High-concentration carbamide peroxide can reduce the sensitivity caused by in-office tooth bleaching: a single-blinded randomized controlled trial

Abstract Objectives A single-blinded, randomized, parallel clinical trial evaluated the use of 37% carbamide peroxide (CP) on bleaching effectiveness and tooth sensitivity reported by patients undergoing in-office tooth bleaching, in comparison with the results of using 35% hydrogen peroxide. Material and Methods Forty patients were allocated to receive two sessions of in-office tooth bleaching using either 35% hydrogen peroxide (HP) or 37% CP. Each patient’s sensitivity level was evaluated during and up to 24 h after bleaching. The effectiveness of the bleaching procedures was evaluated with a spectrophotometer one week after each session and 30 days after the last session. The impact of tooth bleaching on the patients’ perceptions regarding smile changes, in addition to the bleaching procedures and their results, were also recorded. Absolute and relative sensitivity risks were calculated. Data on sensitivity level were analyzed using the Mann-Whitney or T-test, and data from the color evaluation were subjected to 2-way repeated measures ANOVA. Results The use of CP reduced the risk and level of tooth sensitivity to values close to zero, whereas the difference between the bleaching agents disappeared after 24 h. An increased bleaching effect was observed for HP, mainly due to an improved reduction of redness and yellowness. Participants perceived improved tooth bleaching for HP and reduced sensitivity for CP, but no differences regarding the comfort of the techniques were noted. Conclusions In our study, 37% CP resulted in reduced tooth sensitivity but decreased the tooth bleaching effectiveness. However, both bleaching agents resulted in high levels of patient satisfaction.


Introduction
Tooth bleaching is a non-invasive technique to solve aesthetic complaints from patients regarding their smile. The technique consists in the application of peroxide-based bleaching agents over the buccal surface of discolored teeth. Radicals produced by the peroxide breakdown oxide the organic components of the dental tissue, resulting in whiter teeth 9,15 . The bleaching agent can be applied by clinicians using an in-office technique (commonly hydrogen peroxide at high concentrations) or delivered by trays filled with less concentrated peroxide (typically carbamide peroxide) using an at-home bleaching technique.
Despite the high success rate of both techniques in bleaching discolored teeth, the tooth sensitivity reported by patients is the most common adverse effect related to the bleaching procedure, especially when high-concentrated hydrogen peroxide is used 8,19,27 .
Tooth sensitivity is the result of peroxide and its products reaching the pulp chamber, resulting in an inflammatory response of the pulp tissue 1,17,22 . Clinical trials have demonstrated that the average absolute risk of tooth sensitivity is approximately 51% and 63% for at-home and in-office bleaching techniques, respectively 28 . The lower incidence of tooth sensitivity using at-home techniques is associated with the reduced concentration of peroxides in the bleaching agents used by this technique 8,23,28 . In contrast with athome techniques, during an in-office bleaching higher concentrations of peroxides are used to compensate for the reduced time of tooth exposure to the bleaching agent. However, previous studies demonstrated that the use of lower concentrations (20%) of hydrogen peroxide for in-office techniques yields bleaching effects like those obtained with more concentrated peroxide (approximately 35%) 22,28 . However, hydrogen peroxide used at low concentrations (e.g., 6%) yields reduced color changes despite the lower incidence of tooth sensitivity 4 .
Several bleaching agents with different hydrogen peroxide concentrations are now available on the market for in-office techniques, including carbamide peroxide-based agents 16,20 . Carbamide peroxide is commonly used for at-home bleaching using a traybased technique and dissociates into hydrogen peroxide (approximately a third of its former concentration) and urea, which further breaks down into water and

Sample size calculation
The sample size calculation was based on an absolute risk of 90% tooth sensitivity as a primary outcome, as reported in a previous study using a similar bleaching agent (35% HP) and protocol (three 15-min applications) 24 . The calculation was performed for a superiority trial with a binary outcome considering a power test of 80%, a significance level of 5%, and a decrease of 40% for the experimental treatment  Tooth sensitivity risk results are reported in Table 1. Irrespective of the tooth bleaching session, carbamide peroxide reduced the tooth sensitivity risk measured during the bleaching procedure compared with that following treatment with hydrogen peroxide. However, no difference in tooth sensitivity risk was noted between the bleaching agents 24 h after each bleaching session. Figure 3 presents the tooth sensitivity results measured using the VRS.
Irrespective of the tooth bleaching session, carbamide peroxide resulted in a lower level of sensitivity, except when the measurement was performed after 24 h.
The sensitivity results reported through the VAS are presented in Figure 4. Regardless of the bleaching session, tooth bleaching with hydrogen peroxide resulted in a higher level of tooth sensitivity during and following the procedure. However, no differences in sensitivity between the bleaching agents were noted 24 h after each session.
Patients' perceptions regarding the bleaching procedure and their own smiles are presented in Table   2. No differences were observed between bleaching agents regarding the comfort of procedures performed previously and during the tooth bleaching. A lower sensitivity than expected was observed primarily in participants who had their teeth bleached with carbamide peroxide. In contrast, a higher concordance was noted when teeth became whiter than expected, and increased satisfaction with the tooth bleaching results was observed when hydrogen peroxide was used. Participants allocated to receive hydrogen peroxide also reported more improvement in their smile after tooth bleaching.

Discussion
The tooth sensitivity reported by patients subjected to in-office bleaching remains the main concern related to this procedure 14,21 . Several approaches have been used by clinicians to reduce this adverse effect, including preemptive use of desensitizers 3,26 or antiinflammatory drugs 10,24,26 . The use of low-concentration peroxides can also be a promising alternative for painless in-office tooth bleaching if the pain response is strongly related to an inflammatory process caused by the presence of peroxides and sub-products in the pulp tissue 4,14,18 . Carbamide peroxide-based bleaching agents are commonly used for at-home techniques using customized trays at concentrations ranging from 10 to 22% 8 . In the present study, a 37% carbamide peroxide bleaching agent was used in-office during a single 40-min application and resulted in reduced tooth sensitivity (both risk and level). However, the bleaching effectiveness was reduced compared with that of the procedure performed with 35% hydrogen peroxide. Thus, the hypothesis of the study was accepted.
In contrast to at-home bleaching procedures in which

Medians (1st / 3rd quartiles) obtained for the following questions (scores 1 to 5)
Scores: 1 -completely agree, 2 -partially agree, 3 -no opinion, 4 -partially disagree, 5 -completely disagree.   It is important to emphasize that the bleaching procedures performed with carbamide peroxide achieved greater than 5 units of ΔE, which is the threshold for the bleaching to be considered effective 2 .
In fact, although the bleaching effect was lower than that expected for most patients who undergo tooth bleaching with carbamide peroxide, at least half of the patients (median score of 2) were satisfied with the results achieved with tooth bleaching. When the patients who received tooth bleaching with hydrogen peroxide were evaluated, more than 75% (score of 2 in the 3 rd quartile) agreed that the bleaching procedures yielded whiter teeth than expected or achieved satisfactory results. The best perceptions of treatment results were noted in patients who underwent tooth bleaching with hydrogen peroxide according to smile perception data. The average smile perception score following bleaching with hydrogen peroxide was 2-fold higher than that observed for carbamide peroxide.
Despite the reduction in bleaching effect, the presence of fewer reactive oxygen species from peroxide breakdown also reduces the negative effects of in-office bleaching related to tooth sensitivity 30 .
During the bleaching procedures, the use of carbamide peroxide reduced the tooth sensitivity risk from 67 to 89% when compared with the risk associated with using hydrogen peroxide. Regarding the level of tooth sensitivity reported by patients, data on carbamide peroxide assessed by the VRS demonstrated that the 3 rd quartile experienced no sensitivity regardless of the assessment time. These data indicate that more than 75% of patients did not report any level of tooth sensitivity. Moreover, the VAS demonstrated levels High-concentration carbamide peroxide can reduce the sensitivity caused by in-office tooth bleaching: a single-blinded randomized controlled trial J Appl Oral Sci. 2018;26:e20170573 9/10 of tooth sensitivity close to zero when carbamide peroxide was used. The sensitivity reported by patients following tooth bleaching procedures is related to inflammatory processes induced by the presence of peroxide and its products in the pulpal chamber, reducing pulpal cell proliferation, metabolism, and viability, and compromising the pulp-reparative capacity 6,17,30 . Thus, it is reasonable to associate lower concentrations of peroxide and its products with reduced tooth sensitivity levels and risk, in accordance with the findings of this study.
Regardless of the reported increased sensitivity and worse scores attributed to the question about tooth sensitivity to hydrogen peroxide, an important observation was that more than 75% (3 rd quartile was lower than 3) of the participants with teeth bleached by this agent did not disagree that the sensitivity experienced was lower than that expected. In fact, the average level of tooth sensitivity reported using the VAS was approximately 2 cm (maximum was 10 cm), and only one patient reported severe sensitivity (in the second session). Thus, despite the high risk of sensitivity observed for in-office bleaching with high concentrations of hydrogen peroxide (approximately 63% according to a previous systematic review), the level of this sensitivity is relatively low (mean of 2.8 cm on the VAS) 28 . Moreover, even when moderate to severe pain is present, tooth sensitivity tends to be significantly reduced or disappear 24 h after the bleaching procedure.
The findings of this clinical trial demonstrated that high concentrations of carbamide peroxide effectively achieve satisfactory bleaching effects when used in a single 40-min in-office application. In addition, despite a reduced color change compared with that resulting from the use of 35% hydrogen peroxide, 37% carbamide peroxide significantly reduced both the risk and level of the tooth sensitivity reported by patients.
As sensitivity is the main concern of most patients who undergo tooth bleaching, products promoting pain reduction must be considered in any bleaching protocol. Regarding the reduced bleaching effect, the addition of any activating component to 37% carbamide peroxide could increase the pH solution and improve its bleaching effect. Therefore, further studies are necessary to confirm this last assumption.

Conclusions
In-office tooth bleaching using 37% carbamide peroxide in a single 40-min application resulted in reduced risks and tooth sensitivity level with values close to zero, despite the reduced color change when compared with that achieved using 35% hydrogen peroxide.