Preemptive use of etodolac on tooth sensitivity after in-office bleaching: a randomized clinical trial

Abstract Purpose This study determined the effectiveness of the preemptive administration of etodolac on risk and intensity of tooth sensitivity and the bleaching effect caused by in-office bleaching using 35% hydrogen peroxide. Material and methods Fifty patients were selected for this tripleblind, randomized, crossover, and placebo-controlled clinical trial. Etodolac (400 mg) or placebo was administrated in a single-dose 1 hour prior to the bleaching procedure. The whitening treatment with 35% hydrogen peroxide was carried out in two sessions with a 7-day interval. Tooth sensitivity was assessed before, during, and 24 hours after the procedure using the analog visual scale and the verbal rating scale. Color alteration was assessed by a bleach guide scale, 7 days after each session. Relative risk of sensitivity was calculated and adjusted by session, while overall risk was compared by the McNemar's test. Data on the sensitivity level of both scales and color shade were subjected to Friedman, Wilcoxon, and Mann-Whitney tests, respectively (α=0.05). Results The preemptive administration of etodolac did not affect the risk of tooth sensitivity and the level of sensitivity reported, regardless of the time of evaluation and scale used. The sequence of treatment allocation did not affect bleaching effectiveness, while the second session resulted in additional color modification. The preemptive administration of etodolac in a single dose 1 hour prior to in-office tooth bleaching did not alter tooth color, and the risk and intensity of tooth sensitivity reported by patients. Conclusion A single-dose preemptive administration of 400 mg of etodolac did not affect either risk of tooth sensitivity or level of sensitivity reported by patients, during or after the in-office tooth bleaching procedure.


Introduction
Tooth whitening is a simple and non-invasive treatment commonly carried out to reestablish smile aesthetics. High success rates have been demonstrated for bleaching techniques applying 35% hydrogen peroxide (HP35%) 2 . Hydrogen peroxide (H 2 O 2 )-based bleaching agents at high concentrations (typically 15-38%) are currently used for in-office techniques due to their high oxidizing ability 12,25 . However, the low molecular weight of H 2 O 2 allows its penetration across the entire dentin tissue, reaching the pulp chamber and promoting damage of pulp stem cells, which is reported by patients as tooth sensitivity 15,29 .
Prior clinical trials have reported absolute risk of tooth sensitivity as high as 95% when highly concentrated H 2 O 2 is used for in-office tooth bleaching 9,20,23,25 . Thus, the preemptive use of desensitizer agents 3,30 or anti- Thus, this study aimed to evaluate the effectiveness of the preemptive prescription of etodolac on risk of tooth sensitivity during and after in-office bleaching treatment. The first hypothesis evaluated was that etodolac would reduce both level and risk of tooth sensitivity when administrated in a single dose prior to in-office bleaching. The second hypothesis tested was whether the use of etodolac would reduce tooth sensitivity with no effect on tooth bleaching.

Participants
Patients from 18 to 35 years old with good oral health were included in this clinical trial. From the patients who received placebo/etodolac, 6 were men and 19 were women, and for etodolac/placebo, 12 were men and 13 were women; the average age was 23 years; 64% were women.
Patients with any of the six upper anterior teeth with caries, restoration, severe discoloration (e.g., stains caused by tetracycline), enamel hypoplasia, gingival recession, dentin exposure, pulpitis, or endodontics were excluded, as well as smokers. Participants

Sample size calculation
The sample calculation was based on the primary binary outcome (sensitivity risk 24 hours after the procedure) for superiority trial. The power of the test was set at 80%, considering a type I error of 0.05 and risk of tooth sensitivity of 90%, based on a prior study using a similar bleaching agent 23 ; moreover, a reduction around 30% was expected after treatment.
The calculation resulted in fifty patients.

Randomization
A randomized list was computer-generated by a person not involved in intervention or evaluation.
Participants were defined as blocks in the randomization process, in which the sequence of treatment (placebo or etodolac) was randomly set for each block by computer-generated tables (www.sealedenvelope. com). The sequence was inserted into sealed envelopes numbered from 1 to 50 that were opened by the operator only at the moment of intervention. Each answer to the survey instrument was scored on a scale from 1 to 5 (four questions) and the sum of scores was used to determine the level of anxiety: low was under 12, moderate was between 12 and 14, and high was over 14.  Tooth sensitivity was assessed during bleaching, immediately after removing the bleaching agent, and after 24 hours. For this last assessment, only the VRS was used due to the difficulty of patients to fill the VAS at home. One week after each session, tooth color was evaluated again using the same procedure described previously.  Figure 1 shows the flow chart of patients assessed for eligibility, who were included in the study and analyzed. There was no difference among the sequences of treatment for any demographic characteristic analyzed (age: p=0.089 and gender: p=0.140). Table 2 shows the results of tooth sensitivity risk.

Results
The treatment that patients received prior to the   bleaching procedure did not affect the risk to sensitivity at any of the moments of evaluation (during and immediately after: p=1.0; after 24 hours: p=0.683).  Similar results were observed when the VAS was used ( Figure 3).
In regards to bleaching effectiveness, the bleaching procedure carried out in this study was able to significantly reduce the shade scores from the bleach guide, while the second session resulted in additional bleaching effect (Figure 4). The sequence of treatment did not affect bleaching effectiveness.

Discussion
Tooth bleaching performed by patients at home using low-concentration peroxides has been reported as the first-choice technique for vital bleaching, and probably the most widely used one 5,11 . However, procedures using high-concentration bleaching agents applied in office by clinicians remain an important protocol used to bleach discolored teeth for specific indications of tooth bleaching. This protocol is separate and intended to aid patients who cannot adapt to the use of home-based bleaching trays and who have contraindications related to the gastric system, because it reduces the risk of gel intake 14 , and to control the risk factor for developing gingival irritation 10 . In-office bleaching is also indicated to patients requiring faster results, while this technique can be combined with at-home bleaching 26 .
In-office techniques have demonstrated high bleaching effectiveness using high-concentration hydrogen peroxides 26 . However, high-concentrated bleaching agents also result in increased tooth sensitivity reported by patients during and up to 24 hours after the bleaching procedure, which is the main adverse effect related to in-office tooth bleaching 9,20,21 .
Even though tooth sensitivity is related to the inflammatory process of pulp tissue 20 , the findings of this study showed that the preemptive use of etodolac in a single dose did not affect the risk and level of tooth sensitivity caused by in-office bleaching. As expected, preemptive administration of etodolac also did not affect the bleaching results. Thus, the first hypothesis of the study was rejected and the second one was accepted.
Unlike the tooth sensitivity typically reported by patients presenting teeth with dentin exposure, which relates mainly to thermal stimuli, bleached teeth can hurt even in the absence of any stimulus, showing that the pain mechanism related to peroxides is different from other types of tooth pain 20 . Moreover, the sensitivity caused by tooth bleaching tends to increase within a few hours following the bleaching procedure, when most patients described the pain as a "twinge" or "shock-like." It has been demonstrated that the oxidizing agents used during the bleaching procedure cause a reduction on metabolism, viability, and cell proliferation 20 , allowing to increase the expression of inflammatory mediators, such as substance P and bradykinin, which is a vasoactive peptide released by nerves resulting in a neurogenic inflammation 6 . Thus, a preemptive administration of anti-inflammatories could be a reasonable approach to reduce tooth sensitivity associated with bleaching procedures. However, in this study, sensitivity was not lower during and 24 hours after the bleaching procedure. Unfortunately, the peak of tooth sensitivity was not measured in this study, even though this outcome could allow to assess a possible effect of etodolac on sensitivity following the end of the bleaching procedure.
A prior study demonstrated that etodolac presents higher effectiveness on bradykinin inhibition than other drugs commonly used to control the inflammatory process, motivating its use in this study 18 . Regarding pharmacokinetics, etodolac reaches its maximal plasma concentration around 1 to 2 hours after its Another important observation regarding pharmacokinetics is that a crossover design was used in this study with a 1-week interval period. Considering that the half-life of etodolac after oral administration is around 13 hours 16 , it is expected to find no residual effect after 1-week. Moreover, the crossover design avoids bias related to pain thresholds of patients 1 .
Participants included in this study were predominantly young females presenting low level of anxiety. All these demographics characteristics of the studied population might be associated with differences in pain thresholds. Higher tooth sensory threshold has been demonstrated in males due to differences in crown diameters of teeth and underlying mechanisms such as neurological differences or behavior aspects 8 . Regarding the age of participants, a recent review did not find any relation between age and the risk to or level of tooth sensitivity 27 . However, it is important to emphasize that most participants from trials included in that review were under 30 years old 27 . Another important demographic aspect assessed in this study was the participants' level of dental anxiety prior to bleaching procedures. It has been demonstrated that dental anxiety is a strong predictor of pain and that anxious participants are prone to develop painful responses 24 . In this research, almost 90% of participants presented low anxiety prior to bleaching procedures, which can be justified by the low invasive aspect of intervention, despite the patients' concern about tooth sensitivity. In fact, despite 66% of participants reporting various level of tooth sensitivity (high risk), the actual level of sensitivity reported was low (medians below moderate at VRS, and means lower than 2 at VAS).
In addition to the evaluation of tooth sensitivity,

Conclusions
The preemptive administration of a single dose of etodolac previously to the two bleaching sessions with 35% hydrogen peroxide did not affect tooth color change, risk of sensitivity and level of pain reported by the patients (during the sessions, immediately after, and 24 h after sessions).