Effect of Analgesic Drugs on Tooth Sensitivity Induced by In-office Dental Bleaching: A Systematic Review and Meta-analysis
This systematic review evaluates the effect of preemptive analgesia on tooth sensitivity induced by in-office tooth bleaching. The review was structured based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. The methods were recorded at PROSPERO (CRD42018095440). Randomized clinical trials, studies published in English, and studies in which the efficacy of preemptive analgesia with analgesic and anti-inflammatory medications prior to in-office tooth bleaching was compared with that of placebo were included. PubMed/MEDLINE, Scopus, Web of Science, and Cochrane Library were used for searching. The electronic search provided 373 articles, and seven of them were selected based on the inclusion criteria. Immediately after time point, a significant reduction of dental sensitivity was observed in the drug group compared to the control group (p=0.02; mean difference [MD]: −0.90; confidence interval [CI]: −1.63 to −0.16), while there was no significant difference at up to one-hour (p=0.22; MD: −0.42; CI: −1.09 to −0.25), at 1-24–hour (p=0.88; MD: −0.05; CI: −0.61 to 0.72), or 24-48–hour (p=0.69; MD: 0.05; CI: −0.21 to 0.32) time points. The incidence of sensitivity during the procedure was not statistically different between the groups (p=0.64; MD: 0.91; CI: 0.92 to 1.15). The nonsteroidal anti-inflammatory drug group showed a statistically significant reduction (p=0.04; MD: −0.69; CI: −1.36 to −0.03) in tooth sensitivity compared with the other groups. This systematic review and meta-analysis demonstrated that the medications analyzed did not interfere with the incidence of sensitivity symptoms. Regarding the intensity, no difference was observed between the drug and placebo groups at the up to one-hour, 1-24–hour, or 24-48–hour time points, and there was a statistically significant difference at the zero-hour time point in favor of the drug group. However, based on the variables that influenced this result, it should be considered with prudence because a small difference was observed.SUMMARY
Objective:
Methods:
Results:
Conclusions:
INTRODUCTION
Tooth bleaching is a simple, successful, and widely used technique that aims to improve the esthetics of the smile by lightening the coloration of teeth.1-3 The most effective techniques are performed in office and at home under the supervision of a dentist.4 The main agents that promote bleaching are hydrogen peroxide5 and carbamide peroxide.6
At hydrogen peroxide concentrations higher than 35%, tooth sensitivity is a common side effect during and after the procedure.1,3,7 This effect is attributed to the free radicals released by H2O2. As a result of its low molecular weight, the hydrogen peroxide molecule can traverse the dentin and reach the pulp cavity, resulting in inflammatory reactions of the pulp cells. Patients perceive the manifestation of an acute, temporary, and short-term painful reaction to an external stimulus as tooth sensitivity.2,3,5,8
To reduce the sensitivity induced by dental bleaching, clinical studies have tested the use of bleaching gels at lower concentrations with/without a shorter application time,9-11 desensitizing dentifrices,12 and topical desensitizing agents.13-15 In addition, the use of preprocedure medication to control tooth sensitivity has also been studied1-5,7,8,16 as a different approach for the control of tooth sensitivity induced by in-office dental whitening.
Therefore, the aim of this systematic review was to evaluate the effectiveness of drugs with analgesic effect on tooth sensitivity induced by in-office dental bleaching when hydrogen peroxide is used. The null hypothesis states that the medications with analgesic effect do not interfere with tooth sensitivity when in-office bleaching is performed using hydrogen peroxide.
METHOD
Registry Protocol
This systematic review was structured based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist.17 The methods for this systematic review were recorded on the international prospective register of systematic reviews (PROSPERO-CRD42018095440).
Eligibility Criteria
The selected studies are in accordance with the PICO strategy. The following elements were included: (P) Population: patients subjected to in-office tooth bleaching; (I) Intervention: patients subjected to in-office tooth bleaching with preemptive administration of analgesic drugs; (C) Comparison: Patients subjected to in-office tooth bleaching without the use of preemptive analgesia (negative control); and (O) Outcome: reduction of in-office tooth bleaching–induced sensitivity. Thus, the question asked was “Does the preoperative use of analgesic or anti-inflammatory drugs with analgesic effects minimize the sensitivity induced by in-office tooth bleaching?”
The following inclusion criteria were applied: 1) randomized clinical trials; 2) studies published in English; and 3) studies comparing the efficacy of preemptive analgesic drugs—that is, analgesic and anti-inflammatory medications—administered prior to in-office tooth bleaching with a placebo.
The following exclusion criteria were applied: 1) in vitro studies; 2) animal studies; 3) case series or case reports; 4) retrospective studies; 5) revisions and commentaries of revisions; 6) studies evaluating other nonanalgesic and anti-inflammatory drugs; and 7) studies that did not have a control group.
Information Sources
Two authors (RTFC and CAAL) independently performed an electronic search in the following databases: PubMed/MEDLINE, Scopus, Web of Science, and Cochrane Library; searches were performed using the following terms: bleaching, anti-inflammatory, teeth bleaching, tooth bleaching, whitening, in-office bleaching, sensitivity, analgesic, and nonsteroidal.
In each database, studies were selected based on the title and abstract. To determine inclusion, each article was read in its entirety. The choices made by the two evaluators were analyzed by the third author (SLDM), and consensus was reached through discussion.
The same author performed a manual search for the articles published in the following journals: Operative Dentistry, Journal of Dentistry, Journal of Dental Research, Clinical Oral Investigations, and Quintessence International, in addition to the grey literature.
Data Collection Process
One author (RTFC) collected the information from the articles, and another author (CAAL) reviewed the results. The choices made by the two evaluators were analyzed by the third author (SLDM), and consensus was reached through discussion.
The variables collected from the articles were as follows: author, type of study, bleaching agent, number of bleaching sessions, bleaching agent protocol, mean age, drug used to perform preemptive analgesia, dosage, mode of administration, time points of sensitivity assessment, type of scale used for the measurement of sensitivity, mean degree of dental sensitivity, absolute risk, and relative risk.
Risk of Bias
Two investigators (RTFC and CAAL) rated the quality and risk of bias of the randomized controlled trials using the Cochrane risk-of-bias tool.18 This tool evaluates selection bias (random sequence generation and allocation), performance bias (blinding of participants and personnel), bias detection, attrition bias (incomplete outcome data), reporting bias (selective reporting), and biases from other sources.
Summary Measures
The meta-analysis (Reviewer Manager 5 software, Cochrane Group) was based on the Mantel-Haenzel and inverse variance methods. Data from eligible studies were either dichotomous (tooth sensitivity incidence), evaluated using the risk ratio (RR), or continuous (tooth sensitivity intensity), evaluated using mean differences (MDs), with corresponding 95% confidence intervals (CIs). RR and MD values were considered statistically significant at the p < 0.05 level.
Heterogeneity analyses evaluated the I2 value (25%=low, 50%=moderate, and 75%=high). The meta-analyses effects were based on the heterogeneity study. When the heterogeneity was statistically significant (p<0.10), random effects meta-analyses were conducted; otherwise, meta-analyses were performed using fixed effects.19
Additional Analysis
The Kappa score was used to evaluate concordance between the examiners in determining the studies that must be included among those identified through the initial database search. It was performed as an additional analysis with the objective of verifying agreement between the two examiners in the search for articles in the databases. Any disagreement between authors was discussed and consensus reached.
RESULTS
Literature Search
The electronic search provided 373 articles: 236 from PubMed/Medline, 119 from Web of Science, 10 from Cochrane Library, and 16 from Scopus. After duplicate articles were removed, the remaining 280 articles were searched manually for those published in the journals; one study was selected. The titles and abstracts of the articles were then read, and the eligibility criteria were applied; 12 articles were subjected to analysis. After reading the full articles, five were excluded for the following reasons: the medication used was an antimicrobial20 or an antioxidant drug;6 the article was a commentary on a study;21 the drug used was banned in the United States and most of Europe;3 and the clinical trial did not include a control group.22 Thus, seven studies were selected for this systematic review. The flow chart in Figure 1 details the search strategy.
Citation: Operative Dentistry 45, 2; 10.2341/18-250-L
The Kappa scores for the articles selected from PubMed/MEDLINE (0.8), Scopus (1.0), Web of Science (1.0), and the Cochrane Library (1.0) suggested a high level of agreement among the examiners. Based on the results of the Kappa test, there was an “almost perfect agreement” between the reviewers.23
Description of the Studies
Tables 1 and 2 summarize the information from the seven studies included. Six studies were randomized, triple-blinded clinical trials and one was a double-blinded clinical trial. All studies included a placebo control group. The bleaching agent used in all of the studies was hydrogen peroxide, and it was applied in office at a concentration ranging from 35% to 38%. A total of 359 patients were evaluated.
The most commonly used bleaching agent was Whitening HP Maxx (FGM, Joinville, Brazil).4,7,8,16 In-office bleaching was the procedure of choice in all of the studies, and it was performed in two sessions in all of the studies,2,4,5,7,8,16 with the exception of one study, in which the procedure was performed in one session.1 The majority of the studies used the drug only preoperatively,1,2,5,7 whereas the remaining studies4,8,16 administered the drug both preoperatively and postoperatively. The drugs selected for the studies varied; however, ibuprofen1,8 was used in two studies.
The pharmacokinetic information on each medicine was obtained from the package leaflet, except when a medicine was no longer manufactured by the company. In such an instance, the package leaflet of a drug with the same constitution, but different pharmaceutical manufacturer, was used.
Quality Assessment of the Studies
A low risk of bias in random sequence generation and allocation concealment (selection bias) was verified for all the studies, with the exception of one;1 this unverified study was classified as “uncertain” risk of bias. Under the category of blinding the participants and personnel (performance bias), all the studies were verified. Blinding of the outcome assessment (bias detection) was verified in most studies; under this category, only one study1 was judged as “unclear” risk of bias. Incomplete outcome data was verified in most studies, with the exception of one; this unverified study was classified as “high” risk of bias. All of the selected studies were considered to have low risk of selective reporting (Figure 2).
Citation: Operative Dentistry 45, 2; 10.2341/18-250-L
Meta-analysis
Sensitivity Level
Tooth sensitivity was measured using the visual analogue scale (VAS) method. Sensitivity was measured immediately after the end of bleaching procedure (0h) and up to one hour (up to 1h), from 1 to 24 hours (1-24h), and from 24 to 48 hours (24-48h) after the procedure.
Immediately After
Two studies evaluated the sensitivity immediately after tooth bleaching (0h).1,5 In both of the studies random effects showed statistically significant differences between the drug and placebo groups (p=0.02; MD: −0.90; CI: −1.63 to −0.16). The data were heterogeneous (X2: 3.03; I2=67%; p=0.08), and both the studies showed a common effect size; this suggests that there are differences in the incidence of tooth sensitivity between the analgesic drug and placebo groups (Figure 3).
Citation: Operative Dentistry 45, 2; 10.2341/18-250-L
Up to 1h
Five studies assessed tooth bleaching–induced sensitivity up to 1h after the procedure based on continuous outcome data via visual analogue scales using visual measurements.1,4,7,8,16 Random effects did not show significant differences between the drug and placebo groups (p=0.22; MD: −0.42; CI: −1.09 to −0.25). Heterogeneity was not significant (X2: 3.09; I2=0%; p=0.54), and all studies included in the analysis shared a common effect size (Figure 3).
1-24h
As shown in Figure 3, five studies1,4,7,8,16 reported bleaching sensitivity from 1-24 hours after the procedure; sensitivity was assessed by visual measurements. In all of these studies, random effects showed no significant difference between the drug and placebo groups (p=0.88; MD: −0.05; CI: −0.61 to 0.72). The data were not heterogeneous (X2: 1.12; I2=0%; p=0.89), and all studies included in the analysis shared a common effect size.
24-48h
Four studies reported tooth bleaching sensitivity from 24 to 48 hours after the procedure; in these studies sensitivity was assessed by visual measurements.4,7,8,16 The results showed no difference between the drug and placebo groups (p=0.69; MD: 0.05; CI: −0.21 to 0.32). The data were not heterogeneous (X2: 0.66; I2=0%; p=0.42), and all the studies included in the analysis shared a common effect size (Figure 3).
Sensitivity Incidence
Six studies assessed the incidence of sensitivity (Figure 4).2,4,5,7,8,16 The results showed no significant difference between the drug and placebo groups (p=0.64; MD: 0.91; CI: 0.92 to 1.15). The data were heterogeneous (X2: 6.29; I2=21%; p=0.28), and all the studies shared a common effect size.
Citation: Operative Dentistry 45, 2; 10.2341/18-250-L
Drug Groups
Subgroup analyses were conducted to examine the effect of medication on the intensity of sensitivity. The nonsteroidal anti-inflammatory drug (NSAID) group showed a significant decrease in tooth sensitivity immediately after the bleaching procedure (p=0.04; MD: −0.69; CI: −1.36 to −0.03). The data did not show heterogeneity (X2: 2.03; I2=0%; p=0.57) (Figure 5).
DISCUSSION
The current results show that analgesia with preemptive medication was effective in decreasing tooth sensitivity immediately after the in-office bleaching procedure. However, there was no difference in the incidence of sensitivity-associated symptoms between the drug and placebo groups at the 1-24h or 24-48h time points. Thus, the null hypothesis is partially rejected in this study.
The decreased sensitivity immediately after the bleaching procedure can be attributed not only to the peak plasma concentration of the drug during this period5 but also to the fact that the production of prostaglandins, which signal inflammation, occurs primarily within the first hour after the stimulus of damage is initiated. According to de Paula and others,8 another explanation for the long-term ineffectiveness of preemptive analgesia in tooth whitening is the possibility that other inflammatory mediators (other than COX-1 and COX-2) are activated over time and are involved in the mechanism of pain, with the possibility of a neurogenic reaction.2,8,24,25
The administration of preemptive medication has been suggested1-8,16,20 to minimize discomfort immediately after in-office bleaching. The oral route of administration is associated with good bioavailability, and it is the most common route of administration used in clinical trials.1-5,7,8,16 NSAIDs, corticosteroids, and analgesics are all oral medications. The meta-analysis found that the one drug category that had a positive effect on sensitivity was NSAIDs when a single preprocedure dose is administered alone or with accompanying additional doses at the 24h time point after the procedure. This finding is not fully understood. However, Fernandes and others5 state that it may be related to the effect of NSAIDs on bradykinin, which inhibits the synthesis of prostaglandin, a mediator of the inflammatory process. Preemptive administration of other doses or combinations of medications, in addition to a longer lead time, are possibly more effective. However, further studies are needed to identify new drug regimens that could eliminate odontogenic pain.
Despite the effectiveness of bleaching techniques, tooth sensitivity is the main adverse effect during in-office procedures.9,13,20,26 The gels used in office are predominantly hydrogen peroxide–based,2,4,5,27 with H2O2 concentrations ranging from 15% to 38%;2 the most commonly used concentration is 35%. According to Bortolatto and others,9 the gel concentration may have a significant influence on sensitivity. This product acts by penetrating the dental structure and promoting the lysis of macromolecules in the pigment through an oxy-reduction reaction.9 However, the gel is also capable of inducing changes in the odontoblasts layer and triggering an inflammatory reaction in the dental pulp.22,28 This can lead to the release of inflammatory mediators that are responsible for painful sensations, local vasodilatation, and increased vascular permeability.16
Although the mechanisms involved in hydrogen peroxide–induced pain are not fully understood yet,2,24,29 the sensitivity caused by tooth bleaching tends to increase during the first hours after the procedure, and this sensitivity is described as “zingers” by Haywood.30
The studies included in this systematic review and meta-analysis reported the presence of sensitivity during and up to 48 hours after the bleaching procedure and showed that the peak of pain is experienced within this time interval. As reported in the literature, tooth sensitivity occurs predominantly during the first 24 hours postprocedure,4,6,25 and the symptoms may persist for several days.16,31 However, Charakorn and others1 have suggested that the peak of dental sensitivity is experienced between one and six hours after bleaching.
Regardless of the type of drug administered, no difference was observed in the incidence of dental sensitivity between the drug and placebo groups, confirming the results reported in previous studies.6,10,32,33 Regarding the intensity of the tooth sensitivity, the only observed statistically significant result was that the analgesic drugs can reduce the intensity of tooth sensitivity at the immediately after time point (p=0.02). However, as only two studies were used in this comparison and one of them presented a high risk of bias, this led us to consider that not only the p-value must be taken into consideration, according to Glick and Greenberg34 and Best and others.35 It is believed that the quality of the studies and the CI must also be taken under consideration to interpret the p-value.
Importantly, the included studies present strong evidence; all of these studies were double-blinded or triple-blinded randomized clinical trials (RCTs). According to Higgins and others,18 RCTs provide optimal scientific evidence, and when carried out following preestablished standards, they can be decisive in the construction of a systematic review. In addition, the absence of heterogeneity and the high quality of RCTs confirmed by the bias risk analysis were significant; these results allow us to state that the studies shared the same effect size. Moher and others17 stated that the absence of heterogeneity is highly relevant in the verification of scientific evidence.
One limiting factor of this study was that the age range of the study participants was narrow. This review predominantly included young adults, which hinders the universalization of these results to the general population. However, the response to pulp sensitivity is more evident in young individuals than in older individuals because they present wider dentinal tubules and thinner dentin layers.36,37 Therefore, to determine the efficacy of preemptive analgesia in reducing bleaching-induced dental sensitivity, further randomized clinical trials evaluating different routes of administration and drugs classes should be carried out in varied age groups.
CONCLUSIONS
This systematic review and meta-analysis demonstrated that the medications analyzed did not interfere with the incidence of sensitivity symptoms. Regarding the intensity, no difference was observed between the drug and placebo groups at the up to 1h, 1-24h, or 24-48h time points, and there was a statistically significant difference at the 0h time point in favor of the drug group. However, based on the variables that influenced this result, it should be considered with prudence because a small difference was observed. This study also confirmed the need for more trials of the effect of the drugs with analgesic effect on tooth sensitivity induced by in-office dental bleaching, especially with NSAIDs.
Flowchart describing the search and selection strategies.
Assessment of the risk of bias in the included studies based on the Cochrane Risk of Bias Tools. (red), High risk of bias; (yellow), Uncertain risk of bias; (green), Low risk of bias.
Forest plot for the event “sensitivity measurements.”
Figure 4. Forest plot for the event “sensitivity incidence.”
Figure 5. Forest plot for the event “subgroup medication group (NSAIDs) analyses to evaluate the effect on the intensity of sensitivity.”
Contributor Notes
Juliana Raposo Souto-Maior, DDS, MS, PhD, School of Dentistry, Pernambuco University, Camaragibe, Pernambuco, Brazil