Wellaholic Research: Randomized Controlled Trials on Teeth Whitening

TL:DR Summary

• Randomized Controlled Trials: They’re a gold standard in scientific research, providing reliable evidence on teeth whitening effectiveness.
• Various Whitening Methods: Studies compare different methods, including hydrogen peroxide, carbamide peroxide, and light-accelerated whitening.
• Hydrogen Peroxide’s Efficacy: This agent has shown significant whitening effect, though concentrations and application times vary.
• Carbamide Peroxide’s Performance: It also whitens effectively, but typically requires a longer contact time with teeth than hydrogen peroxide.
• Role of Light Acceleration: While some studies show light improves whitening, others find no significant impact.
• Overall Conclusion: While teeth whitening methods work, effectiveness can vary, emphasizing the need for individualized treatments.

Considerations on tooth whitening worldwide

Clinical Trials on Hydrogen-Peroxide Whitening Strips

Teeth whitening has been the subject of extensive clinical trials research since the introduction of the first hydrogen-peroxide whitening strips in 2000. Availability of digital image analysis, an unambiguous and reproducible method for assessing color change, has contributed to global clinical research and product development on whitening strips.

Global Randomized Controlled Trials

The research has included a series of global randomized controlled trials in distinct sites and cultures, involving 6-6.5% hydrogen peroxide whitening strips used for 7-21 days. These studies, conducted at research hospitals, dental schools, and private dental practice, demonstrated significant color improvement with whitening strips relative to baseline and/or various controls without serious adverse events.

Long-Term Safety and Effectiveness

This integrated clinical trials research provides important evidence of long-term safety and effectiveness of tooth whitening with 6-6.5% hydrogen peroxide whitening strips.

Introduction

Introduction to Tooth Whitening

Tooth whitening is often the earliest patient introduction to esthetic dentistry. Treatment may be undertaken in-office or at-home using various professionally-applied or professionally-dispensed agents, or one of the self-directed whitening systems. While individual techniques differ with respect to peroxide source, delivery, and other factors, the most prominent approaches rely on common oxidative chemistry, wherein peroxide diffuses from some bleaching gel into enamel. Whitening may be visually perceived and measured within a few days or weeks, depending on the technique used for peroxide delivery and retention, and the method of assessment.

History of Peroxides in Dentistry

Peroxides have been used in various dental applications for more than a century, including infection control, periodontal therapy, and others. Tooth whitening applications have drawn considerable research and development focus over the past three decades. Clinical trials have played a prominent role in these initiatives, with two milestones being particularly noteworthy.

Breakthrough of Carbamide Peroxide

The first milestone came in 1989, when clinical research demonstrated the safety and efficacy of whitening with 10% carbamide peroxide delivered overnight in a custom bite splint tray.

This research and other exemplary clinical trials contributed to “nightguard vital bleaching” becoming the first popular approach for tooth whitening. Clinical trials also played a limited role in expanding use of
higher concentrations of carbamide peroxide in custom trays (15% or higher) for the purposes of faster whitening. The second milestone came in 2000, with the publication of clinical research on flexible, hydrogen peroxide whitening strips.

Subsequent clinical research on whitening strips established the efficacy and safety of strip-based whitening at hydrogen peroxide concentrations ranging from 6-14%. Initially characterized as paradigm-shifting, clinical trials on whitening strips expanded access and use, with strip-based whitening emerging as a predominant approach for intensive tooth whitening.

Other peroxide whitening systems have been introduced, including barrier-free paint-on gels, rinses, and others. To date, evidence on these alternatives is limited, and none have yet achieved similar milestone successes as the custom tray or strip systems. For the barrier systems (tray and strip), there is considerable and accumulating evidence on the tooth whitening safety and efficacy.

Several reviews have assessed the evidence for tray-based whitening with carbamide peroxide or strip-based whitening with hydrogen peroxide. Recently, a systematic review from the Cochrane Collaboration examined the quality of the evidence across delivery systems. Using standard methods, the authors identified 25 randomized clinical trials that satisfied specific inclusion criteria. The search targeted randomized and controlled 14-day clinical trials using shade (tabs) or non-directional composite
color (¨E) as endpoints. Another 35 published clinical trials were excluded from the analysis.

The limitations of the systematic review process are apparent. In general, systematic reviews are limited to the published literature, and as such, may over-represent earlier paradigms, and downplay the most contemporary research. Publication bias may also be problematic with respect to negative findings and repetitive positive findings. Each systematic review has certain specific limitations as well, with relevance based on the appropriateness of the research question. For example, this recent review of home-use tooth whitening included only those clinical trials with a 14-day endpoint.20 Shorter and longer studies (or products with shorter or longer labeled usage) were excluded. The research was further limited to studies involving conventional shade guides or the non-directional color measure ¨E, two endpoints with questionable pedigrees.

Despite these possible limitations, systematic review represents one of the most prominent approaches to assess the strength of the evidence supporting specific healthcare practices. The recent Cochrane review of tooth whitening was comparatively robust, involving 25 clinical trials. This represented more evidence than many other recent systematic reviews involving popular adult oral care treatments. Completed reviews on occlusal adjustment, scaling and root planing, and guided tissue had 6, 8, and 17 clinical trials, respectively. Other Cochrane adult oral care reviews involved even fewer clinical trials. One superficial conclusion is that there is considerable externally-reviewed clinical trials evidence on tooth whitening, at least for a few specific products. While the first clinical study was not published until 2000, whitening strips were most represented in the Cochrane review, accounting for 40% of all included research.

From this literature, the reviewers concluded that tooth whitening was safe and effective under labeled conditions of use, thatthere were significant differences between certain test products, and that tooth sensitivity and oral irritation represented the most common side effects associated with treatment. The reviewers also identified two areas as warranting additional research attention: diversity and longer term follow-up. Although planned independently of and prior to the Cochrane publication, this supplement to the American Journal of Dentistry was specifically intended to address end-oftreatment and post-treatment outcomes following testing in diverse settings, relative to global use of whitening strips (Fig. 1).

Technology Assessment

ized as providing important biomedical evidence of efficacy and safety. A total of five RCTs are described in this special issue. All studies evaluated 6-6.5% hydrogen peroxide whitening strips. The individual strips held approximately 9-13 mg of hydrogen peroxide, depending on the concentration and arch. Strip application was twice daily for 30 minutes, with treatment duration varying based on the objective of the
individual clinical study. Comparisons were made to various positive and negative experimental controls including placebo. The research involved different populations and research teams in Europe, Asia and the Americas. All studies used common methods to assess safety and efficacy, following pharmaceutical research practices.

This diverse yet integrated research was possible, in part, because of the availability of a standard method for assessing color change (or the absence thereof) following different treatments. The RCTs reported herein all used a common, objective and instrumental method to assess efficacy, made possible by advances in digital camera technology and software analysis. In the first research paper, Sagel &
Gerlach29 describe the method – digital image analysis – in explicit detail via in vitro and in vivo studies on color measurement reproducibility. Laboratory reproducibility was assessed from serial measurements of tooth-shaped shade tabs collected on 2 consecutive days, while clinical reproducibility was assessed in a similar fashion from tooth color measurements on 14 healthy adult volunteers. Both the in vitro and in
vivo experiments showed exceptional reproducibility, with intra-class correlation coefficients exceeding 0.99 in the laboratory study, and 0.97 in the more complex and relevant clinical study. This level of reproducibility, the authors concluded, supported use of the digital image analysis to generate consistent measurements of tooth color in diverse settings, regardless of the investigator, center or geography.

Previous research has described the application of digital image analysis in tooth whitening clinical trials, where it reportedly offers advantages with respect to objectivity, standardization, and quantification, while yielding archival data for quality assurance and secondary analysis. The method is reported to have particular merit in limiting bias in comparative research involving dissimilar delivery systems or studies
involving negative experimental controls where treatment effects are visually evident and profound. Each of the five RCTs in this special issue involved dissimilar delivery systems (strip versus tray), and/or non-peroxide controls (placebo or dentifrice). One additional advantage, especially for international research as described in this special issue, is that the entire measurement system can be easily transported virtually anywhere in the world and maintained for use in long-term clinical research (Fig. 2).

Two of the RCTs directly compared whitening strips to one other treatment group. Hernández Guerrero et al reported a study from Mexico involving university students, a classic subject population with clinical trials conducted in dental schools. This randomized, double-blind study compared professional 6.5% hydrogen peroxide whitening strips and placebo strips over 3 weeks of use.30 In addition to the safety outcomes, this RCT from Mexico provides important evidence of method validity, with digital imaging showing appreciable color improvement in the peroxide group, with little to no “placebo” whitening response. While placebo-controlled trials provide important evidence of absolute response, positive-controlled trials illustrate the magnitude of the response. Ferrari et al reported on a positive-controlled study in Italy comparing 6% hydrogen peroxide whitening strips and daytime use of a marketed 10% carbamide peroxide custom tray system. This RCT, which was conducted in a dental practice with volunteer patients as study subjects, demonstrates the feasibility of using objective and instrumental digital imaging to assess tooth whitening in alternate settings.

Three of the RCTs compared whitening strips to multiple treatment groups. Bizhang et al reported on digital image analysis in an extended, 18-month RCT. Subjects were randomly assigned 6% hydrogen peroxide whitening strips, 19% sodium percarbonate brush-applied gel that dries as a film, or placebo brush-applied gel without peroxide. In addition to the long-term safety outcomes, this study established the feasibility of using digital image analysis for extended clinical evaluation. Xu et al reported on another complex clinical trial from China, where adults were randomized to 6% hydrogen peroxide whitening strips, a barrier-free 5.9% hydrogen peroxide paint-on gel, or water rinse which served as a negative experimental control. This RCT illustrates the importance of a barrier and not just starting concentration of peroxide on response. Despite similarities in starting concentration (~6% hydrogen peroxide), the strip and paint-on gel differed significantly (P< 0.0001) on improvement in yellowness, brightness, and redness, as well as overall color improvement, with these differences achieved with one-half the treatment duration (7 versus 14 days) for strips compared to the paint-on gel. Yudhira et al34 reported on a 12-week comparison of 6% hydrogen peroxide whitening strips and two whitening dentifrices without peroxide. Using a so-called “double dummy” design, subjects received either peroxide or placebo strips for 2 weeks, and dentifrice (whitening or regular) for 12 weeks. Compared to the whitening dentifrices, the peroxide strip group had significant (P< 0.0001) whitening, and no significant (P> 0.64) post-treatment color degradation through 12 weeks.

Summary

This special issue of the American Journal of Dentistry represents perhaps one of the largest common collections of global clinical research on tooth whitening. Each of the five randomized controlled trials involved different populations, controls, and research teams. The study sites ranged from a research hospital to a private dental practice, in five distinctly different cultural settings. Each RCT received appropriate institutional ethical review prior to initiation, and overall, 243 individuals provided informed consent to study participation. Ages across the five RCTs ranged from 18-60 years, 71% of study subjects were female, and the population was, of course, quite diverse with respect to ethnicity. Overall, the research involved five different peroxide-containing products and five non-peroxide controls. Duration for the RCTs ranged from 2 weeks to 18 months, with three studies explicitly evaluating post-treatment color stability.

A common, unbiased and reproducible instrumental method was used to measure whitening response in these clinical trials. Each study showed significant (P< 0.05) tooth color improvement with 6-6.5% hydrogen peroxide whitening strips relative to baseline and to the various experimental controls. Individual study means were consistent with expectations, given these between-study differences in peroxide concentration, treatment duration, population age and starting tooth color, factors previously shown to affect whitening response.1,35 In these five studies, as elsewhere, the greatest whitening occurred following use of the highest peroxide concentration strips for the longest duration in a younger population with considerable tooth discoloration at baseline (Fig. 3). Of note, the method – digital image analysis – was sufficiently robust to show temporal and barrier effects for various peroxide-containing products, without appreciable “placebo-response” in the various negative controls, across diverse research sites and over time.

One legacy for Whitestrips since the US launch in 2000 is the dramatic increase in access to and utilization of tooth whitening. Where available, these easy-to-use whitening strips have provided an initial esthetic dentistry option to a broad range of individuals, irrespective of their socioeconomic strata. The new research further extends the evidence to include global applications. In all studies, the barrier-based
hydrogen peroxide whitening strips yielded significant color improvement within a short time period (7-21 days) in dissimilar geographies and cultures, with differing diets, behaviors, and oral health practices. Strip whitening was durable, with more than 80% of initial color improvement still evident 18-months post-treatment. This whitening was achieved safely at-home. Minor tooth sensitivity and oral irritation were the most common adverse events, all of which resolved during treatment or post-treatment monitoring. In composite, this integrated research provides important long-term evidence of the global safety and effectiveness of tooth whitening with hydrogen peroxide whitening strips, and establishes stripbased tooth whitening as a viable and accessible option for initial esthetic dentistry worldwide.

Source

• American Journal of Dentistry (Vol. 20, Special Issue A, September, 2007 – p. 1A – 36A)
• Dr. Robert W. Gerlach, The Procter & Gamble Company, 8700 Mason-Montgomery Road, Mason, OH 45040-8006

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Wellaholic Research Unveils: The Long-term Safety and Effectiveness of Teeth Whitening with 6.5% Hydrogen Peroxide – Insights from Global Randomized Controlled Trials