis, random-

ized controlled trial

IntroductionDentin hypersensitivity (DH) is a frequently reported dental condition that is

typically characterized by brief, sharp pain that cannot be ascribed to any other form

of dental defect or pathology and arises from exposed dentin in response to thermal,

evaporative, tactile, osmotic, or chemical stimuli.1 DH is increasingly recognized as

an important issue to be addressed from both diagnostic and problem-management

perspectives because the improved success of caries prevention and periodontal dis-

ease management measures have resulted in improved oral health status and dentition

function throughout life. The reported prevalence of DH ranges from 2% to 57%

worldwide.2 A commonly supported mechanism for DH is the hydrodynamic theory,

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Yang et al

which assumes that painful stimulation increases fluid flow

within the dentinal tubules, causing activation of resident

baroceptors.3 Accordingly, the ideal treatment for DH should

reduce fluid flow within the dentinal tubules or block the pulp

nerve response. Dozens of in-office sensitivity treatments

and mass-market sensitivity relief toothpastes are available

worldwide, and fluoride dentifrice is generally accepted.

There are two types of sensitivity relief toothpastes. One

type contains potassium salts; the potassium ions have a

depolarizing effect on electrical nerve conduction, thereby

causing nerve fibers to be less excitable by stimuli4 and,

consequently, reducing the patient’s sensation of pain. The

other type of sensitivity relief toothpaste includes dentifrices

that occlude the exposed dentin tubules to block the hydro-

dynamic mechanism of pain stimulation. Examples include

strontium-containing toothpaste and stannous-containing

toothpaste,5–10 but the effects of these toothpastes are inferior

to potassium-containing toothpastes. Clinical studies have

demonstrated the efficacy of arginine-containing dentifrices

in reducing DH.11–29 To assess whether arginine-containing

dentifrices are efficacious in reducing DH compared with

toothpastes containing potassium, strontium, or fluoride,

a systematic review of the literature is required. We

therefore performed a meta-analysis to assess the efficacy of

arginine-containing dentifrices compared with toothpastes

containing potassium, strontium, or fluoride for future clini-

cal applications.

Materials and methodsAll experimental procedures in this study were approved by

the ethics committee of the Stomatology Hospital Affiliated

to Chongqing Medical University.

eligibility criteria1. Inclusion criteria.

1.1. Research design: randomized controlled trials

(RCTs) published in full; there were no limitations

on language.

1.2. Patient: studies performed on adult humans

(age .18 years) with a clinical diagnosis of DH

caused by cervical dentin exposure.

1.3. Intervention and comparison: the test group used

an arginine-containing dentifrice daily, whereas

the control group used toothpaste containing other

desensitizing components daily.

1.4. Outcome: the results were evaluated based on the

score of the improvement of dentin sensitivity

(tactile sensitivity and air-blast sensitivity).

2. Exclusion criteria: 1) in vitro study; 2) review literature;

3) studies not reporting complete data; and 4) repeated

published literature or papers with duplicate data.

literature search of clinical trialsA thorough literature search of computerized databases,

including PubMed, Cochrane Controlled Clinical Trial

Register (First Journal, 2014), Web of Science, China

National Knowledge Infrastructure, VIP Database for

Chinese Technical Periodicals, China Biology Medicine disc,

and the Wangfang Data, was performed through February

2014 by two independent researchers to identify RCTs of

arginine-containing dentifrices compared with toothpastes

containing other desensitizing components with a cura-

tive effect on DH. To avoid selection bias, no restrictions

were applied with regard to language or year. Moreover,

to identify unpublished literature and further examine

trends in the literature, the Google search engine was used.

The Chinese keywords were arginine (精氨酸), toothpaste

(牙膏), tooth (牙齿), dentin (牙本质), and hypersensitivity

(过敏,敏感). The English keywords were toothpaste, tooth

paste, dentifrice, dentifrices, desensitize, agent, efficacy,

effect, dentin, dentine, tooth, teeth, root, hypersensitivity,

hypersensitive, sensitivity, sensitive, and oversensitive. In

the case of PubMed, the specific retrieval strategy presented

in Figure 1 was used.

literature screening, data extraction, and quality assessmentLiterature reviews were performed by two independent

evaluators to include and exclude literature according to the

literature and to cross-check the details. The title was first

read; if the title met the eligibility criteria, the full text was

read. If the full text met the eligibility criteria, the study was

included. Disagreements were resolved in consultation with

a third researcher.

The data was then extracted to a table and the RCT bias

risk assessment tool recommended by the Cochrane Review-

ers’ Handbook 5.1.030 was used to evaluate the risk of bias

in the included studies.

statistical analysisData were combined for the meta-analysis using a statistical

software package (RevMan software, version 5.2, The Nordic

Cochrane Center, The Cochrane Collaboration, Copenhagen,

Denmark). Continuous outcomes used the standardized

mean difference (SMD) or mean difference (MD) with

95% confidence intervals (CIs) as effect measures, whereas

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Clinical, Cosmetic and Investigational Dentistry 2016:8

#1 randomized controlled trials

#2 random allocation

#3 #1 or #2

#4 Arginine

#5 (toothpaste or tooth paste or dentifrice or dentifrices or (desensitizer and (agent or efficacy or effect)))

#6 #4 and #5

#7 (dentin or dentine or tooth or teeth)

#8 (hypersensitivity or hypersensitivie or sensitivity or sensitive or over-sensitive)

#9 #7 and #8

#10 (endodont* or whitening or cracked (tooth or teeth) or caries)

#11 #3 and #6 and #9 not #10

Figure 1 Specific retrieval strategy for PubMed searches.Note: *Wildcard symbol for truncation searching.

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3

arginine-containing desensitizing toothpaste for dentin hypersensitivity

dichotomous outcomes used the risk ratio with 95% CIs

as effect measures. Heterogeneity was assessed using the

χ2-based method and I2 measurement. P-values and 95%

CIs were then calculated. For P,0.1 and I2.50%, the

random-effect model was used; otherwise, the fixed-effect

model was used. Descriptive analysis was performed when

the data could not be combined.

sensitivity analysisSensitivity analysis was performed by removing one result

and performing statistical analysis again. The new result

was compared with the original to explore the effects of

removing the result on the effect size. If no difference was

observed, the results of the meta-analysis were considered

reliable.

grading of the evidenceThe GRADE (Grading of Recommendations Assessment,

Development, and Evaluation) approach was adopted to

evaluate the overall quality of the evidence.31,32 We applied the

following definitions of quality of the evidence.33

• High quality: further research is unlikely to change con-

fidence in the estimate of the effect. There are no known

or suspected reporting biases; all domains are fulfilled.

• Moderate quality: further research is likely to have an

important effect on confidence in the estimate of the effect

and might change the estimate; one of the domains was

not fulfilled.

• Low quality: further research is likely to have an impor-

tant effect on confidence in the estimate of the 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.

Resultsliterature searchElectronic and manual searches identified 382 articles. After

step-by-step screening, 18 studies including 1,423 patients

were qualified for inclusion in the meta-analysis. A PRISMA

(Preferred Reporting Items for Systematic Reviews and Meta-

Analyses) flowchart of the complete study-selection process is

illustrated in Figure 2. The basic characteristics of the included

studies are presented in Table 1. The methodological quality

analysis of the included studies is presented in Table 2.

Meta-analysis resultsBased on the interventions evaluated, the included studies were

classified into three types: arginine-containing dentifrice com-

pared with potassium-containing toothpastes, arginine-containing

dentifrice compared with strontium-containing toothpastes,

382 articles were found by the electronic and manual searches:

Records identified through database searching (n=216):

PubMed (n=60), the Cochrane Central Register of Controlled Trials (n=36),

Web of Science (n=25), CBM (n=3), CNKI (n=37), VIP (n=2),

Wanfang Data (n=58)

Records identified through other sources (n=166)

238 repeating documents were removed

110 articles were excluded as they did not meetthe inclusion standards

34 records screened

Full-text articles assessed for eligibility(n=34)

Studies included in quantitativesynthesis (meta-analysis) (n=18)

16 articles excluded accordingto the exclusion criteria (n=16)

Figure 2 PRISMA flowchart of the search strategy.Abbreviations: CBM, China Biology Medicine; CnKI, China national Knowledge Infrastructure; PrIsMa, Preferred reporting Items for systematic reviews and Meta-analyses.

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Yang et al

Tab

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Bas

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s, a

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core

; Tr

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the

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gro

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as,

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and arginine-containing dentifrice compared with fluoride

toothpastes. We evaluated the tactile and air-blast DH scores

of the arginine-containing dentifrice with control toothpastes at

days 0 and 3; weeks 2, 4, and 8; and more than 12 weeks.

Comparison of instant tactile hypersensitivity between arginine-containing dentifrice group and the control groupInstant tactile hypersensitivity was compared between

the arginine-containing dentifrice group (313 persons)

and the control group (321 persons). A random-effect

model was used in the meta-analysis due to statistical

heterogeneity among the studies. The analysis excluded

Kapferer et al’s study26 (because the 95% CI lines were

invalid vertical lines and the results were not significant).

The mean tactile hypersensitivity scores measured

immediately (0 day) were significantly higher for the

arginine-containing dentifrice group than the control group

(SMD =1.66, 95% CI [1.00, 2.31], P,0.00001), indicat-

ing that the arginine-containing dentifrice was superior

to toothpastes containing other desensitizing components

(Figure 3).

Table 2 Methodological quality analysis of the included studies

Included studies

Sequence generation

Allocation concealment

Blinding participants

Free of incomplete data bias

Free of selective reporting

Other sources of bias

schiff et al25 Unclear Unclear Yes Yes no noayad et al23 Unclear Yes Yes Yes no noCummins11 Unclear Unclear Yes Yes no noDocimo et al13 Unclear Yes Yes Yes no noDocimo et al14 Unclear Yes Yes Yes no noKakar et al16 Unclear Yes Yes Yes no noKakar et al17 Unclear Yes Yes Yes no noQue et al15 Yes Unclear Yes Yes no noDocimo et al19 Unclear Unclear Yes Yes no noschiff et al18 Yes Yes Yes Yes no nonathoo et al21 Unclear Unclear Yes Yes no noFu et al22 Unclear Unclear Yes Yes no noayad et al12 Unclear Yes Yes Yes no nohamlin et al24 Unclear Unclear Yes Yes no noKapferer et al26 Unclear Unclear Yes Yes no noli et al20 Unclear Yes Yes Yes no nohamlin et al27 Unclear Unclear Yes Yes no nohe et al28 Unclear Unclear Yes Yes no nohe et al29 Unclear Unclear Yes Yes no no

ExperimentalStudy or subgroup Mean MeanSD SDTotal Total Weight

Control

1.15.1 Arginine vs potassium: instant

Ayad et al12

Nathoo et al21

Subtotal (95% CI)

Heterogeneity: τ2=2.03; χ2=20.69, df =1 (P<0.00001); l2=95%Test for overall effect: Z=2.63 (P=0.009)

1.15.3 Arginine vs fluoride: instant

Fu et al22

Hamlin et al24

Hamlin et al27

Kapferer et al26

Schiff et al25

Subtotal (95% CI)

Total (95% CI)

Heterogeneity: τ2=0.66; χ2=41.96, df =4 (P<0.00001); l2=90%


Test for subgroup difference: χ2=1.73, df =2 (P=0.42); l2=0%

Test for overall effect: Z=3.35 (P=0.0008)

Test for overall effect: Z=4.97 (P<0.00001)

1.15.2 Arginine vs strontium: instant

Li et al20

Subtotal (95% CI)

Heterogeneity: not applicable


33.17

35.36

29.02

25.62

39.89

1.7

25.62

36.1

14.86

8.07

14.28

5.22

11.57

2

5.22

10.17

41

4283

41

32

46

29

32180

313

5050

40

4181

40

36

49

29

36190

321

5050

12.6%

11.7%24.3%

12.8%

12.3%

12.9%

12.6%

12.3%62.8%

100.0%

12.9%12.9%

1.70 (1.19, 2.21)

3.76 (3.03, 4.49)2.71 (0.69, 4.73)

1.20 (0.73, 1.68)

2.14 (1.54, 2.75)

1.03 (0.60, 1.46)

−0.05 (−0.57, 0.46)

−4 −2Favors (control) Favors (experimental)

0 2 4

2.14 (1.54, 2.75)1.28 (0.53, 2.03)

1.66 (1.00, 2.31)

1.53 (1.08, 1.98)1.53 (1.08, 1.98)

14.38

13.54

15.88

14.31

26.63

1.8

14.31

20

4.11

0.37

5.3

5.22

13.71

1.8

5.22

10.69

Std mean differenceIV, random, 95% CI


Figure 3 Meta-analysis of the comparison of instant tactile hypersensitivity between the arginine-containing dentifrice group and the control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.

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Yang et al

Comparison of instant air-blast hypersensitivity between the arginine-containing dentifrice group and control groupInstant air-blast hypersensitivity was compared between the

arginine-containing dentifrice group (384 persons) and the

control group (388 persons). A random-effect model was used

in the meta-analysis due to statistical heterogeneity among

the studies. Because the total 95% CI lines were invalid

vertical lines and the results were not significant, we con-

cluded that the immediate effects of the arginine-containing

dentifrice and toothpastes containing other desensitizing

components for the treatment of DH did not differ signifi-

cantly (Figure 4).

Comparison of 3-day tactile hypersensitivity between the arginine-containing dentifrice group and control groupThree-day tactile hypersensitivity was compared between the


control group (160 persons). A random-effect model was

used in the meta-analysis due to statistical heterogeneity

among the studies. The mean tactile hypersensitivity scores

were significantly higher in the arginine-containing dentifrice

group than the control group at 3 days (SMD =2.21, 95%

CI [1.13, 3.29], P,0.0001). We thus concluded that the

arginine-containing dentifrice was superior to toothpastes

containing other desensitizing components (Figure 5).

Comparison of 3-day air-blast hypersensitivity between the arginine-containing dentifrice group and control groupThree-day air-blast hypersensitivity was compared between the



in the meta-analysis due to statistical heterogeneity among the

studies. Ayad et al’s study23 was excluded because the total

95% CI lines were invalid vertical lines and the results were

not significant. We concluded that the effects of the arginine-

containing dentifrice and the toothpastes containing other

desensitizing components did not differ significantly for the

treatment of DH at 3 days (Figure 6).

Comparison of 2-week tactile hypersensitivity between the arginine-containing dentifrice group and control groupTwo-week tactile hypersensitivity was compared between

the arginine-containing dentifrice group (323 persons) and

the control group (327 persons). A random-effect model was




group than the control group at 2 weeks (SMD =1.20, 95%

CI [0.84, 1.57], P,0.00001). We thus concluded that the




Control

1.16.1 Arginine vs potassium: instant

Ayad et al12

Nathoo et al21

Subtotal (95% CI)

Heterogeneity: τ2=0.45; χ2=6.80, df =1 (P=0.009); l2=85%Test for overall effect: Z=3.97 (P<0.0001)

1.16.3 Arginine vs fluoride: instant

Fu et al22

Hamlin et al24

Hamlin et al27

Kapferer et al26

Schiff et al25

Subtotal (95% CI)

Total (95% CI)

Heterogeneity: τ2=0.14; χ2=11.63, df =4 (P=0.02); l2=66%


Test for subgroup differences: χ2=5.79, df =2 (P=0.06); l2=65.5%



1.16.2 Arginine vs strontium: instant

Li et al20

He et al28

He et al29

Subtotal (95% CI)

Heterogeneity τ2=6.17; χ2=160.42, df =2 (P<0.00001); l2=99%Test for overall effect: Z=1.03 (P=0.30)

1.260.92

1.181.261.45

1.41.37

1.162.332.43

0.750.57

0.520.580.64

0.80.55

0.680.2

0.04

414283

4122462932

170

384

504140

131

404181

4023492936

177

388

504040

130

10.1%10.0%20.0%

10.0%9.9%

10.2%10.0%10.0%50.1%

100.0%

10.1%10.1%9.6%

29.8%

−1.53 (−2.03, −1.03)−2.55 (−3.14, −1.97)−2.03 (−3.03, −1.03)

−1.82 (−2.35, −1.30)−1.54 (−2.21, −0.87)−0.74 (−1.15, −0.32)−1.05 (−1.60, −0.50)−1.28 (−1.80, −0.75) −1.26 (−1.67, −0.86)

−0.62 (−1.57, 0.34)

−1.23 (−1.66, −0.80)1.32 (0.84, 1.80)4.46 (3.62, 5.29)

1.49 (−1.34, 4.33)

2.242.29

2.062.171.96

2.22.08

1.981.912.25

0.490.49

0.430.580.730.7

0.55

0.640.4

0.04

−4 −2Favors (experimental) Favors (control)

0 2 4



Figure 4 Meta-analysis of the comparison of instant air-blast hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.

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7



Control

1.17.1 Arginine vs potassium: 3-day

Ayad et al23

Ayad et al12

Nathoo et al21

Subtotal (95% CI)



1.17.2 Arginine vs fluoride: 3-day

Fu et al22

Subtotal (95% CI)


Test for overall effect: Z 6.50 (P<0.00001)

13.77

33.29

39.17

33.41 13.06

0

14.69

7.72

41

41

121

162

38

41

42

40

40

120

160

39

40

41

34.0%

34.0%

66.0%

100.0%

34.1%

31.9%

16

13.77

16.25

15.58

5.91

0

4.77

5.47

Not estimable

1.54 (1.04, 2.04)

3.49 (2.79, 4.18)

2.50 (0.59, 4.41)

−4 −2

Favors (control) Favors (experimental)

0 2 4

2.21 (1.13, 3.29)

1.69 (1.18, 2.21)

1.69 (1.18, 2.21)



Total (95% CI)


Test for subgroup differences: χ2=0.63, df =1 (P=0.43); l2=0%

Test for overall effect: Z 4.01 (P<0.0001)

Figure 5 Meta-analysis of the comparison of 3-day tactile hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.


Control

1.18.1 Arginine vs potassium: 3-day

Ayad et al23

Ayad et al12

Nathoo et al21

Subtotal (95% CI)Heterogeneity: τ2=0.98; χ2=31.84, df =2 (P<0.00001); l2=94%


1.18.2 Arginine vs fluoride: 3-day

1.18.3 Arginine vs strontium: 3-day

Fu et al22

He et al29

Subtotal (95% CI)

Subtotal (95% CI)

Heterogeneity: not applicableTest for overall effect: Z=8.53 (P<0.00001)

Heterogeneity: not applicableTest for overall effect: Z=8.39 (P=0.00001)

2.64

1.170.6

0.83

2.23

0.06

0.680.47

0.44

0.06 40

41

41

40

202

121

38

41

42

40

40

40

40

200

120

39

40

41

19.9%

19.9%

19.9%

19.9%

100.0%

60.2%

20.1%

20.1%

20.0%

−2.53 (−3.12, −1.94)

−2.53 (−3.12, −1.94)

−1.41 (−2.56, −0.25)

−0.33 (−0.78, 0.12)

−1.59 (−2.09, −1.09)

−2.33 (−2.89, −1.76)

2.07

1.93

2.66

2.11

2.01

0.06

0.42

0.06

0.47

0.71

−4 −2Favors (control)Favors (experimental)

0 2 4



Total (95% CI)Heterogeneity: τ2=3.63; χ2=198.09, df =4 (P<0.00001); l2=98%

Test for subgroup differences: χ2=148.13, df =2 (P<0.00001); l2=98.6%


2.64 (2.03, 3.25)

2.64 (2.03, 3.25)

−0.83 (−2.52, 0.86)

Figure 6 Meta-analysis of the comparison of 3-day air-blast hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.


Control

1.3.1 Arginine vs potassium: 2-weekAyad et al23

Docimo et al13

Docimo et al14

Kakar et al16

Docimo et al19

Subtotal (95% CI)Heterogeneity: τ2=0.09; χ2=7.78, df =3 (P<0.05); l2=61%Test for overall effect: Z=5.12 (P<0.00001)

1.3.3 Arginine vs fuoride: 2-weekCummins et al11

Kakar et al17

Que et al15

Subtotal (95% CI)

Total (95% CI)






1.3.2 Arginine vs strontium: 2-week

Subtotal (95% CI)Heterogeneity: not applicable


23.12

25.8726.45

25.76

27.2

35.4627.536.5

6.87

8.166.99

5.57

8.76

11.144.64

12.26

38

4040

46164

50

109

50

353440

39

4040

42161

50

116

327

50

354041

12.9%

12.7%12.7%

12.7%51.0%

13.2%

35.8%

100.0%

13.2%

12.4%10.8%12.6%

0.46 (0.01, 0.92)1.08 (0.61, 1.55)1.01 (0.55, 1.48)

1.36 (0.90, 1.83)0.98 (0.60, 1.35)

0.93(0.44, 1.43)2.66 (2.02, 3.29)1.25 (0.77, 1.73)1.59 (0.65, 2.53)

1.20 (0.84, 1.57)

1.10 (0.68, 1.52)1.10 (0.68, 1.52)

323

19.9

18.6319.3

18.92

19.2

24.9715.12

22.2

6.87

4.676.99

4.21

5.19

11.144.59

10.37

−4 −2Favors (control)Favors (experimental)

0 2 4



Figure 7 Meta-analysis of the comparison of 2-week tactile hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.

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8

Yang et al


Control


Docimo et al13

Docimo et al14

Kakar et al16

Docimo et al19

He et al28

He et al29

Subtotal (95% CI)Heterogeneity: τ2=0.00; χ2=1.24, df =3 (P=0.74); l2=0%Test for overall effect: Z=7.13 (P<0.00001)

1.4.3 Arginine vs fluoride: 2-week

Cummins et al11

Que et al15

Subtotal (95% CI)

Total (95% CI)

Heterogeneity: τ2=0.78; χ2=23.96 df =2 (P<0.00001); l2=92%







Subtotal (95% CI)


1.86

1.591.65

1.73

1.45

2.232

0.86

1.18

0.41

0.590.51

0.45

0.62

0.30.09

1.75

0.56

2.22

1.912.17

2.07

1.93

0.971.6

1.74

1.99

0.41

0.360.51

0.39

0.42

0.50.09

1.75

0.45

−0.87 (−1.34, −0.40)−0.65 (−1.10, −0.20)−1.01 (−1.48, −0.54)

−0.80 (−1.23, −0.36)−0.83 (−1.05, −0.60)

38

4040

46

50

4140

35

40

164 161

131 130

116109

404 407

−0.50 (−0.97, −0.02)

−1.58 (−2.08, −1.08)−1.47 (−2.51, −0.42)

Favors (experimental) Favors (control)

−0.15 (−1.09, 0.79)

2.17 (−1.22, 5.55)

−0.90 (−1.31, −0.49)3.04 (2.39, 3.68)4.40 (3.58, 5.23)



39

4040

42

50

4040

35

41

40.4%

29.6%

30.0%

100.0%

10.1%

10.1%10.1%

10.1%

10.1%

9.9%9.6%

10.1%

10.0%

−4 −2 20 4

Kakar et al17 1.54 0.39 2.55 0.4534 −2.36 (−2.96, −1.76)40 9.9%

Figure 8 Meta-analysis of the comparison of 2-week air-blast hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.

Comparison of 2-week air-blast hypersensitivity between the arginine-containing dentifrice group and the control groupTwo-week air-blast hypersensitivity was compared between




among the studies. Because the total 95% CI lines were

invalid vertical lines and the results were not significant,

we concluded that the effects of the arginine-containing

dentifrice and toothpastes containing other desensitizing

components did not differ significantly for the treatment of

DH at 2 weeks (Figure 8).

Comparison of 4-week tactile hypersensitivity between the arginine-containing dentifrice group and control groupFour-week tactile hypersensitivity was compared between


the control group (357 persons). A random-effect model

was used in the meta-analysis due to statistical heterogene-

ity among the studies. Kapferer et al’s study26 was excluded

because the 95% CI lines were invalid vertical lines and the

results were not significant. The mean tactile hypersensitivity

scores were significantly higher in the arginine-containing

dentifrice group than the control group at 4 weeks (SMD

=1.95, 95% CI [1.14, 2.76], P,0.00001). We therefore con-

cluded that the arginine-containing dentifrice was superior

to toothpastes containing other desensitizing components

(Figure 9).

Comparison of 4-week air-blast hypersensitivity between the arginine-containing dentifrice group and control groupFour-week air-blast hypersensitivity was compared between

the arginine-containing dentifrice group (349 persons) and the



the studies. Docimo et al’s study13 was excluded because the

95% CI lines were invalid vertical lines and the results were

not significant. The mean air-blast hypersensitivity scores


group than the control group at 4 weeks (SMD =−1.60, 95%

CI [−2.14, −1.05], P,0.00001). Thus, we concluded that the



Comparison of 8-week tactile hypersensitivity between the arginine-containing dentifrice group and control groupEight-week tactile hypersensitivity was compared between






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9



Control


Docimo et al13

Docimo et al14

Kakar et al16

Docimo et al19

Subtotal (95% CI)Heterogeneity: τ2=0.11; χ2=8.76, df =3 (P=0.03); l2=66%Test for overall effect: Z=4.73 (P<0.00001)


Que et al15

Schiff et at25

Subtotal (95% CI)

Total (95% CI)






Test for overall effect: Z =5.76 (P<0.00001)


Subtotal (95% CI)


1.09

0.890.92

0.93

1.54

1.211.35

1.35

0.350.370.56

0.38

−1.27 (−1.76, −0.78)−0.50 (−0.94, −0.05)−0.76 (−1.22, −0.31)

−1.32 (−1.79, −0.86)−0.96 (−1.35, −0.56)

0.35

0.820.56

0.24

38

4040

46164 161




39

4040

4245.7%

11.3%11.5%11.5%

11.4%

1

1.40.75

1.33

2.31

2.21.82

2.24

0.380.8

0.38

0.52

−3.58 (−4.33, −2.83)−0.99 (−1.53, −0.44)−2.25 (−2.81, −1.69)

−1.73 (−2.29, −1.17)

0.34

0.80.55

0.52

34

2940

32

40

2941

36

10.%11.1%11.0%

11.0%

0.6 1.44 0.39 −2.25 (−2.75, −1.74)−2.25 (−2.75, −1.74)

0.35 5050 50

5011.2%

−2.11 (−3.08, −1.14)135 146 43.1%

−1.60 (−2.14, −1.05)349 357 100.0%

11.2%

−4 −2 20 4

Kapferer26

Kakar et al17



Control


Docimo et al13

Docimo et al14

Kakar et al16

Docimo et al19

Subtotal (95% CI)

Heterogeneity: τ2=0.29; χ2=16.87, df =3 (P=0.0008); l2=82%Test for overall effect: Z=4.75 (P<0.00001)

1.5.3 Arginine vs fuoride: 4-week

Que et al15

Schiff et at25

Subtotal (95% CI)

Total (95% CI)








Subtotal (95% CI)


36.21

40.7540.98

35.65

6.75

7.37.87

3.59

29.59

31.6231.52

26.78

6.758.047.87

3.79

0.97 (0.50, 1.44)1.18 (0.70, 1.65)1.19 (0.71, 1.67)

2.38 (1.83, 2.94)1.42 (0.83, 2.00)

38

4040

46164 161

357


1.95 (1.14, 2.76)



39

4040

4245.3%

100.0%

11.4%

42.5 5.91 27.9 6.23 2.39 (1.87, 2.90)2.39 (1.87, 2.90)

5050

5050

11.3%

33.82 3.27 17.75 4.66 3.90 (3.10, 4.69)34 40 10.6%1.5 1.9 2.4 2.6 −0.39 (−0.91, 0.13)29 29 11.3%

45.5 6.58 26.59 11.64 1.97 (1.44, 2.51)40 41 11.2%27.03 3.73 10.83 3.73 4.29 (3.41, 5.18)32 36 10.4%

11.3%

2.42 (0.31, 4.53)135

349

146 43.5%

11.3%11.3%

11.2%

−4 −2 20 4

Kapferer26

Kakar et al17


group than the control group at 8 weeks (SMD =2.01, 95%

CI [1.41, 2.61], P,0.00001). Thus, we concluded that the



Comparison of 8-week air-blast hypersensitivity between the arginine-containing dentifrice group and control groupEight-week air-blast hypersensitivity was compared

between the arginine-containing dentifrice group (435 per-

sons) and the control group (440 persons). A random-effect

model was used in the meta-analysis due to statistical

heterogeneity among the studies. Cummins’ study11 and

Docimo et al’s study14 were excluded because the 95% CI

lines were invalid vertical lines and the results were not

significant. The mean air-blast hypersensitivity scores were

significantly higher in the arginine-containing dentifrice

group than the control group at 8 weeks (SMD =−1.41,

95% CI [−1.83, −0.98], P,0.00001). Thus, we concluded

that the arginine-containing dentifrice was superior to

toothpastes containing other desensitizing components

(Figure 12).

Comparison of .12-week tactile hypersensitivity and air-blast hypersensitivity between the arginine-containing dentifrice group and control groupTactile hypersensitivity and air-blast hypersensitivity at time

points longer than 12 weeks were compared between the

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10

Yang et al


Control Std mean differenceIV, random, 95% CI


1.2.1 Arginine vs potassiumAyad et al23

Docimo et al13

Cummins11

Docimo et al14

Kakar et al16

Subtotal (95% CI)Heterogeneity: τ2=0.31; χ2=25.75, df =4 (P<0.0001); l2=84%Test for overall effect: Z=3.65 (P=0.0003)

1.2.2 Arginine vs strontiumDocimo et al19

Schiff et al18

Heterogeneity: τ2=0.00; χ2=0.25, df =1 (P=0.62); l2=0%Subtotal (95% CI)


1.2.3 Arginine vs fluoride

Que et al15

Subtotal (95% CI)Heterogeneity: τ2=0.63; χ2=18.32 df =2 (P=0.0001); l2=89%Test for overall effect: Z=4.21 (P=0.0001)

Kakar et al17

Hamlin et al27

Total (95% CI)Heterogeneity: τ2=0.40; χ2=70.74, df =9 (P<0.00001); l2=87%

Test for subgroup differences: χ2=4.71, df =2 (P=0.10); l2=57.5%Test for overall effect: Z=6.52 (P<0.00001)

−1.50 (−2.01, −0.99)−0.47 (−0.92, −0.03)

−1.47 (−1.91, −1.02)−1.62 (−2.03, −1.21)−1.55 (−1.85, −1.25)

−1.17 (−1.61, −0.73)−2.53 (−3.15, −1.91)−2.48 (−3.06, −1.89)−2.04 (−2.99, −1.09)

−1.41 (−1.83, −0.98)

−0.70 (−1.15, −0.25)−0.51 (−0.95, −0.06)−1.84 (−2.34, −1.33)−0.99 (−1.53, −0.46)50.4%

20.6%

29.0%

100.0%

10.2%9.9%

10.2%10.2%

10.2%10.4%

10.3%9.2%9.4%

9.9%200

130

440

110

3939

40

5060

494041

4042

0.460.39

0.310.390.29

0.930.760.680.690.85

0.891.67

1.722.152.19

38

204

111

120

435

40404046

0.390.460.340.390.25

0.340.540.450.490.35

1.020.35 0.35 0.38

0.620.450.46

0.450.34

0.81.350.5

0.440.820.56

5061

463440

Favors (experimental) Favors (control)−4 −2 20 4



Control


Docimo et al13

Cummins11

Docimo et al14

Kakar et al16

Docimo et al19

Schiff et al18

Subtotal (95% CI)Heterogeneity: τ2=0.78; χ2=49.24, df =4 (P<0.00001); l2=92%




Que et al15

Subtotal (95% CI)

Total (95% CI)





Test for overall effect: Z =6.55 (P<0.00001)


Subtotal (95% CI)


47.3445.75

38 3939.8740.8840.4733.09

2.46 (1.87, 3.06)0.95 (0.49, 1.42)1.02 (0.55, 1.49)0.92 (0.46, 1.38)3.06 (2.44, 3.68)1.66 (0.85, 2.47)

45.6345.4

42.93200204




3939

4040404046

3.356.113.955.3

3.084042

6.113.35

5.185.33.3

50.7%

10.3%9.9%

10.3%10.3%

9.8%

37.6142.7948.5

23.8819.7530.12

13.284.07

12.57

1.06 (0.63, 1.49)6.10 (4.99, 7.21)1.94 (1.40, 2.47)

12.463.3

4.113446

404049

41

10.4%8.0%

10.1%28.5%

46.634.43

36.322.75

7.27.27

1.76 (1.29, 2.22)1.84 (1.42, 2.27)1.80 (1.49, 2.12)

3.975.17

5061

111 110

5060

20.7%

2.95 (0.87, 5.04)120 130

2.01 (1.41, 2.61)435 440 100.0%

10.3%10.4%

−4 −2 20 4

Kakar et al17

Hamlin et al27





the studies. Because the total 95% CI lines were invalid verti-

cal lines and the results were not significant, we concluded

that the effects of the arginine-containing dentifrice and the

toothpastes containing other desensitizing components did

not differ significantly for the treatment of DH at .12 weeks

(Figures 13 and 14).

sensitivity analysisSensitivity analysis in which each study was eliminated indi-

vidually followed by a new meta-analysis demonstrated that

the direction of the effect did not change. Thus, the results

of the meta-analysis were deemed reliable.

Publication bias analysisDue to the difference in the number of included studies, we

generated a funnel plot at 8 weeks. The funnel plot analysis

of the 18 included studies was symmetrical, indicating no

publication bias (Figure 15).

DiscussionDH is a clinically frequent oral health problem in which

eating, breathing, and brushing teeth can cause brief, sharp

pain. DH can affect the quality of daily life. Two mechanisms

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11







Total (95% CI) 107 114 100.0%




0.04 (−0.77, 0.85)

Favors (control) Favors (experimental)

−4 −2 20 4


Subtotal (95% CI)

Subtotal (95% CI)

Kapferer et al26 1.2

10.63 2.11 32 10.83 1.89 36

6561

1.3 29 2.2 1.9 29 32.5%

33.3%

65.8%

Schiff et al25

Hamlin et al27 40 11.79 46 30.1 13.33 49 34.2%

34.2%4946


0.78 (0.36, 1.20)

0.78 (0.36, 1.20)

Heterogeneity: τ2=0.06; χ2=1.96 df =1 (P=0.16); l2=49%


−0.61 (−1.13, −0.08)

−0.10 (−0.58, 0.38)

−0.34 (−0.84, 0.16)

Figure 13 Meta-analysis of the comparison of .12-week tactile hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.





Subtotal (95% CI)

Kapferer et al26

Schiff et al25

Heterogeneity: τ2=0.03; χ2=1.53 df =1 (P=0.22); l2=35%




Subtotal (95% CI)

Hamlin et al27


Total (95% CI)



Test for overall effect: Z=1.40 (P=0.16)Favors (control)Favors (experimental)

−4 −2 20 4

31.0%29

36

65

0.34

1.21.3291

0.342.73

0.9

1.11 0.81 46 49

49

114

1.69 0.83

46

107

32

61

2.7 33.0%

64.0%

36.0%

36.0%

100.0%

−0.36 (−0.88, 0.16)

−0.12 (−0.56, 0.31)

−0.70 (−1.12, −0.29)

−0.70 (−1.12, −0.29)

−0.33 (−0.80, 0.13)

0.09 (−0.39, 0.56)

Figure 14 Meta-analysis of the comparison of .12-week air-blast hypersensitivity between the arginine-containing dentifrice group and control group.Abbreviations: SD, standard deviation; CI, confidence interval; Std, standardized; df, degree of freedom.

have been proposed for DH: 1) the function of odontoblasts

and their processes in dentinal receptor mechanisms and

2) stimulation of pulp nerves by a hydrodynamic mechanism3

and modulation of nerve impulses in the pulp by the release

of specific polypeptides during pulp injury. The most widely

used and available desensitizing toothpaste ingredients are

potassium compounds. In vitro studies have indicated that

increases in the concentration of potassium ions in the extra-

cellular fluid above physiological levels can induce nerve

cell polarization. Thus, potassium ions may block the action

potential generated in intradental nerves. Many clinical tri-

als have demonstrated that potassium-containing toothpaste

is more effective than fluoride-containing toothpaste for

the treatment of DH.34 A Cochrane systematic review also

demonstrated that potassium-containing toothpaste is more

effective for the treatment of DH.35 Strontium-containing

toothpastes are increasingly used to treat DH. The tooth

enamel and dentin absorb the strontium salt. Dentin has

a high affinity for strontium ions. Strontium carbonate

is generated when the strontium ions react with calcium

carbonate in the teeth, enhancing the acid resistance of the

teeth. Strontium salts can combine with other organic mat-

ter in dentin (such as oxyhemoglobin) and penetrate deeply

into the tooth, significantly reducing the permeability of

hard tissues and contributing to acid desensitization. Stron-

tium chloride can calm the dentin nerve and relieve pain,

slowing the conduction of the odontoblastic process and

accelerating the formation of tertiary dentinogenesis. These

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Yang et al

effects of strontium contribute to analgesic desensitization.

A toothpaste containing 8% arginine is effective for promot-

ing the closing of dentin tubules, and many clinical trials have

demonstrated a remarkable desensitization curative effect.

superiority of the meta-analysisA randomized, double-blinded, controlled study is the gold

standard of a curative effect evaluation. In this study, we per-

formed a comprehensive, strictly screened, and summarized

classification of RCTs of arginine-containing toothpaste for

DH. We systematically evaluated the research quality of

clinical studies of arginine-containing toothpaste and the treat-

ment effect of arginine-containing toothpaste in the treatment

of DH was compared to a control group in which toothpastes

contain other desensitizing components. We identified evi-

dence supporting the effective treatment of DH by arginine-

containing toothpaste. The measurement of DH is subjective,

and thus it is difficult to objectively measure and evaluate

DH. The responses to various stimuli differ, and stimuli used

to index DH must be measurable and reproducible. To avoid

mutual interference, sufficient time must be allowed for dentin

recovery between stimuli. Thus, studies should use at least two

types of stimuli (Yeaple Electronic Pressure Sensitive Probe

and Air Blast Sensitivity Assessment) to evaluate DH. This

study combined the results according to the time of evalua-

tion and the method of measuring DH. The study sample size

in each group was larger than 30 subjects, which conformed

to the requirement of the DH evaluation test and evaluation

index. Data for the tactile sensitivity scores and air-blast sen-

sitivity scores from days 0 and 3; weeks 2, 4, and 8; and more

than 12 weeks were merged. We determined that the arginine-

containing toothpaste was superior to the control toothpastes

in relieving DH at weeks 4 and 8, but was not significantly

more effective at days 0 and 3 and week 2 as indicated by the

results of the air-blast test and at more than 12 weeks as indi-

cated by the results of the tactile sensitivity and air-blast tests.

Thus, we conclude that over time, the arginine-containing

toothpaste was more effective than the other toothpastes for

the treatment of DH, but beyond 12 weeks, the effects of the

toothpastes were similar.

limitations of the meta-analysisAlthough the baseline of the included literature in this study

was comparable, the results were for subgroup analysis.

Because the data were heterogeneous, a randomization method

was adopted to assign participants to study groups to ensure

that the groups are balanced for known and unknown risk

factors to minimize bias. For the analyses, the main causes of

heterogeneity were as follows. First, there were insufficient

RCTs to evaluate the effect of the arginine-containing tooth-

paste for DH, and evidence of systematic evaluation of its

effectiveness was limited. Second, the quality of the overall

research was not high. According to the evaluation standard

for the quality of clinical trials (Cochrane Collaboration), the

risk of bias was low. The research sites were predominantly

located in the USA, Canada, and Italy, and only four research

studies were performed in the People’s Republic of China.

Thus, data on the effectiveness of arginine-containing tooth-

paste for DH in Chinese populations were insufficient. Thus,

regional differences in results cannot be ruled out. Third, there

were individual differences in subjects, and it was difficult to

treat the subjects similarly for the toothpaste dose and meth-

ods. In addition, subject compliance could not be properly

evaluated. Finally, the research cycle and measurement of

0

0.1

0.2

0.3

0.4

0.5−4 −2 0 2 4

SubgroupsArginine vs potassium Arginine vs strontium Arginine vs fluoride

SMD

SE (SMD)

Figure 15 Funnel plot analysis of the comparison of the 8-week hypersensitivity effect between the arginine-containing dentifrice group and control group.Abbreviations: se, standard error; sMD, standardized mean difference.

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the results differed greatly. Although the clinical trials for DH

treatment were normative (the evaluation results could not

avoid subjective factors completely), the specific designs of

the included studies differed greatly. For the same interven-

tions, the cycle of research and the time of evaluation were

different, and for the same measurement method, the result

index and analysis method also differed. Thus, it was difficult

to obtain a more comprehensive conclusion due to the effects

of quantitatively merging the results. Because most of the

studies were limited to time points of 8 weeks, longer term

effects on sensitivity resistance were not observed.

ConclusionThis study examined 18 RCTs including 1,423 patients. The

results support the efficacy of arginine-containing toothpaste

at 4 and 8 weeks. The effects of arginine-containing tooth-

paste exhibited a superior therapeutic effect compared to

toothpastes containing other desensitizing components as

indicated by the tactile sensitivity test (SMD =1.95, 95%

CI [1.14, 2.76]) and the air-blast test (SMD =−1.60, 95%

CI [−2.14, −1.05]) at 4 weeks and the tactile sensitivity test

(SMD =2.01, 95% CI [1.41, 2.61]) and the air-blast test

(SMD =−1.41, 95% CI [−1.83, −0.98]) at 8 weeks. However,

no significant differences between the arginine-containing

toothpaste and toothpastes containing other desensitizing

components were observed at days 0 and 3 and week 2 in the

air-blast test and more than 12 weeks in the tactile sensitivity

and air-blast tests. However, this meta-analysis is subject to

limitations (heterogeneity, quality of the evidence, limita-

tion of time, and other factors), and stronger evidence of

the superiority of arginine-containing toothpaste for DH for

providing clinical recommendations will require additional

high-quality RCTs with large sample sizes.

AcknowledgmentsThis work was supported by the Key Project of Medical

Research Program of Chongqing Municipal Health Bureau

(Grant Number: 2013-1-032) and the Science and Technol-

ogy Planning Project (Grant Number: 2014-S-013) of Yubei

District, Chongqing, People’s Republic of China.

DisclosureThe authors report no conflicts of interest in this work.

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arginine-containing desensitizing toothpaste for the