Clinical Oral Investigations

https://doi.org/10.1007/s00784-021-03994-6

REVIEW

Topical application of a desensitizing agent containing potassium

nitrate before dental bleaching: a systematic
review and meta-analysis
E. C. Martini 1 & M. W. Favoreto 1 & M. Rezende 2 & J. L. de Geus 2 & A. D. Loguercio 1 & A. Reis 1

Received: 6 July 2020 / Accepted: 17 May 2021

# The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Objectives To conduct a systematic review and meta-analysis to evaluate the risk and intensity of tooth sensitivity (TS) after
topical application of desensitizers containing potassium nitrate before dental bleaching.
Methods We searched PubMed, Scopus, Web of Science, LILACS, BBO, Cochrane Library, and SIGLE. We also surveyed gray
literature without restrictions. We meta-analyzed the data using the random-effects model to compare potassium nitrate and
placebo in terms of risk and intensity of TS and color change (ΔSGU or ΔE). The quality of the evidence was rated using the
GRADE approach. The risk of bias (RoB) of the included studies was analyzed using the Cochrane RoB tool.
Results After the database screening, 24 articles remained. A significant 12% lower risk for the groups where desensitizing
agents were applied (p = 0.02), with a risk ratio of 0.88 (95% CI 0.78 to 0.98). About the intensity of TS, a significant average
mean difference of − 0.77 units of VAS units (95%CI − 1.34 to − 0.19; p = 0.01) in favor of the desensitizer group. In the NRS
scale, a significant average mean difference of − 0.36 (95% CI − 0.61 to − 0.12; p value = 0.004) in favor of the desensitizer
group. No significant difference was observed in color change (p > 0.28) in ΔSGU and ΔE.
Conclusions Although a significant reduction in the risk and intensity of TS was observed in groups treated with a potassium
nitrate at some point during the bleaching, the clinical significance of this reduction is subtle and clinically questionable. Color
change is not affected by the use of agents.
Clinical relevance The reduction in the risk and intensity of TS with the topical application of potassium nitrate–based
desensitizing agents in dental bleaching is subtle and maybe clinically questionable.

Keywords Tooth bleaching . Dentin sensitivity . Hydrogen peroxide . Dentin desensitizing agents . Randomized clinical trials .
Systematic review

Introduction usually associated with good oral health status [3]. These fac-
tors are the reasons why tooth bleaching has been desired for
Patients’ facial appearance is affected by the smile and, when many patients.
within esthetic standards, can improve self-esteem and social Currently, there are two dentist-supervised techniques
relationships [1, 2]. Although the attractiveness of a smile is available for dental bleaching: at-home bleaching [4, 5] and
related to the shape and position of the teeth, tooth color has a in-office bleaching [5, 6]. Although both techniques provide
strong effect on the social perceptions, as brighter teeth are similar results [6–9], some patients prefer the in-office
bleaching as they need faster bleaching results and are not
willing to use bleaching trays for prolonged periods.
* E. C. Martini In a recent study, the authors reported that the risk of TS for
eve_fcs@hotmail.com in-office bleaching and at-home bleaching was quite similar
[8]; however, the TS intensity was much higher for in-office
1
Department of Restorative Dentistry, State University of Ponta
bleaching (2.8 ± 2.9) than at-home (0.5 ± 0.9) when measured
Grossa, Avenida Carlos Cavalcanti, 4748, Bloco M, Sala 04, Ponta in a 0–4 pain scale [8].
Grossa Paraná 84030-900 Brazil This common and inconvenient adverse effect of TS has
2
Paulo Picanço School of Dentistry, Fortaleza Ceará Brazil encouraged researches to investigate protocols to prevent or
 Clin Oral Invest

minimize its occurrence. Some of the approaches include the Theses database, and (5) clinical trial registries (current con-
reduction of the concentration and usage time of the bleaching trolled trials, International Clinical Trials Registry Platform,
gel [10, 11], the application of topical desensitizing agents ClinicalTrials.gov, ReBEC, and EU Clinical Trials Register).
[12–14], the administration of systemic drugs [15–18], and
the incorporation of desensitizing agents, into the formulation Eligibility criteria
of the bleaching gels [19, 20].
Among all these approaches, the topical application of We included parallel and split-mouth randomized clinical trials
desensitizing agents showed promising results for the reduc- (RCTs) that evaluated the application of potassium nitrate as a
tion of the risk and intensity of TS [21–23], but there are recent topical desensitizing agent on the risk and intensity of TS dur-
reports that do not reach the same conclusions [14, 22, 24]. ing in-office and at-home dental bleaching in adult patients. We
Although a systematic review of the literature concluded excluded RCTs if studies (1) incorporated the potassium nitrate
that the application of desensitizing agents based on potassi- only into the bleaching gel; (2) evaluated dentifrices containing
um nitrate and sodium fluoride reduces the bleaching-induced potassium nitrate; (3) evaluated desensitizing agents other than
TS [25], there are significant methodological differences potassium nitrate; (4) did not have a placebo or no-
when compared to the present systematic review. Besides, desensitizing agent group for comparison; and (5) included
other randomized controlled trials (RCTs) on this topic were both groups but did not compare bleaching gels with equivalent
published in the most recent years, and this systematic review concentrations.
requires updating. Initially, review authors removed duplicates and non-
Therefore, this systematic review aimed to answer the fo- relevant articles by screening titles and abstracts. The full-
cused research question, based on the PICO acronym text paper of the relevant articles was obtained, and subse-
(Participant-Intervention-Comparator-Outcome): “Are the quently, four reviewers (E.M., M.F., J.L.G., and M.R.) classi-
risk and intensity of TS lower when potassium nitrate–based fied those that met the inclusion criteria. Each study received a
desensitizers are applied before dental bleaching in adults, study ID, combining the first author and the year of
compared to a placebo?” publication.
Details about study methods, designs and settings, partici-
pant’s characteristics, bleaching protocol, and desensitizing
Methods protocol were extracted from the eligible studies using cus-
tomized extraction forms.
Protocol and registration
Risk of bias in individual studies
This study protocol was registered at the International
Prospective Register of Systematic Reviews (PROSPERO - Four reviewers assessed, independently, the risk of bias of the
CRD 42018104598), and the present report follows the rec- eligible studies using the Cochrane Collaboration tool for
ommendations of the Preferred Reporting Items for assessing risk of bias in randomized trials [27]. This tool con-
Systematic Reviews and Meta-Analyses (PRISMA) statement tains seven items: sequence generation, allocation conceal-
for report [26]. ment, blinding of the participants and the outcome assessors,
incomplete outcome data, selective outcome reporting, and
Information sources and search strategy other sources of bias (not used in the present study). Any
disagreements between the reviewers were resolved through
We used controlled vocabulary (MeSH terms) and free key- discussion and, if necessary, by consulting a fifth reviewer
words for the concepts Participants and Intervention to define (A.R.).
the search strategy for the following databases: Cochrane Each domain from the risk of bias tool was scored follow-
Library, MEDLINE via PubMed, Latin American and ing recommendations as described in the Cochrane Handbook
Caribbean Health Sciences Literature database (LILACS), for Systematic Reviews of Interventions 5.1.0 (http://
and Brazilian Library in Dentistry (BBO). We also searched handbook.cochrane.org). The judgment for each entry
for some citation databases, such as Scopus and Web of involves the judgments of low risk of bias, high risk of bias,
Science. No restrictions on publication date or languages were or unclear risk, indicating either lack of information or
made. Table 1 depicts the search strategies employed. uncertainty over the potential for bias.
Some sources of gray literature were investigated: (1) ab-
stracts of the annual conference of the International Summary measures and synthesis of the results
Association for Dental Research (1990–2020), (2) System
for Information on Grey Literature in Europe (SIGLE), (3) As the RCTs usually report TS intensity in different time
dissertations and theses in ProQuest, (4) Periodicos Capes assessments, we collected data from the worst scenario.
Clin Oral Invest

Table 1 Electronic database and search strategy. Search performed on February 22, 2019, and last updated on March 11, 2020

When more than one experimental or placebo group was eval- Color change was also evaluated. Data from studies using
uated in the primary study, we merged the corresponding the same color measurement tool was evaluated separately.
groups. In case medians and interquartile ranges were provid- The same approaches used for missing cases for the TS were
ed, the medians were used as the best estimates of means, and applied for color change data.
the interquartile ranges converted to standard deviation [SD] For all meta-analysis, we used the random-effects models
(the width of the interquartile range corresponds to approxi- as this is the most appropriate model for studies performed in
mately 1.35 SD for normally distributed data). Data provided different populations. Subgroup analyses based on the type of
in a numerical rating scale (NRS) and visual analog scale bleaching (at-home and in-office) were performed. We evalu-
(VAS) were collected and evaluated separately. ated the heterogeneity in all meta-analysis with at least four
In some cases, standard deviations were not reported in the studies. For this purpose, we used the Cochran Q test (which
primary articles. As standard deviations of pain scales usually test the null hypothesis that all studies share the same effect
range between half of the reported mean and the mean itself, size), I2 statistics (which describe the proportion of the ob-
we imputed a standard deviation equal to the mean in the served heterogeneity is due to real variation of the true effect
missing cases. To evaluate the impact of such imputation, sizes), and the 95% prediction interval (which is the dispersion
we conducted a sensitivity analysis to check if other imputa- of the observed effect sizes). Sensitivity analyses were con-
tions such as half of the mean could affect the overall ducted to investigate the reasons for high heterogeneity,
conclusions. whenever detected.
Data were analyzed using Revman 5.3 (Review Manager
Version 5.3, The Cochrane Collaboration, Copenhagen, Assessment of the quality of the evidence using
Denmark). The risk of TS from the eligible studies was sum- GRADE
marized by the risk ratio and the 95% confidence interval,
while the intensity of TS was summarized by the mean differ- We graded the quality of the evidence for primary outcomes
ence and the 95% confidence interval. across the studies (body of evidence) by using the Grading of
 Clin Oral Invest

Recommendations: Assessment, Development, and March 11, 2020). After database screening and duplicate re-
Evaluation (GRADE) (http://www.gradeworkinggroup.org/) moval, 4896 studies were identified (Fig. 1). After title screen-
to determine the overall strength of the evidence for each ing, 206 studies remained, and after abstract screening, 34
meta-analysis [28]. The GRADE pro Guideline studies remained. This number was reduced to 24 after careful
Development Tool (available online at www.gradepro.org) examination of the full texts.
was used to create a summary-of-findings table, as suggested From the 34 studies, a total of ten studies were excluded
in the Cochrane Handbook for Systematic Reviews of since (1) they did not have a placebo group [13, 14, 29, 30];
Interventions 5.0.2 (http://handbook.cochrane.org) for the (2) they did not use a desensitizer based on potassium nitrate
primary outcomes in two study follow-ups. [31, 32]; (3) they were not a RCT, but a clinical case report
The GRADE approach for RCTs addresses five reasons [33]; (4) they incorporated potassium nitrate only in denti-
(risk of bias, imprecision, inconsistency, indirectness of evi- frices [34, 35]; and (5) they were ongoing studies without
dence, and publication bias) to possibly downgrade the quality results [36].
of the evidence (1 or 2 levels). Each of these topics was
assessed as having “no limitations,” “serious limitations,” or
“very serious limitations” to categorize the quality of the ev- Characteristics of the included studies
idence into high, moderate, low, and very low.
The characteristics of the 24 selected studies are listed in
Table 2. The split-mouth design was used in six studies
Results [37–42]. The parallel design was used in 18 studies [12,
21–24, 43–55]. VAS pain scale [21, 23, 37, 39, 40, 42,
Study selection 46–48, 51–53, 55], and NRS pain scale [12, 21–24, 37, 38,
40, 41, 44, 45, 50] were the ones mostly employed. The study
The search strategy was conducted initially on February 22, of Leonard [49] assessed patients’ risk of sensitivity through a
2019, and updated twice (in December 14, 2019, and questionnaire applied before and during bleaching.
Clin Oral Invest

Fig. 1 Flow diagram of study

identification. Search date:
February 22, 2019; update on
December 14, 2019, and
March 11, 2010

For color evaluation, eight studies used only shade guides Regarding the bleaching protocol, in 22 out of 24 studies,
[12, 21, 23, 24, 42, 46, 50, 53], and six studies used shade HP gels were employed [21–24, 37–48, 50–55] with HP con-
guides and objective color measure instruments (spectropho- centrations varying from 20 to 35%. Two RCTs used 10% CP
tometer or colorimeter) [22, 37, 39, 40, 43, 55]. In two studies, [49] and 16% carbamide peroxide (CP) [12]. The most used
only spectrophotometer was used [38, 52]. In other eight stud- protocol with HP was two sessions with three applications of
ies [41, 44, 45, 47–49, 51, 54], the authors did not evaluate 15 min each [21–24, 37, 40, 41, 52, 53, 55]. However, other
color change. protocols were also employed. The use of CP ranged from 4 to
The number of patients per group included in these studies 6 h daily for 2 to 5 weeks [12, 49]. Two studies used LED
ranged from 15 to 58. The mean age of all participants includ- activation during HP bleaching [23, 55].
ed in the clinical trials was approximately 25 ± 3 years, and the About the desensitizing protocol, 5% potassium nitrate was
minimum age to participate in the study was 18. In six out of the most used, applied for 10 min before bleaching [12,
the twenty-four studies, most of the participants were female 21–24, 37, 38, 41–43, 45–47, 50–52, 54], and 30 min before
[22, 38, 41, 47, 49, 53]. Only one study reported that gender bleaching [49, 55]. Other concentrations and application times
distribution was similar [12], and in other 12 studies, this were also observed. For instance, a study applied 6% potassi-
information was not reported [21, 23, 37, 39, 42, 44, 46, 48, um nitrate for 30 min before bleaching [39], and another one
50, 51, 54, 55]. applied 10% potassium nitrate 10 min before bleaching [40].
Table 2 Summary of the studies selected for qualitative analysis this systematic review

Study ID Study Subject’s age in Male/total Bleaching protocol Desensitizing protocol Outcomes
design mean ± SD number of
[range] (years) participants Color evaluation criteria Pain evaluation criteria Gingival
[time assessment] [time assessment] irritation

Abbud 2018 [39] Split-mouth 26.9 ± n.r. n.r./31 35% HPd ; three 8-min 6% potassium nitrate and 0.11% ΔSGU (Vita Classicaln, Vita Risk and intensity with Not
[20 ± 54] applications/2 sodium fluorides [30 min before Bleachedguide)q and ΔE VAS and NRS evaluated
sessions/1-week interval each bleaching session] (Easyshade)n [baseline, [during/up to 1 h, 24 h,
after 1 and 2 weeks and 1 and 48 h post-bleaching]
month post-bleaching]
Araujo 2012 [44] Parallel n.r.35% 40-min application/3 sessions; 1-week interval n.r.% potassium nitrate and n.r.%
± n.r.HPn.r.; one n.r./30 Not evaluated Risk and intensity with Not
[n.r.] sodium fluoride [10 min before NRS scale [before and evaluated
the bleaching session] immediately after the 1st
and 2nd session]
Barbosa 2015 Split-mouth 26 12/30 35% HPa; three 15-min 5% potassium nitrate and 2% sodium ΔE (Easyshade)o Risk and intensity with Not
[38] [18 ± 41] applications/3 fluorideg [10 min before the [baseline, after 1st week of NRS [at the end of each evaluated
sessions/1-week interval bleaching] bleaching, after 2nd week, bleaching session]
after 21 days, after 1 week
of end, and 1 month of end
of bleaching]
Bonafé et al. Parallel 24.8 ± 4.3 10/30 35% HPa three 15-min 5% potassium nitrate and 2% sodium ΔSGU (Vita Classical)n and Risk and intensity with Not
2014 [22] [18 ± 35] applications/2 sessions; fluorideg [10 min before each ΔE (Easyshade)o [1 week NRS [during/up to 24 h evaluated
1-week interval bleaching session] and 6 months after post-bleaching]
bleaching]
Calheiros 2015 Parallel 28.7 ± 8.5 37/60 35% HPa; three 15-min 5% potassium nitrate and 2% sodium Not reported Intensity with NRS [before Not
[45] [18 ± 40] applications/ fluorideg [10 min before and and after each bleaching evaluated
three sessions/1-week interval 10 min after the bleaching] session for 7 days]
Cerqueira et al. Parallel n.r. n.r./30 20% HPt; one 50-min 5% potassium nitrate and 2% sodium ΔSGU (Vita Classical)n Risk and intensity with Not
2013 [46] [18 ± 40] application/2 sessions; fluorideg [10 min before the [baseline, after 1 and 2 VAS and NRS [up to evaluated
1-week interval bleaching] weeks post-bleaching] 48 h post-bleaching]
Crescente et al. Parallel 22.7 7/32 35% HPu; one 40-min 5% potassium nitrate and 2% sodium Not evaluated Risk and intensity with Not
2016 [47] [18 ± 46] application/3 sessions; fluorideg; 5% potassium nitrate VAS and NRS evaluated
1-week interval and 0.2 % sodium fluoridev [immediately after each
[10 min before the bleaching] session]
De Paula et al. Split-mouth 24.0 ± n.r. 22/100 35% HPa; three 15-min 5% potassium nitrate and 2% sodium Not evaluated Risk and intensity with Not
2019a [41] [18 ± 30] applications/two fluorideg [10 min before the NRS [during/up to 21 evaluated
sessions/1-week interval bleaching] days post-first session of
5% potassium nitrate and 2% sodium bleaching]
fluorideg [10 min before the
bleaching] + laserr [16 s]
De Paula et al. Parallel 21.8 ± 2.9 [18 ± 60/115 35% HPw; one 50-min 5% potassium nitrate and 0.2% ΔSGU (Vita Classicalm, Vita Risk with VAS [during/up Not
g
2019b [43] n.r.] applications/2 sodium fluoride [10-min for 10 Bleachedguide)q and ΔE to 48 h post-bleaching] evaluated
sessions/1-week interval days before the 4 bleaching, in the (Easyshade)n [baseline and
week interval and 2 days after the 1-month post-bleaching]
second session]
Dias 2017 [48] Parallel n.r. n.r./60 35% HPn.r.; 45-min applications/ 5% potassium nitrate and 2 % Not evaluated Intensity with VAS Not
[18 ± 40] 2 sessions/1-week interval sodium fluoriden.r. [n.r.] [during, up to 6 days evaluated
post-bleaching]
n
Godoy 2016 [42] Split-mouth 22.5 ± n.r. n.r./20 35 % HPa; two 15-min 5% potassium nitrate and 2% sodium ΔSGU (Vita Classical ) Risk and intensity with Not
[20 ± 25] applications/one session fluorideg [10 min before the [baseline and 1 week after the VAS and NRS [during, evaluated
bleaching] bleaching treatment ends] up to 1 h, 24 h, and 48 h
Clin Oral Invest
Table 2 (continued)

Study ID Study Subject’s age in Male/total Bleaching protocol Desensitizing protocol Outcomes
design mean ± SD number of
Clin Oral Invest

[range] (years) participants Color evaluation criteria Pain evaluation criteria Gingival
[time assessment] [time assessment] irritation

post-bleaching]
Kose et al. 2011 Parallel 24 ± n.r. 30/60 16% CPb at least 6h/night [until 5% potassium nitrate and 2% sodium ΔSGU (Vita Classical)n Risk and intensity with Not
[12] [18 ± 30] it reaches color B1 or A1 (5 fluorideg [10 min before each [after 30 days] NRS [daily evaluation] evaluated
weeks average)] daily bleaching]
Leonard et al. Parallel n.r. EXP: 4/40 10% CPc for 14 days (time of 3% potassium nitrate and 0.11% Not evaluated Risk of TS Risk of GI
2004 [49] [19 ± 53] PL: 1/40 bleaching not reported) fluorideh [30 min before daily
bleaching]
Loguercio et al. Parallel 23.3 ± 5.4 22/40 35% HPa three 15-min 5% potassium nitrate and fluoride ΔSGU (Vita Classical)n Risk and intensity with Not
2015[24] [18 - n.r.] applications/2 sessions 9000 ppmz [10 min before the [baseline, after 1 and 2 weeks] NRS [during sessions evaluated
[10 min before the bleaching] bleaching] and 48h post-bleaching]
n
Martins et al. Parallel n.r. n.r./30 35% HPu; one 40-min 5% potassium nitrate and 2% sodiumΔSGU (Vita Classical) Risk and intensity with Not
2011 [50] [18 ± 40] application/2 sessions; fluorideg [10 min before each [baseline, after each bleaching NRS scale [daily, did not evaluated
1-week interval daily bleaching] session] report for how long]
Nanjundassetty Parallel n.r. n.r./69 35% HPd three 15-min 5% potassium nitrate and 0.7% Not evaluated Risk and intensity with Not
et al. 2016[51] [18 ± 30] applications/1 session sodium monofluorophosphatei VAS [after 24 h and 7 evaluated
[10 min after bleaching] days post-bleaching]
Palé et al. 2014 Parallel n.r. n.r./32 28% HPe Three 15-min applica- 5% potassium nitratej [30 min before ΔSGU (Vita Classical)n and Risk and intensity with Not
[55] [n.r. ± n.r.] tions with LED 15-min the bleaching] ΔE (MHT Optic Research VAS [baseline and 24 h evaluated
activation/1 session SpectroShade)p post-bleaching]
[immediately after 2 weeks
and 3 months]
Parreiras et al. Split-mouth 22.1 ± n.r. n.r./42 35% HPa; three 15-min 5% glutaraldehyde and 5% ΔSGU (Vita Classicaln, Vita Risk and intensity with Not
2018 [37] [18 ± 52] applications/2 potassium nitratel [10 min before Bleachedguide)p and ΔE VAS and NRS evaluated
sessions/1-week interval each bleaching session] (Easyshade)o [baseline, [immediately, up to 24 h
after 1 and 2 weeks and 1 and 48 h post-bleaching]
month post-bleaching]
Pierote 2019 [52] Parallel n.r. 58/108 35% HPa; three 15-min 5% potassium nitrate and 2% sodium ΔE (Easyshade)o [baseline, Intensity with VAS Not
[18 ± 30] applications/2 fluorideg ; 5% potassium nitrate after 4 weeks and 24 weeks [immediately, up to 24 h evaluated
sessions/1-week interval and 8% plus arginine after starting bleaching] and 24 weeks after
(experimental desensitizer) starting bleaching]
[10 min before each bleaching
session]
Reis et al. 2011 Parallel n.r. n.r./30 35% HPa; three 15-min applica- 5% potassium nitrate and 2% sodium ΔSGU (Vita Classical)n Risk and intensity with Not
[23] [18 ± n.r.] tions with LED 5-min fluorideg [10 min before each [baseline, after 1 and 2 VAS and NRS evaluated
activation/2 sessions/1-week bleaching session] weeks post-bleaching] [immediately, up to 24 h
interval and 48 h post-bleaching]
Rezende et al. Split-mouth 24.3 ± n.r. 29/43 35% HPa; three 15-min 10% potassium nitraten.r. [10 min ΔSGU (Vita Classicaln, Vita Risk and intensity with Not
2019 [40] [18 ± 51] applications/2 before the bleaching] Bleachedguide)q and ΔE VAS and NRS [during, evaluated
sessions/1-week interval (Easyshade)n [baseline, up to 1 h, 24 h and 48 h
after 1 and 2 weeks and 1 post-bleaching]
mouth post-bleaching]
Santos 2017 [54] Parallel n.r. n.r./60 35% HPa; 45-min 5% potassium nitrate and 2 % Not evaluated Intensity with VAS Not
[18 ± 40] applications/one session sodium fluorideg [10 min before [during, up to 6 days evaluated
the bleaching session] post-bleaching]
Tawfik et al. Parallel 32.1± 5.3 6/36 5% potassium nitrate + 0.22% ΔSGU (Vita Classical)n Not
2019 [53] [18 ± 40] sodium fluoride and 0.75% [baseline, after 24 hours evaluated
Table 2 (continued)

Study ID Study Subject’s age in Male/total Bleaching protocol Desensitizing protocol Outcomes
design mean ± SD number of
[range] (years) participants Color evaluation criteria Pain evaluation criteria Gingival
[time assessment] [time assessment] irritation

30% HPx; three 15-min amorphous calcium phosphate and 1 week each session Intensity with VAS
applications/2 (ACP)y [before; after or before + and 6 months] [immediately and 24 h, 1
sessions/1-week interval after] week and 1 month after]
Tay et al. 2009 Parallel n.r. n.r./30 35 % HPa; three 15-min 5% potassium nitrate and 2 % ΔSGU (VITA Classical)n Risk and intensity with Not
[21] [18 ± n.r.] applications/2 sodium fluorideg [10 min before [baseline, after 1 and 2 VAS and NRS evaluated
sessions/1-week interval each bleaching session] weeks post-bleaching] [immediately and up to
24 h post-bleaching]

Abbreviations: CP carbamide peroxide; HP hydrogen peroxide; n.r. not reported; ΔSGU shade guide units; ΔE color difference measured with a spectrophotometer; VAS visual analog scale, NRS numeric
rating scale; GI gingival irritation; EXP experimental group; PL placebo group
a
Whiteness HP Maxx 35%, FGM, Joinville, SC, Brazil
b
Whiteness Perfect CP 16%, FGM, Joinville, SC, Brazil
c
Opalescence CP 10%, Ultradent, South Jordan, UT, USA
d
Pola office HP 35%, SDI Innovative Dental Products, Australia
e
Flashwhite HP 28%, Corpora®, Barcelona, Spain
f
Whiteness class with Calcium 4%, FGM, Joinville, Santa Catarina, Brazil
g
Desensibilize KF 2%, FGM Dental Products, Joinville, SC, Brazil
h
UltraEZ—3% potassium nitrate and 0.25% by weight fluoride ion, Ultradent, South Jordan, UT, USA
i
Potassium nitrate 5% and sodium monofluorophosphate 0.7%, Sensodent KF, Indoco Remedies Ltd. (Warren) Mumbai, India
j
5% potassium nitrate, Flashwhite Corpora®, Barcelona, Spain
k
Sensodyne® (potassium nitrate 5% and 1187 ppm monofluorophosphate), GSK, Glaxo Smith Kline, Brazil
l
Experimental gel composed of 5% glutaraldehyde and 5% potassium nitrate (pharmaceutical laboratory at the local university)
m
Colgate-Palmolive®, New York, USA
n
VITAPAN classical, VITA Zahnfabrik, Bad Säckingen, Germany
o
Vita Easyshade Advance 4.0 ®; Vita Zahnfabrik, Bad Säckingen, Germany
p
MHT Optic Research AG SpectroShade spectrophotometer, Zurich, Switzerland
q
VITA Bleachedguide 3D-MASTER, Vita Zahnfabrik, Bad Säckingen, Germany
r
PBM-LLLT. Photon Laser III infrared DMC Equipments (São Carlos, SP, Brazil)
s
Soothe® 6%, SDI Limited, Bayswater, Victoria, Australia
t
Whiteness HP Blue 20%, FGM, Joinville, SC, Brazil
u
Whiteness HP Blue 35%, FGM, Joinville, SC, Brazil
v
Desensibilize KF 0,2 %, FGM Dental Products, Joinville, SC, Brazil
w
Whiteness HP Automixx, FGM Dental Products, Joinville, SC, Brazil
x
Discus dental, Culver City, 91761 USA
y
Relief® ACP (Discus Dental, Culver City, 91761 USA)
Clin Oral Invest

z
Nano-P paste, FGM, Joinville, SC, Brazil
Clin Oral Invest

Incomplete outcome
Assessment of the risk of bias

Adequate sequence

Free of selective
data addressed?
concealment?
Regarding randomization, 16 out of the 24 studies evaluated

generation?
Allocation

reporting?
reported the randomization method used [12, 21–24, 37,

Blinding?
39–43, 45, 50–53]. Only eight of the 24 studies reported the
allocation concealment [22, 24, 37, 39, 40, 43, 52, 53].
Blinding was reported in 13 studies [12, 21–24, 37–43, 53].
At the study level, 17 studies [12, 21, 23, 24, 38, 41, 42, 44, Abbud, 2018 39
46–52, 54, 55] were judged as having an unclear risk of bias. One Araújo, 2012 44
study was judged as having a high risk of bias [45] for selective
outcome reporting. The authors reported that color change would Barbosa, 2015 38
be measured, but they did not present the results (Fig. 2).
Bonafé et al, 2014 22
Meta-analysis Calheiros, 2015 45

Tooth sensitivity Cerqueira et al, 2013 46

The risk of TS was calculated from a total of 16 studies. This Crescente et al, 2016 47
systematic review of the literature showed that desensitizing
De Paula et al, 2019ª 41
application produced a relative ratio reduction (RRR) of 12%
in the risk of having TS (p = 0.02), with a risk ratio of 0.88 De Paula et al, 2019b 43
(95%CI 0.78 to 0.98) (Fig. 3). Heterogeneity was detected (p
= 0.003), and more than half of the observed variability was Dias, 2017 48
due to variation in the true effect sizes (I2 = 59%).
Godoy, 2016 42
To make this easier to understand, we can put it in other
words. The RRR can be applied to different baseline risks of Kose et al, 2011 12
having TS. For example, approximately 80% of the partici-
pants who have their teeth bleached with in-office bleaching Leonard et al, 2004 49
gels suffer from TS. If we apply this RRR of 12% over the
Loguercio et al, 2015 24
baseline risk of 80% risk, we end up with an absolute reduc-
tion of 9.6%. This gives us the number needed to treat (NNT) Martins et al, 2011 50
of 10 (100/9.6), meaning that 10 patients will need to be treat-
ed for one patient to benefit from it. If we apply the same Nanjundassetty et al, 2016 51
calculations to lower baseline risk of TS, such as for at-
Pale et al, 2014 55
home bleaching, which has an approximately 50% risk, we
end up with an absolute reduction of 6%, which is equivalent Parreiras et al, 2018 37
to a NNT of 17.
The intensity of TS was meta-analyzed using two different Pierote, 2019 52
pain scales. In the VAS scale (Fig. 4), ten studies were includ-
Reis et al, 2011 23
ed, giving a significant average mean difference of − 0.77
units of VAS units (95%CI − 1.34 to − 0.19; p = 0.01) in Rezende et al, 2019 40
favor of the desensitizer group. Heterogeneity was detected
(p = 0.01), and it was attributed mainly to variations in the true Santos, 2017 54
effect sizes (I2 = 57%).
Tawfik et al, 2019 53
To make the understanding of the reported reduction in the
intensity of TS more familiar, we can rewrite it in other terms. Tay et al, 2009 21
The non-weighted average of the intensity of TS in the control
groups of the eligible studies in this systematic review was Fig. 2 Summary of the risk of bias assessment according to the Cochrane
Collaboration tool
approximately 4 units in a 0–10 VAS scale. The present meta-
analysis showed that the use of a desensitizer can reduce this
mean TS by an average of 0.77, which means that the In the NRS scale (Fig. 5), a total of 14 studies were
desensitizer-treated patients would have a mean VAS pain included, with a significant average mean difference of
of 3.23 units. − 0.36 (95% CI − 0.61 to − 0.12; p = 0.004) in favor
 Clin Oral Invest

Prediction interval 0.88 [0.63, 1.21]

Fig. 3 Forest plot of the risk of TS for dental bleaching with desensitizer vs without desensitizer

of the desensitizer group. Heterogeneity was detected (p difference was observed in color change (p > 0.28).
value < 0.001), and it was mainly due to variations in Heterogeneity was not detected in none of the meta-analysis
the true effect sizes (I2 = 66%). (p > 0.25, Figs. 6, 7, 8, and 9).

Color change
Subgroup analysis
Data from color change were meta-analyzed in ΔSGU Vita
Classical (six studies; MD = 0.14; 95% CI − 0.21 to 0.48), We performed subgroup analysis based on the type of
final SGU Vita Classical (six studies; MD = − 0.02; 95% CI − bleaching protocol employed (at-home or in-office
0.29 to 0.24), ΔSGU Vita Bleachedguide (four studies; MD = bleaching), as can be seen in the forest plots of the outcomes.
0.10; 95% CI − 0.35 to 0.54), and ΔE (seven studies; MD = − The bleaching protocol did not explain the heterogeneity de-
0.22; 95% CI − 0.62 to 0.18). In all cases, no significant tected in the data for TS.

Prediction interval -0.77 [-2.42, 0 .88]

Fig. 4 Forest plot of the intensity of TS using the VAS scale for dental bleaching with desensitizer vs without desensitizer
Clin Oral Invest

Prediction interval -0.36 [-1.24, 0 .52]

Fig. 5 Forest plot of the intensity of TS using the NRS scale for dental bleaching with desensitizer vs without desensitizer

Sensitivity analysis outcomes for color change (ΔSGU Vita Classical, Final
SGU Vita Classical, ΔSGU Bleachedguide, and ΔE) were
Imputations had to be made in some cases where standard evaluated. The certainty of evidence for all these outcomes
deviations were not reported in the full texts, both in data from is summarized in Table 3. Regarding TS, all outcomes were
intensity of TS in VAS scale [48, 52, 54], intensity of TS in graded as low certainty of the evidence due to the fact that
NRS scale [24], and color change in ΔE [55]. Sensitivity anal- most articles included in the meta-analysis were at unclear risk
ysis using more extreme values of imputations were per- of bias and due to unexplained heterogeneity. Data from the
formed, but the overall conclusions were not affected. color change was graded as high (in the meta-analysis com-
Additionally, we suspected that the study of Dias [48] and posed mostly with studies at low risk of bias) or moderate
Santos [54] shared the same experimental group with different (when most of the studies included were at unclear risk of
comparators. In a sensitivity analysis, we excluded one or the bias).
other in the meta-analysis where they were included, but the
conclusions remained the same.

Discussion
Certainty of the evidence
Dental bleaching protocols employ hydrogen peroxide (HP)
A total of three outcomes for TS (risk of TS, intensity of TS in as the oxidizing agent. HP has a low molecular weight and
VAS scale, and intensity of TS in NRS scale) and four thus penetrates the dental substrates fast and easily. However,

Prediction interval -0.14 [-0.34, 0,62]

Fig. 6 Forest plot of the color change in shade guide units (ΔSGU Vita Classical) for dental bleaching with desensitizing vs without desensitizing
 Clin Oral Invest

Prediction interval -0.02 [-0.62, 0.58]

Fig. 7 Forest plot of the color change in shade guide units (Final ΔSGU Vita Classical) for dental bleaching with desensitizing vs without desensitizing

this penetration is not only restricted to the dental hard tissues. Without nerve repolarization, pain impulse does not progress
HP can reach the pulp chamber within few minutes [56–58] through the length of the nerve fibers, and the patient may not
and may cause inflammatory reaction [59, 60], oxidative feel the bleaching-induced TS [69–71].
stress, and cell damage. Not included in this review, studies using toothpastes
This penetration is facilitated by factors such as the pa- containing potassium nitrate in the composition, because
tient’s age, the concentration of the bleaching gel, the appli- the contact time and the concentration of the active ingre-
cation time, the presence of restorations, and the end pH of the dient is very different from the desensitizing potassium
bleaching product [61–64]. Consequently, inflammatory me- nitrate used for topical applications. In the majority of
diators and stimulating nociceptors are released, causing pain the studies, potassium-based desensitizers are usually ap-
transmission [65]. plied for 10 min, while in the best scenario, dentifrices do
The presence of this undesirable side effect is the rea- not stay longer than 3 min in the buccal cavity. When
son why topically applied desensitizing agents have been included in desensitizers, potassium nitrate is incorporated
studied as preventive measures to avoid the undesirable in concentrations that range from 3 to 10% [40]; in den-
bleaching-induced TS. Among these agents, potassium tifrices these concentrations are not superior to 5% [34].
nitrate has been described as an alternative to minimize Additionally, potassium nitrate–based dentifrices are
this side effect [25], although its exact mechanism of leached out by the contact with saliva, which does not
action to reduce TS in the dental bleaching is not well occur in professionally topical application of a
known [66]. desensitizer.
As well as HP, potassium nitrate can penetrate the dental We also decided to exclude from this systematic review
hard tissues and reach the pulp chamber [67, 68], and this studies that included potassium nitrate in the bleaching agent.
penetration is considered time-dependent [68]. Theoretically, When incorporated into the gel, the potassium nitrate stays
in the pulp tissue, potassium nitrate is believed to reduce den- longer in contact with the dental structure, but it is delivered
tinal sensory nerve activity by preventing nerve repolarization simultaneously to the hydrogen peroxide, differently to what
due to excess of K+ ions outside the nerve membrane. occur to potassium nitrate desensitizers applied in a preventive

Predical interval 0.10 [-0.86, 1.06]

Fig. 8 Forest plot of the color change in shade guide units (ΔSGU Vita Bleachedguide) for dental bleaching with desensitizing vs without desensitizing
Clin Oral Invest

Prediction interval -0.22 [-0.74, 0.30]

Fig. 9 Forest plot of the color change in (ΔE*) for dental bleaching with desensitizing vs without desensitizing

manner [72]. The universe of eligible studies included in a with similar populations, treatment protocol, and comparator
systematic review should be narrow enough to collect studies group to avoid a high heterogeneity of the data [73, 74].

Table 3 Summary of findings with the certainty of the evidence using the GRADE approach

Outcomes № of Certainty of the Relative Anticipated absolute effects

participants(studies) evidence(GRADE) effect
(95% CI) Risk with placebo Risk difference with
potassium nitrate–
based desensitizer

Color change in Delta SGU Vita 413(6 RCTs) ⨁⨁⨁⨁HIGH - The mean color change in MD 0.14 Delta SGU
Classical assessed with: Vita Delta SGU Vita higher(0.34 lower to
Classical shade guide Classical was 0 units 0.62 higher)
Color change in Final SGU Vita 220(6 RCTs) ⨁⨁⨁◯MODERATE - The mean color change in MD 0.02 Final SGU
a
Classical assessed with: Vita Final SGU Vita lower(0.29 lower to
Classical shade guide Classical was 0 units 0.24 higher)
Color change in Delta SGU 346(4 RCTs) ⨁⨁⨁⨁HIGH - The mean color change in MD 0.1 Delta SGU
Bleachedguide assessed with: Delta SGU higher(0.35 lower to
Vita Bleachedguide shade guide Bleachedguide was 0 0.54 higher)
units
Color change in Delta E assessed 613(7 RCTs) ⨁⨁⨁⨁HIGH - The mean color change in MD 0.83 units of Delta
with: Spectrophotometer Delta E was 0 units E lower(1.46 lower
to 0.2 lower)
Risk of tooth sensitivity assessed 801(16 RCTs) ⨁⨁◯◯LOW a,b RR 740 per 1,000 89 fewer per
with: dichotomous scale (yes/no) 0.88(0.7- 1,000(163 fewer to
8 to 0.98) 15 fewer)
Intensity of tooth sensitivity using 613(10 RCTs) ⨁⨁◯◯LOW a,b - The mean intensity of tooth MD 0.83 VAS units
VAS scale assessed with: VAS sensitivity using VAS lower(1.46 lower to
scale scale was 0 units 0.2 lower)
Intensity of tooth sensitivity using 747(14 RCTs) ⨁⨁◯◯LOW a,b - The mean intensity of tooth MD 0.36 NRS units
NRS scale assessed with: NRS sensitivity using NRS lower(0.61 lower to
scale scale was 0 units 0.12 lower)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the
intervention (and its 95% CI). CI confidence interval; MD mean difference; RR risk ratio
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a
possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect
Explanations: a. The majority of the studies are at unclear risk of bias; b. Unexplained heterogeneity
 Clin Oral Invest

Another systematic review was recently published address- significant, they represent small effect sizes, with questionable
ing specifically the addition of desensitizers into the bleaching clinical importance. An average of one unit in a VAS 0–10 or
gels [72]; this study concluded that incorporating desensitizers 0.35 unit in a 0–4 NRS scale does not represent a clinically
in the bleaching gel did not reduce the risk of TS, and the relevant reduction in the intensity of the bleaching induced TS.
quality of this evidence was considered moderate. On the oth- Although we could not identify, from a statistical perspective,
er hand, the intensity of TS, color change, and risk of gingival the reasons for the heterogeneity that was observed in the meta-
irritation were similar between groups, but the quality of the analysis, from a clinical view, the observed heterogeneity must
evidence was graded as low or very low. be due to the different bleaching protocols and the different
An earlier systematic review of the literature addressing this compositions of the potassium nitrate–based desensitizers.
issue reported that potassium nitrate agents are effective in reduc- Although all studies applied potassium nitrate, the composition
ing the bleaching-induced TS [25]. In this systematic review, of these desensitizers varied. Changes in the concentration of the
review authors included studies that evaluated the association potassium nitrate and inclusion of other products, such as fluo-
of potassium nitrate with fluorides. It is claimed that fluorides rides, as in most cases [12, 21–24, 38, 39, 41–48, 50, 52–54],
can obliterate the dentinal tubules by precipitation of fluorine glutaraldehyde [37], sodium monofluorophosphate [51], and
crystals, preventing the HP from reaching the pulp [75]. nano-calcium phosphate crystals [24, 49], were observed.
However, in most of the primary studies, patients with Additionally, variations of the bleaching protocols (varied HP
exposed dentin surfaces, where fluorides could have a benefi- concentrations, application times, frequency of application as
cial effect, were excluded from the sample. Therefore, the well as number of clinical sessions) may also affect the overall
benefit of fluorides in these cases is questionable, explaining bleaching-induced TS [6], and therefore, may impact the results.
why, in the present study, we included studies that evaluated We are confident to state that color change is not affected
potassium nitrate alone or in association with other agents. by the application of potassium nitrate–based agents. This
It is also important to note that the systematic review pub- conclusion was reached in the four meta-analyses of color
lished [25] presents flaws, and discussion about them is cru- change, and it is robust enough not to be affected by the type
cial to avoid these common mistakes in future systematic re- of color change instrument used. The HP and the potassium
views. The data replicated from the same study population nitrate can penetrate the pulp tissue, but they do not compete
many times [22, 76, 77] overestimate the reported effect size for the same sites in the hard tissues, as each one has different
in the study and increases the power of the systematic review mechanisms of action [14].
unequivocally. Most of the studies included in the present investigation
Additionally, the authors use a fixed-effect model for the were considered at unclear risk of bias in the domains se-
meta-analysis, which is not the most appropriate to use [76, quence generation and allocation concealment, which agrees
78]. This fixed-effect model assumes that there is a single to what was previously reported in other bleaching studies [8,
effect size, common to all studies. This assumption is unlikely 80]. Adequate random sequence generation and allocation
to be true due to variations in the populations, bleaching pro- concealment are crucial to prevent selection bias, so that we
tocols, and composition of the desensitizing agents. By using can be confident that studies have comparable known and
the fixed-effect model, the confidence intervals for the sum- unknown characteristics at baseline. Thus, the differences ob-
mary effect are smaller than under the random-effect model, tained after the implementation of the treatments can only be
which is the most appropriate statistical model [79]. Thus, the attributed to the treatment itself. The fact that most studies
chances of finding statistically significant results are increased were classified as unclear highlights the need for significant
under the fixed-effect model. Finally, from the time this study improvements in the conduction and report of future RCTs.
was published until today, several new studies on the topic Future RCTs should focus on the investigation of other
have been published, the reason why this study was conduct- types of desensitizing agents and their combination to prevent
ed. In this case, we assume that each study is estimating dif- or reduce the undesirable side effect of bleaching-induced TS.
ferent, yet related, intervention effects, and we want to know Apart from potassium nitrate, which has neural action, other
the average of all these different and related effect sizes along types of desensitizing agents such as fluorides, bioactive
with the heterogeneity of these estimates. agents, amorphous calcium phosphate, nano-hydroxyapatite,
In the present systematic review, we observed that potassium bioglass, or even their association could be the focus of further
nitrate has a positive benefit in preventing the development of randomized controlled trials.
bleaching-induced TS. On average, patients treated with potas-
sium nitrate–based agents have a 12% lower risk of presenting
TS. In terms of pain intensity, the average reduction was less Conclusions
than 1 unit in VAS, and around 0.35 units in the 0-10 NRS
scale. However, these figures should be interpreted with cau- Although a significant reduction in the risk and intensity of TS
tion. Although these positive findings were statistically was observed in groups treated with a potassium nitrate before
Clin Oral Invest

dental bleaching, the clinical significance of this reduction is 12. Kose C, Reis A, Baratieri LN, Loguercio AD (2011) Clinical effects
of at-home bleaching along with desensitizing agent application.
subtle, and it may be clinically questionable. Color change is
Am J Dent 24:379–382
not affected by the preliminary use of a potassium nitrate– 13. Mehta D, Venkata S, Naganath M, LingaReddy U, Ishihata H,
based agent. Finger WJ (2013) Clinical trial of tooth desensitization prior to in-
office bleaching. Eur J Oral Sci 121:477–481. https://doi.org/10.
1111/eos.12067
14. Martini EC, Parreiras SO, Szesz AL, Coppla FM, Loguercio AD,
Declarations Reis A (2019) Bleaching-induced tooth sensitivity with application
of a desensitizing gel before and after in-office bleaching: a triple-
Ethical approval This article does not contain any studies with human blind randomized clinical trial. Clin Oral Investig 24:385–394.
participants or animals performed by any of the authors. https://doi.org/10.1007/s00784-019-02942-9
15. Coppla FM, Rezende M, de Paula E, Farago PV, Loguercio AD,
Informed consent For this type of study, formal consent is not required. Kossatz S, Reis A (2018) Combination of acetaminophen/codeine
analgesics does not avoid bleaching-induced tooth sensitivity: a
Conflict of interest The authors declare that there is no conflict of randomized, triple-blind two-center clinical trial. Oper Dent 3:
interest. E53–E63. https://doi.org/10.2341/17-092-C
16. Rezende M, Bonafe E, Vochikovski L, Farago PV, Loguercio AD,
Reis A, Kossatz S (2016) Pre and postoperative dexamethasone
does not reduce bleaching-induced tooth sensitivity: a randomized,
triple-masked clinical trial. J Am Dent Assoc 147:41–49. https://
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