Etodolac and Post-bleaching Sensitivity
Condition: Medicaments Substances in Therapeutic Use
MeSH terms: Hypersensitivity
Study type: Interventional
Phase: Phase 4

Summary: 
      Objectives: This study will determine the effectiveness of preemptive administration of
      etodolac on risk and intensity of tooth sensitivity caused by in-office bleaching using 35%
      hydrogen peroxide.

      Materials and Methods: Fifty patients will be selected for this triple-blind, randomized,
      cross-over, placebo-controlled clinical trial. Etodolac (400 mg) or placebo will be
      administrated in a single-dose 1 hour prior to bleaching procedure. The whitening treatment
      with 35% hydrogen peroxide will be carried out in two sessions with a 7-day interval. Tooth
      sensitivity will be assessed before, during and 24 hours after the procedure using analog
      visual and verbal scales. Color alteration will be assessed by a bleach guide scale 7 days
      after each session. Relative risk to sensitivity will be calculated and adjusted by session;
      while comparison of overall risk will performed by McNemar's test. Data on the sensitivity
      level for both scales and color shade will be subjected to the Friedman, Wilcoxon and
      Mann-Whitney tests, respectively (α = 0.05).
    

Detailed description: 
      Methods & Materials:

      This clinical trial was approved by the Scientific Review Committee and by the Committee for
      the Protection of Human Subjects of the local university (CAAE 37578714.4.0000.5546).

      Trial design:

      This study will be a randomized, triple-blind, placebo-controlled clinical trial with a
      cross-over design. The patients included will be submitted to two in-office bleaching
      sessions receiving placebo (control) or etodolac prior to the bleaching procedure; while
      different treatments will be allocated for each session. A delay of 1 week between the
      sessions (wash-out) will be established. The study will be conducted at the clinic of the
      School of Dentistry of the local university from November 2014 to July 2015.

      Participants:

      Patients included in this clinical trial will be at least 18 years old with good oral health.
      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 will be excluded. Participants submitted to
      previous bleaching procedures, presenting prior tooth sensitivity, known allergy to any
      component of medication used in the study, pregnant or breastfeeding will be also excluded.
      Only patients presenting all six upper anterior teeth with shade mismatching with 2.5 M2
      (Vita Bleachguide 3D-Master scale, Vita-Zahnfabrik, Bad Sackingen, Germany) or darker will be
      included.

      Sample Size Calculation:

      The sample calculation will be based on the primary binary outcome (sensitivity risk 24 hours
      after the procedure) for superiority trial. Power of the test will be set at 80%, considering
      a type I error of 0.05; risk to tooth sensitivity of 90%, based on a prior study using
      similar bleaching agent, while a reduction around 30% with the treatment will be expected.
      The calculation resulted in fifty patients.

      Randomization:

      A randomized list will be computer-generated by a person not involved in intervention or
      evaluation. The participants were defined as blocks in the randomization process, where the
      sequence of treatment (placebo or etodolac) will be randomly set for each block by using
      computer-generated tables (www.sealedenvelope.com). The sequence will be inserted into sealed
      envelopes numbered from 1 to 50 that were opened by the operator only at the moment of the
      intervention. The patients were numbered according to the sequence of enrollment. Neither the
      participant nor the operator knew the group allocation determining blinding to the protocol.

      Baseline evaluation:

      Prior to bleaching procedure, the teeth will be cleaned using rubber cups associated to
      pumice and water. The shades of six upper anterior teeth will be assessed on a baseline using
      the bleach guide scale. The color analysis will be carried out by two previously calibrated
      evaluators. The two evaluators presented superior color matching competency according to the
      ISO (International Organization for Standardization) 28642:2011. The shades' tabs selected
      will be converted to scores ranging from 1 (whiter shade - 0M1) to 15 (darker shade - 5M3).

      Considering a possible effect of dental anxiety on sensitivity reported by patients, the
      Corah's Dental Anxiety Scale will be used to determine the level of anxiety of each patient
      related to the procedure [26]. Each answer to the survey instrument will be scored on a scale
      from 1 to 5 (four questions); and the sum of scores will be used to determine the level of
      anxiety: low will be lower than 12, moderate will be between 12 and 14, and high will be
      higher than 14.

      Intervention:

      One-hour prior to each bleaching session, the patients will receive a capsule containing 400
      mg of NAISE etodolac or 400mg of placebo (inert content), according to the randomization,
      while the capsules will present the same appearance. The capsules with similar presentation
      will be manufactured by a person not involved in intervention or evaluation and will be
      placed into two bottles identified by letters according to treatment. Neither the operators
      responsible for intervention and evaluation nor the patients knew the content of each
      capsule.

      A light-cured resin dam will be applied (Top Dam, FGM, Joinville, SC, Brazil) on the gingival
      tissue corresponding to the teeth to be bleached. A 35% hydrogen peroxide based bleaching
      agent (Whiteness HP Blue, FGM, Joinville, SC, Brazil) will be mixed and applied on the
      vestibular surface of teeth, remaining for 40 minutes. After this time, the bleaching agent
      will be removed. A second session will beas carried out after 1 week following the same
      procedures. At this time, the patient received a single-dose capsule containing etodolac or
      placebo (different from the ones received at first session) 1 hour before the procedure.

      Evaluations:

      The tooth sensitivity reported by patients will be assessed using a visual analog scale (VAS)
      and verbal rating scale (VRS). The VAS consisted of a scale 10 cm in length ranging from
      green (absence of pain) to red (unsupportable pain). The patient set his or her level of
      sensitivity by pointing to the color corresponding to this level, while the distance from
      this point to the green border will be recorded. For VRS, the patient reported his or her
      level of sensitivity based on scores: 0 = none, 1 = light, 2 = moderate, 3 = considerable and
      4 = severe. The tooth sensitivity will be assessed during the bleaching, immediately after
      bleaching agent removal and after 24 hours. For this last assessment, only the VRS will be
      used. One week after each session the tooth color will be evaluated again using the same
      procedure described previously.

      Statistical Analysis:

      The demographic data from patients will be analyzed to determine age, gender, and anxiety
      level for each allocation sequence. Comparisons between the allocation sequences will be
      performed by the Mann-Whitney test (age) and Fisher's exact (gender) and chi-square (anxiety
      level) tests.

      Based on presence of any tooth sensitivity (scores different from 0 for VRS), the absolute
      risk, odds ratio and relative risk will be calculated regarding the treatments for each
      moment of evaluation/session of bleaching, as well as its confidence intervals (95%). For
      each moment, differences on presence/absence ratios will be analyzed by Fisher's exact test.
      For the overall risk related to each treatment, the odds ratio will be adjusted to
      independent variable "session of bleaching" using the Mantel-Haenszel statistic. The
      homogeneity of odds ratios will be analyzed by the Breslow-Day and Tarone's tests. Following,
      the odds ratio estimated will be converted to relative risk and the overall presence/absence
      ratios will be analyzed by the McNemar's test, considering the study design (cross-over).

      For VRS, the data from scores observed in each time of evaluation/session of bleaching will
      be submitted to the Mann-Whitney rank sum test. Despite the measurement of tooth sensitivity
      using VAS giving a continuous outcome, data assessed with this scale did not show a normal
      distribution (Shapiro-Wilk's test). Thus, data from VAS will be also analyzed by the
      Mann-Whitney rank sum test, while one test per time of evaluation will be carried out.

      For color evaluation, comparisons between the sequences of treatment will be performed using
      the Mann-Whitney rank sum test. The Friedman test followed by Dunn's post hoc test will be
      used to analyze the difference between the moments of evaluation for each sequence of
      treatment. All statistical analyses will be performed adjusting the initial significance
      level (α = 0.05) by Bonferroni correction.
    

Intervention name(s): Etodolac; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The patient will receive a single-dose of Etodolac (400 mg) one hour before the bleaching procedure.; The patient will receive a single-dose of placebo one hour before the bleaching procedure.
Intervention MeSH terms: Etodolac
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Tooth bleaching