The effect of oral anti-inflammatory drugs on reducing tooth sensitivity due to in-office dental bleaching

Original Contributions

Systematic Review The effect of oral anti-inflammatory drugs on reducing tooth sensitivity due to in-office dental bleaching A systematic review and meta-analysis Huthayfa N.S. Almassri, DDS; Qiongyue Zhang, DDS; Xue Yang, DDS; Xiaohong Wu, DDS, PhD ABSTRACT Background. The authors’ aim was to evaluate the effectiveness of anti-inflammatory drugs on tooth sensitivity (TS) during and after in-office dental bleaching procedures. Types of Studies Reviewed. The authors selected randomized controlled trials in which the investigators compared anti-inflammatory drugs with a placebo to evaluate in-office dental bleaching TS. The authors performed an electronic search by using PubMed, ScienceDirect, and Embase. In addition, the authors searched other Web sites, such as ClinicalTrials.gov, to identify ongoing studies. Results. The authors included 7 randomized controlled trials (324 adults) in the review. According to the extracted data, the authors performed the meta-analysis by using risk ratios and their 95% confidence intervals or by using the mean difference with a 95% confidence interval. The authors used the Cochrane Collaboration’s tool to assess study quality. After the evaluation, the authors considered 6 studies to be high quality and a single study to be low quality. The overall results of the evaluation process revealed the absence of a clinically significant effect of anti-inflammatory drugs. Conclusions and Practical Implications. The results of this analytic process indicated that antiinflammatory drugs have no clinically significant effect on the TS that occurs due to in-office bleaching. Readers must analyze these results carefully given the limitations of this review, such as the small samples size and the heterogeneity among the studies in some stages of the evaluation process. The results of this analytical study highlight the need for more clinical studies to reach a significant conclusion because TS is one of the most important reasons for the cessation of bleaching treatment. Key Words. Tooth hypersensitivity; anti-inflammatory drugs; in-office bleaching; meta-analysis; randomized controlled trial. JADA 2019:150(10):e145-e157 https://doi.org/10.1016/j.adaj.2019.05.023

I

n the 21st century, people have become more interested in esthetic treatment because it has played an important role in the quality of life.1 The treatment of dental discoloration is no easy task.2,3 Dental bleaching is one of the best treatment methods for dental discoloration.4,5 Dental bleaching is easier, more conservative, more satisfactory, and less expensive than are other methods.6-9 Usually, the dental vital bleaching is categorized as an in-office (professionally administered), an at-home (professionally dispensed) or an over-the-counter (self administered) procedure that uses products based on hydrogen peroxide or carbamide peroxide.5,10 Although an at-home bleaching technique is the first choice, the most suitable technique for vital teeth, and probably the most common method,11-14 some patients avoid it for several reasons, such as the long duration of the procedure, the lack of clinical supervision, and the fact that treatment results are occasionally unsatisfying.12,15 In this case, in-office bleaching is a proper alternative choice14,16 because it is performed under clinical supervision, so this method is more comfortable and quicker and more satisfying results are obtained during a relatively short period.17,18 JADA 150(10)

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Despite the effectiveness of this technique in achieving the desired tooth whitening results, tooth sensitivity (TS) is the most common adverse adverse effect.19-24 In total, 55% through 90% of patients have had TS pain diagnosed after this procedure.25 The hypersensitivity appears to result from an inflammatory process in the dental pulp26,27 owing to the action of free radicals from the hydrogen peroxide (HP) that spreads through the enamel and dentin, then permeating the pulp chamber. These free radicals launch the inflammatory response of the pulp by activating nociceptive sensors,28-32 leading to continuous pain that may last 48 hours after the procedure.15,33 To treat this adverse effect caused by inflammation of the pulp during dental bleaching, many clinical researchers suggest using anti-inflammatory drugs.15,34-38 These drugs directly affect the process of inflammatory mediator production by blocking the production pathway.39 Our aim in this study was to answer the following population, intervention, comparison, outcome question: Could preventive oral anti-inflammatory drugs reduce TS due to in-office bleaching in adults? METHODS Data sources We performed the electronic search by using PubMed, ScienceDirect, and Embase. In addition, we searched other Web sites, such as ClinicalTrials.gov, to find ongoing studies related to the review topic. We performed the electronic search without any time or language restrictions. We used combinations of controlled terms (Medical Subject Headings) and specific key words for the search procedure (Box). We assessed all of the references for the studies to obtain further studies. We completed the electronic search September 3, 2018. Eligibility criteria We included randomized controlled trials involving adults if the investigators compared oral antiinflammatory medications with a placebo for bleaching-induced TS and if the bleaching procedure involved in-office dental bleaching with high-concentration HP. We excluded studies for the following reasons: use of over-the-counter products or at-home bleaching, in vitro studies, the control group not receiving a placebo, the intervention group not having an anti-inflammatory effect, the topical route being used for administration, and the inclusion of unclear data or data from which it was difficult to extract the required information. Study selection methods At the beginning of the search process, 2 of us (H.N.S.A., X.W.) excluded all duplicate studies by using software (EndNote X7, Clarivate Analytics). Then we screened the titles and abstracts to exclude irrelevant studies. The next step was to assess the full texts of the potentially relevant studies. After this screening process, we included only the studies that met the eligibility criteria. Two of us (H.N.S.A., X.W.) performed this procedure independently to evaluate the search results and determine the included studies. ABBREVIATION KEY DE: Objective color difference. HP: Hydrogen peroxide. NR: Not reported. NRS: Numeric rating scale. NSAID: Nonsteroidal antiinflammatory drug. OTC: Over the counter. RCT: Randomized controlled trial. SGU: Shade guide unit. TRPA1: Transient receptor potential ankyrin 1. TS: Tooth sensitivity. VAS: Visual analog scale. VRS: Verbal rating scale.

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Data extraction Two of us (H.N.S.A., X.W.) independently extracted the data. We extracted the following data: authors, year of publication, total sample size, age, preventive protocol, bleaching agent, data about the risk of experiencing TS, TS intensity levels, and color change evaluation values in the placebo and experimental groups. Quality assessment (risk of bias) Two of us (H.N.S.A., X.W.) independently assessed the quality (risk of bias) of the included studies. The 7 specific domains were sequence randomization (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias. According to the Cochrane Collaboration’s tool,40 we considered any study that contained at least 1 domain at high risk of bias a low-quality study. In addition, we considered any study that contained at least 1 domain at unclear risk of bias JADA 150(10)

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Box. Search terms used for the electronic database search. (bleaching) OR (whitening) OR (brightening) AND (in-office) OR (at-home) OR (OTC* products) AND (dental) OR (teeth) OR (tooth) AND (sensitivity) OR (pain) OR (hypersensitivity) AND (medication) OR (drugs) AND (anti-inflammatory) OR (nonsteroidal anti-inflammatory NSAIDs†) OR (corticosteroid) OR (analgesic) * OTC: Over the counter. † NSAID: Nonsteroidal anti-inflammatory drug.

an unclear-quality study. High-quality studies contained only low risk of bias for all specific domains. We resolved disagreements by means of discussion. Statistical analysis We performed statistical analysis according to the Cochrane Handbook for Systematic Reviews of Interventions.41 We conducted a meta-analysis of the randomized controlled trials to evaluate the efficacy of preventive anti-inflammatory drugs in reducing TS after dental bleaching treatment. We performed all statistical tests by using software (RevMan 5.3, Cochrane Community). We classified data for the outcome measures in this study as either dichotomous or continuous. Data used measured the relative risk of TS were dichotomous data that we summarized by using a risk ratio with a 95% confidence interval (CI). The other outcomes, such as the intensity levels of TS, subjective shade guide unit difference, and objective color difference (DE), were continuous data that we summarized by using the mean difference with a 95% CI. We used the standardized mean difference (SMD) rather than the mean difference when the included studies had the same results measured with different instruments. We used the Cochran test for heterogeneity to evaluate the significance of any variations in the estimates of the treatment effects of the different trials; the heterogeneity value should be taken into account when the value is greater than 0.1.42,43 We evaluated heterogeneity across the studies by using the I2 statistic, which defines the percentage of variation due to heterogeneity rather than chance.44 We considered I2 greater than 50% as indicating moderate to high levels of heterogeneity. We performed subgroup analyses according to the type of anti-inflammatory medications for all of these study outcomes, except 1 outcome that measured intensity levels of TS immediately after the bleaching procedure. In addition, we could not assess publication bias because of the limited number of studies included in the meta-analysis. RESULTS Study selection The electronic search resulted in 1,562 studies (Figure 1). The reviewers excluded 1,547 studies after the first phase of the search and evaluation process; thus, 15 studies remained for the second phase of the evaluation process according to eligibility criteria. The outcome of the second stage was the acceptance of 7 studies and the rejection of 8 studies. We describe the reasons for rejection in Table 1.7,19,25,32,45-48 Included studies characteristics We listed the details of the included studies in Table 2.15,34-38,49 The included studies were published by authors from the United States34 and Brazil15,35-38,49 from 2009 through 2018. The sample size for each study ranged from 15 through 35 patients who received either preventive antiinflammatory medication or a placebo. The total number of patients in this meta-analysis was 324 adults. The inclusion criteria for these studies were patients who were 18 years or older, in good oral health, and with caries-free maxillary anterior teeth without restorations. In all of the studies, the investigators reported the TS evaluation for the maxillary anterior teeth. The type and dosage of anti-inflammatory drugs varied among the included studies; investigators in JADA 150(10)

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Initial search (n = 1,562)

Duplicates (n = 958)

Titles and abstracts screened (n = 604)

Irrelevant studies (n = 589)

Potentially relevant studies (n = 15)

Excluded studies (n = 8)

Included studies (n = 7) Figure 1. Study selection process.

5 studies used nonsteroidal anti-inflammatory drug (NSAIDs; dosage range, 60-600 milligrams),15,34,36,37,49 and investigators in 2 studies used corticosteroid drugs (dosage range, 4-8 mg).35,38 The investigators administered anti-inflammatory drugs and the placebo at different timesdthat is, a single dose preoperatively34,36,49 or multiple doses preoperatively and postoperatively15,35,37,38 (Table 3).15,34-38,49,50-54 In all studies, the investigators administered the placebo as inactive material without any desensitizing substance, except for da Costa Poubel and colleagues35 who provided desensitizing gel (6% potassium nitrate and 0.1% fluoride sodium) with the placebo for research approval and protection of human participants. The investigators administered the drugs and placebo orally. Investigators used HP as the in-office bleaching agent in all studies. The concentration of HP was 35% in 5 studies,15,36-38,49 37.5% in 1 study,35 and 38% in 1 study.34 The investigators reported the relative risk of TS in 6 studies.15,35-38,49 The investigators reported intensity levels of TS in all studies but with different measurement methods: visual analog scale (VAS), verbal rating scale (VRS), and numeric rating scale (NRS). The investigators used VAS for pain assessment in all included studies. The investigators also used VRS for pain assessment in 3 studies.36,37,49 The investigators also used NRS for pain assessment in 2 studies.35,38 Moreover, investigators in 1 study used both the VRS and NRS as additional pain assessment.15 Investigators in all of the included studies, except for the study by Charakorn and colleagues,34 evaluated the effectiveness and the degree of color variation after dental bleaching. These studies’ investigators assessed the subjective color change by using shade guides (including the Vita classical and the Vita Bleachedguide 3D-MASTER [Vita Zahnfabrik]), but investigators in some studies also used an objective color change assessment as an additional evaluation with a spectrophotometer (Vita Easyshade, Vita Zahnfabrik). We performed statistical analysis for studies in which the investigators conducted the evaluation of bleaching-induced TS during or up to 24 hours after dental bleaching or the assessment of color change after 1 month. Risk-of-bias assessment One of the criteria for including a study in the statistical analysis was the determination of the study quality. We used the Cochrane evaluation tool to assess the quality of the studies.40 We considered 6 of the 7 studies that we used for statistical analysis high-quality studies, and we considered the remaining 1 a low-quality study. We reported the judgment for each study in Figure 2.15,34-38,49 This assessment’s results showed that researchers followed the criteria for obtaining high-quality studies e148

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Table 1. Excluded studies with reasons for exclusion. TYPE OF STUDY

STUDY Reis,

45

INTERVENTION GROUP VERSUS CONTROL GROUP

BLEACHING AGENT

OUTCOMES ASSESSED †

REASON FOR EXCLUSION

2012

RCT*

Ibuprofen versus placebo

35% hydrogen peroxide

VAS SGU‡ DE§

Incomplete data, incomplete results reported

de Paula and Colleagues,25 2014

RCT

Ascorbic acid versus placebo

35% hydrogen peroxide

VAS NRS{ SGU DE

Intervention group with antioxidant effect, not anti-inflammatory effect

de Souza and Colleagues,32 2014

Review

NR#

NR

NR

Review study, not interventional study

Faria-e-Silva and Colleagues,46 2015

Review

NR

NR

NR

Systematic review and meta-analysis

da Costa Poubel,47 2016

RCT

Dexamethasone versus placebo

NR

VAS

Incomplete data, incomplete results reported

Carneiro and Colleagues,7 2017

RCT

Paracetamol versus dipyrone

NR

VAS

No placebo as control group

Coppla and Colleagues,48 2018

RCT

Acetaminophen with codeine versus placebo

35% hydrogen peroxide

VAS NRS SGU DE

Intervention group with analgesic effect, not anti-inflammatory effect

Rezende and Colleagues,19 2018

RCT

Dipyrone versus placebo

35% hydrogen peroxide

VAS NRS SGU DE

Topical rather than oral administration route

* RCT: Randomized controlled trial. † VAS: Visual analog scale. ‡ SGU: Shade guide unit (subjective evaluation). § DE: Color difference (objective evaluation with spectrophotometer; VITA Easyshade, VITA Zahnfabrik). { NRS: Numeric rating scale. # NR: Not reported.

Table 2. Details of the included studies. PARTICIPANTS, NO.

STUDY

ANTIINFLAMMATORY DRUG

BLEACHING AGENT

Control, Experimental

OUTCOME Tooth Sensitivity Color Scale Assessment

Risk of Tooth Sensitivity

Charakorn and Colleagues,34 2009

16, 15

NSAID*: ibuprofen

38% hydrogen peroxide

VAS† 0-100

Not reported

No

de Paula and Colleagues,15 2013

15, 15

NSAID: etoricoxib

35% hydrogen peroxide

VAS 0-10 VRS‡ 0-4 NRS 0-4

SGU§ DE{

Yes

Paula and Colleagues,37 2013

15, 15

NSAID: ibuprofen

35% hydrogen peroxide

VAS 0-10 VRS 0-4

SGU DE

Yes

Rezende and Colleagues,38 2016

30, 33

Corticosteroid: dexamethasone

35% hydrogen peroxide

VAS 0-10 NRS# 0-4

SGU DE

Yes

Fernandes and Colleagues,36 2017

25, 25

NSAID: naproxen

35% hydrogen peroxide

VAS 0-10 VRS 0-4

SGU

Yes

da Costa Poubel and Colleagues,35 2018

35, 35

Corticosteroid: dexamethasone

37.5% hydrogen peroxide

VAS 0-100 NRS 0-4

SGU

Yes

Vaez and Colleagues,49 2018

25, 25

NSAID: etodolac

35% hydrogen peroxide

VAS 0-10 VRS 0-4

Bleach guide scale

Yes

* NSAID: Nonsteroidal anti-inflammatory drug. † VAS: Visual analog scale. ‡ VRS: Verbal rating scale. § SGU: Shade guide unit (subjective evaluation). { DE: Color difference (objective evaluation with spectrophotometer; VITA Easyshade, VITA Zahnfabrik). # NRS: Numeric rating scale.

and avoided a significantly high risk of bias in all but 1 study34 in which the investigators had many weaknesses, such as lack of clarity of randomization, allocation, and performance. Moreover, the loss of patients during the procedure indicated that the value of attrition bias was high.

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Table 3. Details of the drug administration protocols.

STUDY

ANTISINGLE OR INFLAMMATORY DOSE SIZE, MULTIPLE DRUGS MILLIGRAMS DOSE

TIME OF ADMINISTRATION

MAXIMUM DOSE, MG PER DAY*

Charakorn and Colleagues,34 2009

NSAID†: ibuprofen

600

Single

30 minutes before bleaching

3,20050

de Paula and Colleagues,15 2013

NSAID: etoricoxib

60

Multiple

1 hour before bleaching and 24 h after

12051

Paula and Colleagues,37 2013

NSAID: ibuprofen

400

Multiple

3 times per day for 48 h; first dose administered 1 h before bleaching

3,20050

Rezende and Colleagues,38 2016

Corticosteroid: dexamethasone

8 and 4

Multiple

8 mg 1 h before bleaching and extra 4 mg every 6 h for 48 h after bleaching

1552

NSAID: naproxen

500

Single

da Costa Poubel and Colleagues,35 2018

Corticosteroid: dexamethasone

8

Multiple

Vaez and Colleagues,49 2018

NSAID: etodolac

400

Single

Fernandes and Colleagues,36 2017

1,00053

1 h before bleaching

1552

8 mg 3 times per day starting 48 h before bleaching

1,20054

1 h before bleaching

* The maximum dose per day values are not related to the included studies. These values indicate the maximum allowable dose per day to be used in general. † NSAID: Nonsteroidal anti-inflammatory drug.

Outcome measures Relative Risk of Experiencing TS We divided 6 studies into 2 subgroups in which the investigators measured the relative risk of experiencing TS during the dental bleaching procedure (Figure 3).15,35-38,49 The pooled risk ratio for TS with use of anti-inflammatory agents versus a placebo was 0.98 (95% CI, 0.87 to 1.10), and the heterogeneity was 8% (I2 ¼ 8%; P ¼ 0.74). Individual and pooled analysis results showed a nonsignificant trend in the reduction of the relative risk of experiencing TS during dental bleaching treatment. TS Intensity During the Procedure Figure 435,36,38 includes 3 studies in which the pooled SMD for TS with use of anti-inflammatory drugs versus placebo was 0.16 (95% CI, 0.13 to 0.45), and the heterogeneity was 0% (I2 ¼ 0%). Statistical analysis results in this figure showed that the anti-inflammatory drugs had a nonsignificant effect on reducing the intensity of TS during dental bleaching. TS Intensity Immediately After Tooth Bleaching Figure 534,36 shows that the pooled SMD for TS with use of anti-inflammatory drugs versus placebo immediately after dental bleaching was 0.40 (95% CI, 1.32 to 0.52; I2 ¼ 75%). The P value was greater than .05 (P ¼ .40). These values showed that the anti-inflammatory drugs had a nonsignificant effect on reducing the intensity of TS immediately after dental bleaching. TS Intensity Up to 1 Hour After Tooth Bleaching Figure 615,34,35,37,38 shows 5 studies in which the investigators assessed TS up to 1 hour after tooth bleaching. The pooled SMD for TS with use of anti-inflammatory drugs versus placebo was 0.22 (95% CI, 0.49 to 0.04; I2 ¼ 0%). The statistical findings in this figure showed that the antiinflammatory drugs had a nonsignificant effect on reducing the intensity of TS up to 1 hour after dental bleaching. TS Intensity Up to 24 Hours After Tooth Bleaching We divided 5 studies into 2 subgroups in which the investigators measured the intensity of TS up to 24 hours after dental bleaching (Figure 7).15,34,35,37,38 The pooled SMD for TS with use of e150

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?

?

?

–

+

+

de Paula and Colleagues,15 2013

+

+

+

+

+

+

+

Paula and Colleagues,37 2013

+

+

+

+

+

+

+

Rezende and Colleagues,38 2016

+

+

+

+

+

+

+

Fernandes and Colleagues,36 2017

+

+

+

+

+

+

+

da Costa Poubel and Colleagues,35 2018

+

+

+

+

+

+

+

Vaez and Colleagues,49 2018

+

+

+

+

+

+

+

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STUDIES

Charakorn and Colleagues,34 2009

DOMAIN Figure 2. Risk-of-bias analysis. (þ): Low risk of bias. (): High risk of bias. (?): Unclear risk of bias.

anti-inflammatory drugs versus a placebo was 0.16 (95% CI, 0.42 to 0.10; I2 ¼ 0%; P ¼ .23). These statistical findings showed that the anti-inflammatory drugs had a nonsignificant effect on reducing the intensity of TS up to 24 hours after dental bleaching. Change in Shade Guide Unit Difference Evaluated 1 Month After Bleaching Investigators in 3 studies evaluated the shade guide unit difference after 1 month. The assessment result was 0.12 (95% CI, 0.72 to 0.97; P ¼ .78). This result in Figure 815,37,38 shows both the antiinflammatory drugs and placebo groups had a clinically significant whitening result. In addition, the anti-inflammatory drugs had no clinically significant effect on bleaching efficacy and color change after bleaching. DE Evaluated 1 Month After Bleaching Figure 915,37,38 shows 3 studies in which the investigators evaluated the tooth shade by using a spectrophotometer. The pooled mean difference for change in DE was 0.17 (95% CI, 1.95 to 1.61; P ¼ .85). This result indicated the anti-inflammatory drugs had no significant effect on bleaching efficacy and color change after bleaching. DISCUSSION Our aim in this study was to perform a systematic review and meta-analysis of the effectiveness of preventive oral anti-inflammatory drugs on bleaching-induced TS. As we have reported, tooth whitening is one of the most common procedures for dental discoloration treatment, and sensitivity after dental bleaching remains a challenge for clinicians because it is considered an adverse effect of in-office bleaching and the most common reason for treatment failure.2,4,5 TS is dental pain that has many different causes.55 However, Haywood56 noticed a different type of TS pain that was not caused by stimulation to feel pain. This observation confirms that dental hypersensitivity may occur in intact teeth without exposed dentin.31 In this case, the adverse effects that occur to the pulp from tooth whitening correlate directly with the effect of the HP particles JADA 150(10)

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Anti-Inflammatory Drug

Placebo

Events Total

Events Total

Study or Subgroup

Risk Ratio

Risk Ratio

Mantel-Haenszel,

Mantel-Haenszel,

Weight Random-Effects Model, (%) 95% CI

Random-Effects Model, 95% CI

1.1.1 Nonsteroidal anti-inflammatory drugs de Paula and Colleagues,15 2013 Paula and Colleagues,37 2013 Fernandes and Colleagues,36 2017 Vaez and Colleagues,49 2018 Subtotal (95% CI)

11 13 14 10

Total events

48

15 15 25 25 80

9 12 10 11

15 15 25 25 80

5.2 12.6 3.9 3.2 24.9

1.22 (0.73 to 2.04) 1.08 (0.79 to 1.49) 1.40 (0.77 to 2.53) 0.91 (0.47 to 1.75) 1.13 (0.90 to 1.42)

30 35 65

41.6 33.5 75.1

1.01 (0.86 to 1.19) 0.85 (0.71 to 1.02) 0.93 (0.78 to 1.11)

145

100.0

0.98 (0.87 to 1.10)

42

Heterogeneity: τ2 = 0.00; χ23 = 1 .09, P = .78; I2 = 0% Test for overall effect: z = 1.03 (P = .30) 1.1.2 Corticosteroid drug Rezende and Colleagues,38 2016 da Costa Poubel and Colleagues,35 2018 Subtotal (95% CI)

30 28

Total events

58

33 35 68

27 33 60

Heterogeneity: τ2 = 0.01; χ21 = 2.01, P = .16; I2 = 50% Test for overall effect: z = 0.81 (P = .42) 148

Total (95% CI) 106

Total events

102

Heterogeneity: τ2 = 0.00; χ25 = 5.46, P = .36; I2 = 8% Test for overall effect: z = 0.33 (P = .74) Test for subgroup differences: χ21 = 1.71, P = .19; I2 = 41.5%

0.2 0.5 Anti-Inflammatory Drug

1

2 Placebo

5

Figure 3. Forest plot of the relative risk of experiencing tooth sensitivity. CI: Confidence interval.

Standardized Standardized Mean Difference IV, Mean Difference IV, Weight Random-Effects Model, Random-Effects Model, Mean (Standard Mean (Standard 95% CI 95% CI Deviation) Total Deviation) Total (%)

Anti-Inflammatory Drug Study or Subgroup

1.2.1 Nonsteroidal anti-inflammatory drugs Fernandes and Colleagues,36 2017 2.51 (2.09) Subtotal (95% CI)

25 25

Placebo

1.66 (2.05)

25 25

27.0 27.0

0.40 (–0.16 to 0.96) 0.40 (–0.16 to 0.96)

Heterogeneity: not applicable Test for overall effect: z = 1.41 (P = .16) 1.2.2 Corticosteroid drug Rezende and Colleagues,38 2016

3.2 (2.7)

da Costa Poubel and Colleagues,35 2018 Subtotal (95% CI)

7.51 (15.46)

33 35 68

2.7 (2.3) 8.09 (17.06)

30

34.5

0.20 (–0.30 to 0.69)

35 65

38.6 73.1

–0.04 (–0.50 to 0.43) 0.07 (–0.27 to 0.41)

90

100.0

0.16 (–0.13 to 0.45)

Heterogeneity: τ2 = 0.00; χ21 = 0.44, P = .51; I2 = 0% Test for overall effect: z = 0.43 (P = .67) Total (95% CI)

93

Heterogeneity: τ2 = 0.00; χ22 = 1.42, P = .49; I2 = 0%

–4

Test for overall effect: z = 1.10 (P = .27) Test for subgroup differences: χ21 = 0.97, P = .32; I2 = 0%

–2

0

Anti-Inflammatory Drug

2

4

Placebo

Figure 4. Forest plot of tooth sensitivity intensity during the procedure. CI: Confidence interval. IV: Inverse variance.

that penetrate the pulp, which leads to pulpal damage on the release of inflammatory mediators.16,20,35 These mediators are soluble and diffusible molecules that act locally in the inflammatory area. These mediators perform many functions, such as vasodilation, increased vascular permeability, phagocytosis, apoptosis, and pain sensation. In general, these features are the signs of inflammation.57,58 According to this theory,31 many investigators expect successful and effective use of preventive anti-inflammatory drugs to reduce or prevent bleaching-induced TS. However, there is no proven and clear theory that explains the causes and mechanism of whitening-induced TS.35,48,49 Usually, the pain is mild to moderate and relieved within 24 through 48 hours after the procedure; however, e152

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Study or Subgroup

Anti-Inflammatory Drug Mean (Standard Total Deviation)

Standardized Placebo Mean Difference IV, Mean (Standard Weight Random-Effects Model, Total (%) Deviation) 95% CI

Standardized Mean Difference IV, Random-Effects Model, 95% CI

1.3.1 Nonsteroidal anti-inflammatory drugs Charakorn and Colleagues,34 2009

5 (9.9)

Fernandes and Colleagues,36 2017

2.09 (2.19)

Subtotal (95% CI)

26.6 (31)

15

16

46.4

25

53.6

0.04 (–0.51 to 0.59)

40

41

100.0

–0.40 (–1.32 to 0.52)

40

41

100.0

–0.40 (–1.32 to 0.52)

2 (2.25)

25

–0.90 (–1.65 to –0.16)

Heterogeneity: τ2 = 0.33; χ21 = 3.95, P = .05; I2 = 75% Test for overall effect: z = 0.85 (P = .40) Total (95% CI) Heterogeneity: τ2 = 0.33; χ21 = 3.95, P = .05; I2 = 75%

–4 –2 Anti-Inflammatory Drug

Test for overall effect: z = 0.85 (P = .40) Test for subgroup differences: not applicable

0

2 Placebo

4

Figure 5. Forest plot of tooth sensitivity intensity immediately after tooth bleaching. CI: Confidence interval. IV: Inverse variance.

Standardized Anti-Inflammatory Drug Placebo Mean Difference IV, Mean (Standard Mean (Standard Weight Random-Effects Model, Deviation) Deviation) Total Total (%) 95% CI

Study or Subgroup

Standardized Mean Difference IV, Random-Effects Model, 95% CI

1.4.1 Nonsteroidal anti-inflammatory drugs Charakorn and Colleagues,34 2009

31.5 (32.1)

15

30.9 (30.5)

16

14.0

0.02 (–0.69 to 0.72)

de Paula and Colleagues,15 2013

37.3 (26.7)

15

40.1 (28.7)

15

13.6

–0.10 (–0.81 to 0.62)

15

3.3 (2.9)

15

12.7

–0.70 (–1.44 to 0.04)

46

40.3

–0.25 (–0.68 to 0.18)

Paula and Colleagues,37 2013

1.5 (2)

Subtotal (95% CI)

45

Heterogeneity: τ2 = 0.01; χ22 = 2.17, P = .34; I2 = 8% Test for overall effect: z = 1.13 (P = .26) 1.4.2 Corticosteroid drug Rezende and Colleagues,38 2016

3.5 (2.7)

da Costa Poubel and Colleagues,35 2018

7.57 (13.46)

Subtotal (95% CI)

33

3.5 (2.9)

30

28.5

0.00 (–0.49 to 0.49)

35

14.31 (20.13)

35

31.1

–0.39 (–0.86 to 0.08)

68

65

59.6

–0.20 (–0.58 to 0.18)

113

111

100.0

–0.22 (–0.49 to 0.04)

Heterogeneity: τ2 = 0.01; χ21 = 1.24, P = .26; I2 = 20% Test for overall effect: z = 1.04 (P = .30) Total (95% CI) Heterogeneity: τ2 = 0.00; χ24 = 3.44, P = .49; I2 = 0% Test for overall effect: z = 1.64 (P = .10) Test for subgroup differences: χ21 = 0.03, P = .87; I2 = 0%

–2 –1 Anti-Inflammatory Drug

0

1 Placebo

2

Figure 6. Forest plot of tooth sensitivity intensity up to 1 hour after tooth bleaching. CI: Confidence interval. IV: Inverse variance.

the pain occasionally worsens, which often leads to treatment failure.15,35 In our study, despite the different mechanisms of action and administration protocol of drugs tested in the included studies, the investigators used all of the drugs for a common goaldnamely, to remedy pain by reducing inflammation.59 NSAIDs reduce pain by acting on the cyclooxygenase enzyme. The cyclooxygenase enzyme synthesizes prostaglandins, which are inflammatory mediators. In general, NSAIDs prevent inflammatory mediator production to reduce or eliminate the pain.60 Steroidal anti-inflammatory drugs prevent the mechanisms that activate the inflammatory response, thus reducing the levels of pro-inflammatory chemical mediators at the inflammatory area and relieving inflammatory signs.35,61 The final results of these studies showed no clinically significant effect of oral preventive antiinflammatory drugs on the risk of experiencing TS during dental bleaching or on the intensity levels of TS evaluated during and up to 24 hours after the dental bleaching procedure. No clinically significant results appeared in all evaluation stages for all except 2 studies.34,36 In the first study, the test group showed a statistically significant lower mean VAS score immediately after bleaching than did the control group, and this study’s results suggested that the result likely was related to the pharmacokinetic properties of the drug.34 The other study’s results showed significance at the second bleaching session.36 The study’s investigators suggested the possibility

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Standardized Standardized Mean Difference IV, Mean Difference IV, Anti-Inflammatory Drug Placebo Mean (Standard Mean (Standard Weight Random-Effects Model, Random-Effects Model, Deviation) Total (%) Deviation) Total 95% CI 95% CI

Study or Subgroup

1.5.1 Nonsteroidal anti-inflammatory drugs Charakorn and Colleagues,34 2009

25.8 (30.8)

15

31.1 (32.6)

16

13.9

–0.16 (–0.87 to 0.54)

de Paula and Colleagues,15 2013

22.5 (29.3)

15

30.6 (28.6)

15

13.4

–0.27 (–0.99 to 0.45)

15

2.4 (2.7)

15

13.4

0.21 (–0.51 to 0.93)

46

40.7

–0.07 (–0.49 to 0.34)

30

28.2

–0.11 (–0.60 to 0.38)

35

31.1

–0.32 (–0.79 to 0.15)

68

65

59.3

–0.22 (–0.56 to 0.12)

113

111

100.0

–0.16 (–0.42 to 0.10)

Paula and Colleagues,37 2013

3 (2.8)

45

Subtotal (95% CI) Heterogeneity: τ2 = 0.00; χ22 = 0.96, P = .62; I2 = 0% Test for overall effect: z = 0.36 (P = .72) 1.5.2 Corticosteroid drug 1.9 (2.6)

Rezende and Colleagues,38 2016 da Costa Poubel and Colleagues,35 2018

33

9.77 (20.55)

Subtotal (95% CI)

35

2.2 (2.8) 16.6 (21.57)

Heterogeneity: τ2 = 0.00; χ21 = 0.37, P = .55; I2 = 0% Test for overall effect: z = 1.26 (P = .21) Total (95% CI) Heterogeneity: τ2 = 0.00; χ24 = 1.61, P = .81; I2 = 0% Test for overall effect: z = 1.20 (P = .23)

–4

Test for subgroup differences: χ21 = 0.28, P = .59; I2 = 0%

–2

0

Anti-Inflammatory Drug

2

4

Placebo

Figure 7. Forest plot of tooth sensitivity intensity up to 24 hours after tooth bleaching. CI: Confidence interval. IV: Inverse variance.

Anti-Inflammatory Drug Placebo Mean Difference IV, Mean Difference IV, Mean (Standard Mean (Standard Weight Random-Effects Model, Random-Effects Model, Deviation) Deviation) Total (%) Total 95% CI 95% CI

Study or Subgroup

2.1.1 Nonsteroidal anti-inflammatory drugs de Paula and Colleagues,15 2013

4.5 (1.6)

15

3.9 (1.8)

15

38.6

0.60 (–0.62 to 1.82)

Paula and Colleagues,37 2013

4.3 (2.7)

15

5.3 (1.9)

15

22.7

–1.00 (–2.67 to 0.67)

30

61.3

–0.09 (–1.65 to 1.46)

30

Subtotal (95% CI) Heterogeneity: τ2 = 0.72; χ21 = 2.30, P = .13; I2 = 57% Test for overall effect: z = 0.12 (P = .91) 2.1.2 Corticosteroid drug Rezende and Colleagues,38 2016

3.4 (2.3)

Subtotal (95% CI)

33

30

38.7

0.30 (–0.92 to 1.52)

33

3.1 (2.6)

30

38.7

0.30 (–0.92 to 1.52)

63

60

100.0

0.12 (–0.72 to 0.97)

Heterogeneity: not applicable Test for overall effect: z = 0.48 (P = .63) Total (95% CI) Heterogeneity: τ2 = 0.10; χ22 = 2.40, P = .30; I2 = 17% Test for overall effect: z = 0.28 (P = .78) Test for subgroup differences: χ21 = 0.15, P = .70; I2 = 0%

–10 –5 Anti-Inflammatory Drug

0

5

10

Placebo

Figure 8. Forest plot of the change in shade guide unit difference 1 month after bleaching. CI: Confidence interval. IV: Inverse variance.

of increased peroxide concentrations in the second session, and the number of times pulp tissue was exposed to a bleaching agent was related closely to the inflammatory response. Therefore, an increased level of inflammatory mediators can be expected after the second session compared with that observed after the first session, thus increasing the effectiveness of the drug. According to Vaez and colleagues49 who had the same study design as all the other studies,15,34,35,37,38 the results did not change in the second session; however, investigators in all studies included 2 sessions, and the probability of increased concentrations of peroxide particles in the second session was mostly the same as the probability of this study. From this perspective, this reason seems insufficient to explain the different results of the second session. Investigators in all of the included studies achieved the bleaching in 2 sessions with a 1-week interval. Investigators assessed TS at both sessions. If they provided the evaluation outcomes separately for each session, we selected the worst results as the final result for analysis. e154

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Study or Subgroup

Anti-Inflammatory Drug Placebo Mean Difference IV, Mean Difference IV, Weight Random-Effects Model, Random-Effects Model, Mean (Standard Mean (Standard (%) Deviation) Total Deviation) Total 95% CI 95% CI

2.2.1 Nonsteroidal anti-inflammatory drugs de Paula and Colleagues,15 2013 Paula and Colleagues,37 2013 Subtotal (95% CI)

8.1 (3.3) 5.9 (2.1)

15 15 30

7.2 (2.5) 7.8 (3.3)

15 15 30

33.1 34.8 67.9

0.90 (–1.20 to 3.00) –1.90 (–3.88 to 0.08) –0.52 (–3.27 to 2.22)

33 33

6 (4.7)

30 30

32.1 32.1

0.60 (–1.57 to 2.77) 0.60 (–1.57 to 2.77)

60

100.0

–0.17 (–1.95 to 1.61)

Heterogeneity: τ2 = 2.84; χ21 = 3.63, P = .06; I2 = 72% Test for overall effect: z = 0.37 (P = .71) 2.2.2 Corticosteroid drug Rezende and Colleagues,38 2016 Subtotal (95% CI)

6.6 (4)

Heterogeneity: not applicable Test for overall effect: z = 0.54 (P = .59) 63

Total (95% CI) Heterogeneity: τ2 = 1.36; χ22 = 4.42, P = .11; I2 = 55%

Test for overall effect: z = 0.19 (P = .85) Test for subgroup differences: χ21 = 0.40, P = .53; I2 = 0%

–10 –5 Anti-Inflammatory Drug

0

5

10

Placebo

Figure 9. Forest plot of change in objective color difference 1 month after bleaching. CI: Confidence interval. IV: Inverse variance.

Although the final results were not as expected, there are many reasons that may explain these findings. The first reason is likely the drug administration route. In this study, we selected clinical studies in which the investigators used the oral route as a pathway for drug or placebo administration. The oral route has a first-pass effect (first-pass metabolism), which is a phenomenon of drug metabolism whereby the concentration of a drug is reduced greatly before it reaches the systemic circulation or the inflammatory area.62 This route may have led to nonsignificant results because the amount of the effective drug substances that reached the inflammatory area was insufficient to induce a significant effect because the drug dose was less likely to have a therapeutic effect, and none of the studies reached the maximum dose per day (Table 2).15,34-38,49 Rezende and colleagues19 used the topical method and obtained a result similar to that in this study. However, the topical route was effective in reducing TS according to a meta-analysis1 that was performed to evaluate the efficacy of desensitizing agents (potassium nitrate and sodium fluoride) for tooth bleaching treatments. The second reason may be related to the rate, the extent of oral drug absorption, and the time of drug arrival to the inflammatory area, which were influenced by physicochemical properties, physiological factors, the dose form of the drug, and the nature of the pulp-dentin complex.25,63 Investigators in all of the studies used the protocol with single or multiple doses before a short period of bleaching, except for da Costa Poubel and colleagues,35 who noted that the antiinflammatory effect often does not occur directly and requires hours or even days to appear because of drug absorption rates and kinetic properties. Although da Costa Poubel and colleagues35 predicted that changing the protocol to another protocol of administering 3 doses of drug 48, 24, and 1 hour before bleaching may inhibit most inflammatory mediators and relieve pain, the results that appeared were similar to those in previous studies.15,34,36-38,49 Thus, this finding may indicate that this explanation has a weak probability of explaining these unexpected results. The third reason is potentially due to the mechanism of pain. It is likely that another mechanism of pain stimulation is related to bleaching-induced TS that is different from the paintriggering mechanisms through which these drugs function. Although the included studies in which the investigators tested drugs involved using drugs that had different mechanisms of actiondthat is, NSAIDs, selective anti-inflammatory medicine, and corticosteroidsdthe investigators in all of the studies arrived at the same conclusion. Results from some studies suggested that dental pain may be attributed to transient receptor potential ankyrin 1 (TRPA1) stimulation.64,65 TRPA1 is a nonselective cation channel that acts as a polymodal sensor with nociception action that is activated by a variety of chemical irritants, endogenous inflammatory mediators, and physical stimuli.66-68 Some clinical researchers noticed that the reactive oxygen species, such as HP, stimulate TRPA1.66,69 In the end, the results from these studies suggest a relationship between the TRPA1 and bleaching-induced TS. Thus, more clinical studies

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are required to understand the nature of the relationship between TRPA1 and bleachinginduced TS. In addition to the evaluation of bleaching-induced TS, the investigators recorded the effect of preventive anti-inflammatory drugs on the efficiency of dental bleaching and color change before and 1 month after dental bleaching.15,37,38 Investigators used the 1-month period to reduce the effect of dehydration and demineralization that resulted from the bleaching procedure on the color change assessment process.38 Results from all of the studies15,37,38 that we included in this meta-analysis showed clinically significant whitening results in both study groups (anti-inflammatory and placebo) according to subjective and objective evaluation methods. Results of the statistical analysis of these studies showed that anti-inflammatory drugs had no effect on the efficiency of dental bleaching or color change. The VAS measurement is a horizontal or vertical line with scores of 0 at the beginning and 100 or 10 at the end according to the length of the VAS measurement.70 Despite the prevalence and simplicity of this measurement for pain intensity evaluation, it is not the standard form of pain measurement because it contains many weak aspects, such as the importance of understanding this measurement to provide correct results, which primarily is observed in patients who are older and illiterate.71 Therefore, investigators in all of the included studies, except Charakorn and colleagues,34 used other measures, such as the VRS and NRS, to confirm the results. CONCLUSIONS The results from this study did not show any clinically significant effect of oral anti-inflammatory drugs on reducing bleaching-induced TS. However, these findings must be analyzed carefully. Therefore, high-quality studies with larger sample sizes and evaluation of other types of antiinflammatory drugs are needed to describe adequately the effectiveness of oral anti-inflammatory drugs on reducing bleaching-induced TS. n

Dr. Almassri is a master’s student, Department of Prosthodontics, Affiliated Hospital of Stomatology, Chongqing Medical University, Yubei District, Chongqing; a master’s student, Chongqing Key Laboratory Oral Diseases and Biomedical Sciences, Chongqing; and a master’s student, Key Laboratory of Oral Diseases and Biomedical Sciences, Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. Dr. Zhang is a master’s student, Department of Prosthodontics, Affiliated Hospital of Stomatology, Chongqing Medical University, Yubei District, Chongqing; a master’s student, Chongqing Key Laboratory Oral Diseases and Biomedical Sciences, Chongqing; and a master’s student, Key Laboratory of Oral Diseases and Biomedical Sciences, Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. Dr. Yang is a master’s student, Department of Prosthodontics, Affiliated Hospital of Stomatology, Chongqing Medical University, Yubei District, Chongqing; a master’s student, Chongqing Key Laboratory Oral Diseases and Biomedical Sciences, Chongqing; and a master’s student, Key Laboratory of Oral Diseases and Biomedical Sciences, Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China.

1. Wang Y, Gao J, Jiang T, Liang S, Zhou Y, Matis BA. Evaluation of the efficacy of potassium nitrate and sodium fluoride as desensitizing agents during tooth bleaching treatment: a systematic review and meta-analysis. J Dent. 2015;43(8):913-923. 2. Alkhatib M, Holt R, Bedi R. Prevalence of selfassessed tooth discolouration in the United Kingdom. J Dent. 2004;32(7):561-566. 3. Xiao J, Zhou XD, Zhu WC, Zhang B, Li JY, Xu X. The prevalence of tooth discolouration and the selfsatisfaction with tooth colour in a Chinese urban population. J Oral Rehabil. 2007;34(5):351-360. 4. Tin-Oo MM, Saddki N, Hassan N. Factors influencing patient satisfaction with dental appearance and

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Dr. Wu is an associate professor, Department of Prosthodontics, Affiliated Hospital of Stomatology, Chongqing Medical University, Yubei District, Chongqing; an associate professor, Chongqing Key Laboratory Oral Diseases and Biomedical Sciences, Chongqing; and an associate professor, Key Laboratory of Oral Diseases and Biomedical Sciences, Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. Address correspondence to Dr. Wu at Department of Prosthodontics, Affiliated Hospital of Stomatology, Chongqing Medical University, No. 426 Songshibei Rd., Yubei District, Chongqing 401147, China, e-mail hiwxh@ hotmail.com. Disclosure. None of the authors reported any disclosures. This work was supported by grant 81200767/H1402 from the National Natural Science Foundation of China, grant cstc2017jcyjAX0215 from Chongqing Science and Technology Commission, China, grant 20170117 from Chongqing Yuzhong Science and Technology Project, China, and a project supported by a program for innovation team building at institutions of higher education in Chongqing, China, in 2016.

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