Effect of CPP-ACP Associated With NaF or SnF₂ on Post-Bleaching Tooth Sensitivity

Efficacy of Casein Phosphopeptide-Amorphous Calcium Phosphate Associated With Sodium Fluoride or Stannous Fluoride in Reducing Tooth Sensitivity After In-office Dental Bleaching: a Randomized Clinical Trial.

This randomized, triple-blind, placebo-controlled clinical trial aims to evaluate the efficacy of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) associated with sodium fluoride (NaF) or stannous fluoride (SnF₂) in reducing tooth sensitivity following in-office dental bleaching.

Tooth bleaching with high-concentration hydrogen peroxide is widely used due to its effectiveness in improving dental aesthetics. However, tooth sensitivity remains the most common adverse effect associated with this procedure, negatively impacting patient comfort and satisfaction. Although several desensitizing strategies have been proposed, there is still no gold-standard protocol for managing post-bleaching sensitivity.

CPP-ACP is a remineralizing agent capable of releasing calcium and phosphate ions, promoting mineral deposition on the tooth surface and potentially occluding dentinal tubules. When combined with fluoride, its effects may be enhanced. Sodium fluoride (NaF) has been widely used in dentistry, while stannous fluoride (SnF₂) has gained attention due to its additional protective and anti-sensitivity properties. Recent evidence suggests that the combination of CPP-ACP and SnF₂ may enhance mineral uptake and improve protective effects on dental tissues.

A total of 66 participants will be randomly allocated into three groups (n=22): (1) CPP-ACP with NaF, (2) CPP-ACP with SnF₂, and (3) placebo control. All participants will undergo in-office bleaching with 35% hydrogen peroxide in two sessions, with a 7-day interval between sessions.

Desensitizing agents or placebo will be applied before and after each bleaching session. Tooth sensitivity will be assessed using a numeric rating scale (NRS) and a visual analog scale (VAS) at multiple time points up to 72 hours after each session. Color changes will be evaluated using a spectrophotometer based on the CIELAB system.

The study will test the hypothesis that CPP-ACP combined with fluoride agents reduces post-bleaching sensitivity without compromising whitening effectiveness. The findings may contribute to the development of more effective clinical protocols for managing bleaching-induced tooth sensitivity.

Study Overview

• Status: Completed
• Conditions: Tooth Sensitivity
• Intervention / Treatment: Drug: Control (placebo); Drug: CPP-ACPF; Drug: CPP-ACP+SnF2

Detailed Description

Tooth bleaching has become one of the most widely performed aesthetic dental procedures due to the increasing demand for whiter teeth and improved smile appearance. The procedure typically involves the use of hydrogen peroxide-based agents, which penetrate dental structures and release reactive oxygen species capable of oxidizing chromogenic molecules responsible for tooth discoloration.

Despite its effectiveness, in-office bleaching using high concentrations of hydrogen peroxide (≥35%) is frequently associated with tooth sensitivity, which is considered the most common adverse effect of the procedure. This sensitivity is believed to result from the diffusion of peroxide through enamel and dentin, reaching the pulp tissue and triggering an inflammatory response that activates nociceptors.

Various strategies have been proposed to minimize post-bleaching tooth sensitivity, including the use of desensitizing agents with neural or tubule-occluding mechanisms, anti-inflammatory drugs, and photobiomodulation therapy. However, no consensus has been established regarding the most effective approach.

Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) is a milk-derived complex with well-documented remineralizing properties. CPP stabilizes calcium and phosphate ions in an amorphous form, facilitating their release in the oral environment. These ions can be deposited on the tooth surface, forming a mineral reservoir that may help occlude dentinal tubules and reduce dentin permeability.

The addition of sodium fluoride (NaF) to CPP-ACP formulations enhances remineralization by promoting the formation of fluorapatite. Clinical studies suggest that CPP-ACP combined with NaF (CPP-ACPF) may reduce post-bleaching sensitivity by limiting the diffusion of reactive oxygen species and enhancing mineral deposition.

Stannous fluoride (SnF₂) has also been widely used in oral care products due to its anti-erosive, antimicrobial, and anti-sensitivity properties. Advances in formulation technology have improved the stability and bioavailability of Sn²⁺ ions, increasing its clinical effectiveness. Recent evidence indicates that combining SnF₂ with CPP-ACP may enhance the uptake of tin and fluoride ions into dental tissues, potentially improving protective and desensitizing effects.

However, there is limited clinical evidence evaluating the combined use of CPP-ACP and SnF₂ in the context of tooth bleaching. Therefore, this study aims to compare the effectiveness of CPP-ACP associated with NaF and CPP-ACP associated with SnF₂ in reducing tooth sensitivity after in-office bleaching, as well as to assess whether these interventions interfere with bleaching efficacy.

This study will be designed as a randomized, parallel-group, triple-blind, placebo-controlled clinical trial, conducted in accordance with CONSORT guidelines and ethical principles outlined in the Declaration of Helsinki. Participants will provide informed consent prior to enrollment.

A total of 66 participants, in good general and oral health, will be recruited. Eligible participants must present an upper right canine shade of A2 or darker according to the Vita Classical shade guide. Exclusion criteria include active caries, periodontal disease, restorations or prostheses in anterior teeth, visible cracks, severe intrinsic discoloration, dentin exposure, previous bleaching, orthodontic treatment, systemic conditions affecting oral health, pregnancy, lactation, and allergies to milk proteins or product components.

Participants will be randomly assigned into three groups (n=22 per group):

1. CPP-ACP with sodium fluoride (MI Paste Plus),
2. CPP-ACP with stannous fluoride (MI Paste ONE Perio),
3. placebo control.

Randomization will be performed using computer-generated allocation, and allocation concealment will be ensured sealed opaque envelopes. The study will be triple-blinded, meaning that participants, operators, and outcome assessors will be unaware of group assignments. The desensitizing agents and placebo will be provided in identical containers.

All participants will undergo in-office bleaching using 35% hydrogen peroxide. Two bleaching sessions will be performed, with a 7-day interval. Each session will consist of three 15-minute applications, totaling 45 minutes.

The desensitizing agents or placebo will be applied before and after each bleaching session, following standardized procedures. Participants will be instructed to avoid eating or drinking for 30 minutes after application.

Tooth sensitivity will be assessed using two validated scales: a 5-point numeric rating scale (NRS) and a visual analog scale (VAS). Participants will record sensitivity at the following time points: during treatment, up to 1 hour, 1-24 hours, 24-48 hours, and 48-72 hours after each bleaching session.

Tooth color will be evaluated using a spectrophotometer (VITA Easyshade) based on the CIELAB color system (L*, a*, b*). Measurements will be taken at baseline, one week after the first session, one week after the second session, and 30 days after treatment. Color differences will be calculated using ΔE*ab and CIEDE2000 (ΔE00) formulas.

Data will be analyzed using appropriate statistical tests based on data distribution. Normality will be assessed using the Shapiro-Wilk test. Parametric or non-parametric tests will be applied accordingly, with a significance level of 5%.

The null hypotheses are that there will be no difference in tooth sensitivity among the groups and that the desensitizing protocols will not affect bleaching effectiveness. The results of this study may provide clinically relevant evidence for optimizing desensitizing protocols in in-office bleaching procedures, improving patient comfort without compromising aesthetic outcomes.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Pará
    • Belém, Pará, Brazil, 66075-110
      • Universidade Federal do Para

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Patients aged 18 years or older, of both sexes
• Good general and oral health
• Upper right canine classified as shade A2 or darker, according to the Vita Classical scale (VITA Zahnfabrik, Bad Säckingen, Germany)

Exclusion Criteria:

• Presence of active caries or periodontal disease
• Visible cracks in upper or lower anterior teeth
• Evident malocclusion
• Restorations or prostheses in anterior teeth
• Gastroesophageal disorders
• Severe intrinsic tooth discoloration (e.g., tetracycline staining, fluorosis, or non-vital teeth)
• Dentin exposure in anterior and/or posterior teeth
• Parafunctional habits
• Tooth sensitivity
• Previous tooth bleaching or orthodontic treatment
• Pregnant or lactating women
• Individuals with allergies or sensitivities to milk protein or hydroxybenzoate-based preservatives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; In this group, an experimental paste without an active ingredient was used, mimicking the color, texture, and flavor of the experimental pastes.	Drug: Control (placebo); This intervention was performed on arm 1. A placebo paste was applied to the buccal surface of the teeth for five minutes. During this period, the patient had to keep their mouth closed and not speak or move.
Experimental: CPP-ACPF; n this group, an experimental paste of CPP-ACP combined with sodium fluoride.	Drug: CPP-ACPF; Apply MI Paste Plus to the buccal surface of the teeth for five minutes. During this time, the patient should keep their mouth closed and should not talk or move. This procedure was performed on arm 2.
Experimental: CPP-ACP+SnF2; In this group, an experimental paste of CPP-ACP combined with stannous fluoride	Drug: CPP-ACP+SnF2; Apply MI Paste One Perio to the buccal surface of the teeth for five minutes. During this time, the patient should keep their mouth closed and should not talk or move. This procedure was performed on arm 3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tooth Sensitivity	Use Kruskal-Wallis ANOVA for within-group analysis and Friedman's test for within-group sensitivity data analysis.	"During bleaching", "1 hour after bleaching", "24 hours after bleaching", "48 hours after bleaching" and "72 hours after bleaching" in each whitening session.

Collaborators and Investigators

• Sponsor: Universidade Federal do Para
• Investigators: Principal Investigator: Silva, Universiade Federal do Pará

Publications and helpful links

General Publications

• Bouya S, Balouchi A, Maleknejad A, Koochakzai M, AlKhasawneh E, Abdollahimohammad A. Cancer Pain Management Among Oncology Nurses: Knowledge, Attitude, Related Factors, and Clinical Recommendations: a Systematic Review. J Cancer Educ. 2019 Oct;34(5):839-846. doi: 10.1007/s13187-018-1433-6.
• Chaves GC, Abi-Saab Arrieche M, Rode J, Mechali D, Reis PO, Alves RV, Stobbaerts E, Aguilar NG, Ribeiro I. [Estimating demand for anti-Chagas drugs: a contribution for access in Latin America]. Rev Panam Salud Publica. 2017 Jun 8;41:e45. doi: 10.26633/RPSP.2017.45. Spanish.
• Morsch P, Pereira GN, Navarro JH, Trevisan MD, Lopes DG, Bos AJ. [Clinical characteristics and social determinants in a sample of non-homebound elderly]. Cad Saude Publica. 2015 May;31(5):1025-34. doi: 10.1590/01021-311X00053014. Portuguese.
• Kim YH, Boykin E, Stevens T, Lavrich K, Gilmour MI. Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches. J Nanobiotechnology. 2014 Nov 26;12:47. doi: 10.1186/s12951-014-0047-3.
• Oliveira Barros AP, da Silva Pompeu D, Takeuchi EV, de Melo Alencar C, Alves EB, Silva CM. Effect of 1.5% potassium oxalate on sensitivity control, color change, and quality of life after at-home tooth whitening: A randomized, placebo-controlled clinical trial. PLoS One. 2022 Nov 17;17(11):e0277346. doi: 10.1371/journal.pone.0277346. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2025
• Primary Completion (Actual): July 20, 2025
• Study Completion (Actual): January 29, 2026

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 28, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 28, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Tooth Sensitivity; Tooth Bleaching; Dentin Desensitizing Agents
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Tooth Diseases; Dentin Sensitivity
• Other Study ID Numbers: UFPara-2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No