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Randomized Controlled Trial Evaluating Use of Two Different Oxalate Products in Adults with Recession-Associated Dentin Hypersensitivity
Athena Papas, BS, DMD, PhD; Mabi Singh, DMD, MS; Britta Magnuson, DMD; Melanie Miner, BS, BA; Paul A. Sagel, BSChE; and Robert W. Gerlach, DDS, MPH
A randomized positively controlled trial was conducted to evaluate the durable effects of 1.5% oxalate strips on dentin hypersensitivity. Informed consent and baseline measurements were obtained from adults with recession and air-related dentin hypersensitivity. Eligible subjects were randomized to one of two oxalate groups, either 1.5% oxalate gel strips (Crest® Sensi-Stop™ Strips, Procter & Gamble) or a professional oxalate-acid, potassium-salt solution (Super Seal® Dental Desensitizer Liner, Phoenix Dental). Test products were professionally administered at examiner-identified sensitive test sites following each manufacturer’s instructions. Subjects received a blinded overwrapped anticavity paste and manual brush, two additional reapplication visits were scheduled over a 1-week period, and subjects returned 1 month later for evaluation. Sensitivity was evaluated using air and water stimuli measured by clinicians (Schiff Index) and subjects (visual analog scale), while safety was assessed by examination. The population (N = 80) was diverse with respect to gender, ethnicity, and age (22 to 82 years). At baseline, the overall mean (SD) air sensitivity was 1.34 (0.47), with individual subject means ranging from 1 to 2.5. Repeated treatment with both the commercial and professional oxalate treatments resulted in significant (P < .05) reductions in sensitivity for all stimuli and methods. At the 1-month posttreatment recall, there were 84% to 86% reductions in clinically measured cool-air sensitivity for each oxalate group. Groups did not differ significantly (P > .57) on examiner or self-graded air or water sensitivity. In a clinical study, use of 1.5% oxalate gel strips yielded similar benefits as professionally applied oxalate treatments for adults with recession-based dentin hypersensitivity.
Dentin hypersensitivity, the sharp tooth pain that many adults experience as part of normal daily activities, is characterized as underdiagnosed and undertreated.1 Occurrence is likely variable, as exemplified by the more than tenfold differences in reported prevalence, and etiology is likely multifactorial, as many individual factors are recognized to contribute to oral pain.2 Despite these uncertainties, longstanding theory implicates provocation as causing hydrodynamic changes in exposed dentin tubules, thereby stimulating receptors that elicit a typical short and sharp pain response.3
Many individuals, perhaps 10% or more of patients in dental practices, are affected.4 Various factors are recognized as necessary in the development of dentin hypersensitivity.5 Prominent among these, for vital teeth, is the presence of exposed patent dentinal tubules and a provocative exogenous stimulus. The latter includes many of the normal stimuli found in daily life (dentin hypersensitivity, after all, is an exaggerated response to these normal stimuli). The former is similarly multifactorial, with hygiene, diet, disease, dentistry, and other factors having been implicated. Irrespective of etiology, gingival recession represents the most common predisposing factor and serves as the principal clinical sign of risk for dentin hypersensitivity.
Population surveys have shown recession to be commonplace. For example, a US national representative survey in the 1990s estimated that over half of individuals 30 years or older had evidence of recession measuring 1 mm or greater, involving more than 20% of teeth. While all age groups were affected, recession prevalence and severity increased with age, and facial surfaces were the most commonly affected.6 Dentin hypersensitivity follows a similar trend, though severity may decrease with age, perhaps due to secondary dentin formation or other mechanisms.7 Because dentin tubule patency is generally unknown, all sites with recession represent areas at risk for sensitivity (past, current, or future).
Common in-office treatment typically focuses on restoration or the use of various precipitating agents, while at-home approaches generally rely on dentifrices using potassium nitrate for nerve desensitization, or stannous fluoride, arginine, or other agents to close dentin tubules with a smear layer.7 One agent, oxalate, may be pertinent for both in-office and at-home use. Relevant in vitro models have shown the topical application of oxalates to form oxalate-based crystals in patent dentinal tubules, and these oxalate occlusions restrict fluid flow in dentin.8,9
New approaches have evolved that enable both in-office and at-home applications of oxalates for the treatment of dentin hypersensitivity. One recent example involves an oxalate-based strip, which embraces easy application using a popular delivery method that has been widely used for in-office and at-home tooth whitening.10 Strip use is similar irrespective of the setting (office or home), with a low amount of oxalate gel applied continuously for 10 minutes directly at sensitive tooth sites. A new clinical trial was conducted to compare this novel oxalate strip directly versus a marketed professional oxalate gel.
A randomized positively controlled trial evaluated the safety and effectiveness of repeat use of a novel 1.5% oxalate gel strip versus a professional in-office treatment. The Tufts University Institutional Review Board reviewed the study protocol, informed consent, and advertising, and approved open screening of up to 300 adults in order to enroll up to 86 subjects. General entrance criteria were used to yield the broadest possible study population. The limited exclusion criteria restricted participation by pregnant or nursing women or individuals undergoing active periodontal therapy. To be included, adult volunteers had to simply present with gingival recession (measured in millimeters using an incremental dental probe) and evidence of one or more teeth with air-related sensitivity at recession sites (measured using the Schiff Index).
At baseline, one or two test sites with recession and sensitivity were identified. Treatments were randomly assigned in blocks of four to one of two oxalate groups in order to balance for age, gender, mean clinical sensitivity, and mean perceived sensitivity. Subjects received either potassium oxalate gel on a flexible polyethylene strip (the experimental group) or a marketed professional oxalate-acid potassium-salt solution (the positive control group). Test products were dispensed in blinded packaging, and all treatments were professionally administered directly at sensitive recession test sites. Safety and effectiveness were assessed before and immediately after treatment at baseline, after treatment on Days 3 and 6, and 30 days thereafter (approximately Day 36).
The test products were a 1.5% oxalate gel on a 10-mm x 30-mm polyethylene strip (Crest® Sensi-Stop™ Strips, Procter & Gamble, www.dentalcare.com) or a professional 3% oxalic-acid potassium-salt paint-on solution (Super Seal® Dental Desensitizer Liner, Phoenix Dental, www.phoenixdental.com). Because the two oxalate products were professionally administered, these test products were dispensed in bulk as 200 strips packaged in individual blank foil pouches for the experimental group, and 50 overlabeled 8-mL vials for the professional control group. In addition to the oxalate test products professionally applied on-site, each subject received two tubes of regular anticavity paste (Crest® Cavity Protection, Procter & Gamble), overlabeled in a plain white tube, plus a manual toothbrush (Oral-B® Indicator® soft, Procter & Gamble) and normal toothbrushing instructions, and, for blinding, these oral hygiene products were dispensed in plain subject-identified kit boxes for at-home unsupervised use.
Different clinicians performed treatment out of the view of the single examiner who assessed sensitivity, maintaining examiner blinding for both safety and efficacy. Professional application followed each manufacturer’s instructions. For the experimental group, strips were applied directly to the test sites sufficient to cover the exposed facial dentin and surrounding tooth/tissue for a timed 10 minutes, then removed and discarded. For the control group, one to two drops of test solution were dispensed to saturate a cotton pellet, which was professionally applied directly at test sites for a timed 30 seconds, followed by a timed 1- to 2-minute drying. Treatments were administered three times beginning at baseline, and approximately every 3 days thereafter, through Day 6.
There were a total of four visits; Baseline, Day 3, Day 6 (the repeated treatment period), and Day 36 (posttreatment evaluation). At each visit, dentin hypersensitivity was assessed using two different provocative stimuli: cool air and cold water. The air stimulus was administered first using 1 second of cool air from a dental air/water syringe (40 psi to 60 psi at a temperature of 70°F ± 5°F). The cold-water stimulus consisted of a single drop of refrigerated water applied using a 3-mL syringe (without a needle). During the treatment period (through Day 6), these provocative challenges were administered immediately after completion of assigned treatment, and similarly the posttreatment visit had only one air/water challenge combination. All challenges were administered by trained clinicians, and for multiple test sites, teeth were tested sequentially in ascending tooth number.
After each stimulus, a clinical examiner, as well as the subject (first-person), assessed dentin hypersensitivity. Clinical assessment used a standard four-point categorical scale, ranging in severity from unresponsive (0) to responsive/painful/discontinue (3), while self-assessment used a tablet application with a linear visual analog scale (VAS), where the subject recorded by mark the level of pain from none (left boundary) to worst pain ever (right boundary). Air assessment preceded water assessment, and each site was measured separately. The clinical examiner and subject assessments were recorded independently, and for VAS the numerical response display in the tablet application was recorded from 0 to 100 using standard methods. Safety was assessed from clinical examination.
Sensitivity scores from the test teeth were averaged for each subject and visit. Analysis was based on the final locked database inclusive of all responses, with cool air as the primary endpoint. Comparisons to baseline used paired difference t-tests, between-group comparisons used analysis of covariance with baseline as a covariate, and temporal effects were assessed using repeated measures models. For the subject-assessed response only, VAS was logit-transformed to meet assumptions of normality for analysis. All comparisons were two-sided using 5% levels of significance.
A total of 147 subjects provided informed consent for screening; 80 subjects were randomized, and 78 subjects completed the study. The randomized population exhibited diversity in age (over a 60-year range), gender (similar representation), and air sensitivity (from mild to severe). Although eligibility was based on air sensitivity, many subjects (42%) also had a measured response to cold water (the second stimulus). Groups were balanced (P > .59) on both demographics and baseline sensitivity levels (Table 1). Two subjects (one per group) discontinued study participation at the Day 6 visit for reasons unrelated to treatment.
As illustrated in Figure 1 and Figure 2, both oxalate groups exhibited immediate posttreatment reductions in air sensitivity measured by the clinician (Schiff Index) and the subject (VAS). Further professional treatment at Days 3 and 6 resulted in incremental measured reductions in air sensitivity, and these treatment effects were evident over the 30-day posttreatment monitoring period. Similar results were observed for subject-assessed air sensitivity.
Statistical analysis versus baseline demonstrated that each group had significant reductions in air sensitivity measured clinically (P < .0001) or subjectively (P < .02) at the immediate posttreatment assessment and after each subsequent treatment (Table 2). There was no statistical evidence of relapse during the posttreatment period. Air sensitivity relief continued over the 30-day posttreatment period, and at Day 36 the oxalate strip and oxalate solution groups exhibited 86% and 84% reductions in Schiff air sensitivity, respectively. Relative to Day 6, repeated measures modeling demonstrated no significant (P > .23) loss of effectiveness during the 30-day posttreatment period for air sensitivity relief measured clinically or subjectively.
While cold-water sensitivity was not an entrance criterion, many subjects presented with sensitivity to both air and water. Results were generally similar for cold-water sensitivity using either the clinical (Schiff) or perceptual (VAS) endpoints, as evident in the time plots (Figure 3 and Figure 4). At 30 days posttreatment, both groups exhibited significant (P < .0001) relief from the direct cold-water stimulus (Table 3).
Both groups had initial and sustained improvement, yet there were a few significant between-group differences. Specifically, groups differed (P < .05) on perceptual air response at the second and third treatment visits (favoring the oxalate paint-on), and on both clinical and perceptual water response after the first treatment (favoring the oxalate strip). There were no significant (P > .61) between-group differences in sensitivity (any stimulus or endpoint) at Day 36. Importantly, most subjects had measured improvements in sensitivity irrespective of stimulus (air or water) or endpoint (clinical or perceived) evident immediately after the first treatment, throughout active treatment, and persisting 30 days after treatment cessation (Table 4).
A total of three adverse events occurred across the two treatment groups during the treatment or posttreatment phases of the study. One of the adverse events in the oxalate solution group, a periodontal abscess, was considered moderate in severity. None of the adverse events were product-related, nor did they contribute to either discontinuing treatment or dropout.
This randomized, positively controlled trial directly compared the dentin hypersensitivity efficacy and treatment safety of repeated professional use of 1.5% oxalate strips to a professional oxalate-acid potassium solution. The population was sufficiently diverse, as characterized by a 60-year age distribution (22 to 82 years of age) and dentin hypersensitivity levels ranging from mild to severe. In this study, treatment was limited to tooth sites with both recession and sensitivity, because that represents a common clinical manifestation of dentin hypersensitivity, and blinded test products were dispensed for repeated professional application at these sensitive recession sites. Two different stimuli—the direct application of cool air and cold water—were used to assess response before treatment, immediately after treatment, after repeated treatment, and 1 month thereafter to assess sustained effects. Because this study directly compared the professional administration of two oxalate devices having plausibly similar occlusive mechanisms, results from this comparative clinical trial provide evidence on the absolute and relative safety and effectiveness of these oxalate products, with implications for oxalate use as part of direct patient care.
The clinical trial demonstrates that oxalates are effective in the absolute in reducing dentin hypersensitivity. Relative to baseline, both groups exhibited a highly significant (P < .0001) reduction in the primary outcome (air sensitivity) after three professional applications. This represented approximately an 85% improvement overall. Effects were robust, and of the 80 subjects who completed the three treatments, most (91%) had measured improvements in induced sensitivity after the last professional application (Day 6). Comparative responses with the two oxalate devices (gel on strip or paint-on solution) were generally similar and evident across different stimuli (cool air or cold water), measures (clinical or subjective), and severity levels (mild to severe). Also, for the latter, baseline severity and Day 6 relief were positively correlated, meaning that more severe cases had greater benefits with treatment.
Outcomes from this new study provide important evidence on the clinical effectiveness of certain oxalates in the treatment of established dentin hypersensitivity. The occlusive effects of oxalates on dentin tubules have been repeatedly demonstrated in preclinical flow cell research and scanning electron microscopy.9,11,12 Even with these bench outcomes and the general availability of professional oxalate products, such as the potassium salt solution studied herein, there has been only limited clinical evidence of oxalate effectiveness, as exemplified by a comprehensive review of the literature through 2010 (prior to the introduction of the oxalate strips) that identified a need for additional clinical trials on the use of oxalates in sensitivity.13 In this new head-to-head research, both oxalate products showed significant robust effects, up to and including complete elimination of established recession-associated sensitivity after repeated professional use. Treatment effects were observed irrespective of severity. Recent clinical research has also shown oxalate rinses to yield antisensitivity effects in the near term; one example is after 6 to 10 1-minute rinses with a 1.4% potassium-oxalate rinse.14 Combined with this new clinical trial on two different oxalates, research outcomes after 2010 help establish the overall effectiveness of certain oxalates, including the direct use of an oxalate strip or paint-on solution for sensitivity relief.
Three outcomes in this study may be particularly pertinent to clinical practice, with respect to benefit onset, re-treatment, and durability. First, there was an evident sensitivity benefit immediately after the first in-office oxalate application. On average, the oxalate groups showed a 49% reduction in air sensitivity, differing significantly (P < .0001) from baseline when this primary outcome was measured immediately after the initial use. This effect was robust (except for the immediate water response with the oxalate paint-on solution) across stimuli and measures, and it suggests a role for professional use of oxalates in-office for sensitivity relief. Second, increased oxalate use improved response. While a single application of oxalates has been shown to obstruct tubules and reduce fluid flow (which is the putative mechanism of dentin hypersensitivity), various factors such as incomplete blockage, new tubular exposure, or reversals may contribute to continued fluid flow and subsequent sensitivity. In this new research, re-treatment can be readily accomplished—particularly for patients with treatment plans requiring multiple office visits—and these additional treatments may yield additional sensitivity relief. Finally, the comparative oxalate clinical trial showed durable effects after completion of the last treatment. For the novel oxalate gel strip, all subjects (100%) in the oxalate gel strip group had a measured improvement from baseline for both air and water sensitivity measured clinically at study completion. On average, this represented 86% and 84% improvements in clinical air and water sensitivity, respectively. Total relief was commonplace, with 70% of subjects experiencing complete elimination of air sensitivity (clinical sensitivity score = 0) and 89% of subjects with water sensitivity showing complete relief. Long-term results were generally similar with the oxalate solution, and the groups did not differ significantly except for the early superior water relief seen with the oxalate strips. One implication is that oxalates provide a durable important benefit, with professional treatment effects that likely persist much longer than the 30-day time point measured in this clinical trial.
The oxalate solution tested in this study has been previously shown to be effective in clinical research when applied professionally to treat scaling-related sensitivity.15 Using this marketed oxalate solution as a positive control, new comparative research was conducted in a university clinic that targeted adults with both recession and clinical sensitivity after air stimulation. Practice implications are apparent because, ostensibly, both recession and sensitivity could be easily assessed in typical practice settings. Dentin hypersensitivity is reported to be most common at facial sites, and recession is recognized as a primary contributing factor to dentin tubule exposure.5,7 A simple screening examination could readily detect the presence or absence of recession, particularly on facial tooth sites. Similarly, the use of an air syringe (which is also readily available in virtually all clinical settings) could be easily used to detect the presence or absence of an immediate painful response on stimulation. Oxalate treatment of facial tooth surfaces (whether via strip or paint-on) was simple and direct. Effects were durable, and achieved without evident safety issues. Moreover, the entrance criteria used in this study were general and inclusive—essentially any subjects with recession and clinical sensitivity were enrolled, irrespective of severity. Research of this nature typically provides the broadest inference, particularly when responses are broad and cross subgroups (such as age or severity). It may be readily adapted to clinical settings and, based on outcomes in this study, may carry implications for many patient types commonly seen in contemporary practice.
A randomized controlled trial directly compared immediate, repeated, and sustained antisensitivity effects of 1.5% oxalate strips to a marketed professional oxalate treatment. Study results demonstrate:
• 1.5% oxalate strips are safe and effective, with sensitivity relief evident across methods (cool-air and cold-water stimulation directly at recession sites with sensitivity) and measures (clinical and subjective).
• Sensitivity relief with 1.5% oxalate strips is similar in magnitude to a marketed professional oxalate control.
• While all sensitivity levels showed benefits, sensitivity severity at baseline and relief after oxalate treatment is positively correlated.
• Both oxalate products provide immediate sensitivity benefits that increase with repeated use and yield relief that is sustained at least 1 month after treatment completion.
Joseph Cimmino and Noe Duenas from Tufts University School of Dental Medicine contributed to the study conduct. Jill Underwood (Procter & Gamble) managed registration (NCT02152826) and supported data collection along with Vickie Widmeyer (Procter & Gamble).
This research was sponsored by Procter & Gamble.
About the Authors
Athena Papas, BS, DMD, PhD
Professor of Research
Co-Head of Geriatric Dentistry, and Director of Oral Medicine Department
Tufts University School of Dental Medicine
Mabi Singh, DMD, MS
Tufts University School of Dental Medicine
Britta Magnuson, DMD
Tufts University School of Dental Medicine
Melanie Miner, BS, BA
Global Statistics and Data Management
Procter & Gamble
Paul A. Sagel, BSChE
Global Oral Care R&D
Procter & Gamble
Robert W. Gerlach, DDS, MPH
Global Oral Care R&D
Procter & Gamble
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