An exploratory clinical trial to evaluate the efficacy of an experimental dentifrice formulation in the relief of dentine hypersensitivity

Abstract

Objectives

This study aimed to investigate whether addition of an octadecene/maleic anhydride copolymer (O/MA) to a potassium nitrate (KNO 3 ) dentifrice could facilitate delivery of potassium to dentine and enhance its efficacy in dentine hypersensitivity relief.

Methods

This was a randomised, examiner-blind, controlled, parallel group study in 139 healthy subjects with at ≥2 sensitive teeth. Assessment of dentine hypersensitivity to tactile (Yeaple probe) and evaporative (air) stimuli (Schiff Sensitivity Scale, visual analogue scale [VAS]) was carried out at baseline and after 1, 2, 4 and 8 weeks twice daily treatment with an experimental 5% KNO 3 /3% O/MA dentifrice, a comparator 5% KNO 3 dentifrice (active comparator), a 0% KNO 3 /3% O/MA dentifrice (placebo) and a regular fluoride dentifrice (negative control). This study was not powered to detect statistically significant differences between treatments.

Results

Across the treatment period an improvement in sensitivity to evaporative air stimulus was observed for all products and to a tactile stimulus for the potassium-containing treatments, with the greatest reductions for the experimental dentifrice (5% KNO 3 /3% O/MA). Reductions in sensitivity observed for the potassium-containing dentifrices compared to the placebo and negative control dentifrices were statistically significantly for Schiff sensitivity score and tactile threshold at all time-points and for VAS at Weeks 4 and 8. Trends in the study data also favoured the experimental dentifrice, compared to the active comparator dentifrice, for all clinical measures. Study treatments were generally well tolerated.

Conclusion

This study provides initial clinical evidence to suggest that addition of a polymer excipient may enhance the anti-sensitivity efficacy of potassium-containing dentifrices.

Clinical significance

Daily use potassium-containing dentifrices are established as efficacious for the relief of dentine hypersensitivity. Inclusion of a polymer excipient in such formulations may facilitate delivery of potassium to the dentine surface and so enhance clinical efficacy. Further clinical studies are required to confirm this hypothesis.

Introduction

Dentine hypersensitivity is described as “pain derived from exposed dentine in response to chemical, thermal, tactile or osmotic stimuli which can’t be explained as arising from any other dental defect or disease” . Dentine hypersensitivity originates from aetiologic factors such as gingival recession, erosion and/or abrasion that result in loss of cementum or enamel and exposure of underlying dentine with patent dentinal tubules .

Many theories have been postulated to explain the sensitive nature of dentine, the most widely accepted being the Hydrodynamic Theory, first described by Gysi in 1900 and expanded by Brännström . This proposes that external stimuli applied to exposed dentine, such as cold, heat and tactile or osmotic pressure, cause movement in the fluid within the micrometer-sized tubules that traverse dentine. This movement is thought to stimulate mechanoreceptors near the base of the tubule (at the dentine-pulp junction) and may, if certain physiological parameters are met, elicit a pain response.

Currently there are two distinct approaches to providing relief from the discomfort of dentine hypersensitivity. The first employs tubule-occluding agents that deposit material on the surface of the dentine to physically block the exposed ends of patent dentinal tubules and attenuate dentinal fluid movement, reducing the potential for mechanoreceptor activation . The second approach employs depolarising agents such as potassium ions (from nitrate, chloride and citrate salts), which are believed to act by reducing the excitability of intra-dental nerves . Numerous clinical studies have shown potassium-containing dentifrices to be effective in reducing the discomfort associated with dentine hypersensitivity, as confirmed by a recent meta-analysis; however, these studies generally demonstrate potassium containing dentifrices may take up to two weeks to show any effectiveness .

When developing a dentifrice for a therapeutic indication, consideration is given to optimising the formulation for delivery and retention of the therapeutic ingredient. Typically, such optimisation focuses on minimising interaction between the active ingredient and formulation excipients to maintain the active in a bioavailable state, but may also involve selection of excipients to maximise dispersion and retention of the active ingredient within the oral cavity and to facilitate delivery to the target site.

One of the most important factors affecting the intra-tubular concentrations of potassium ions is the outward convective flow of dentinal fluid from exposed dentine opposing inward diffusion of potassium ions . This outward movement is more sensitive to reductions in tubule diameter than inward diffusion (where r = tubule radius, outward convection proportional to r 4 , diffusion proportional to r 2 ). Reducing outward flow of dentine tubules by decreasing the permeability of patent dentine tubules, by partial occlusion using a formulation excipient, has been proposed as a useful means to increase tubular potassium ion concentration to the levels required to inactivate intra-dental nerve transmission .

Pashley and colleagues reported greater in vitro transport of potassium ions though dentine for a marketed potassium dentifrice formulated with a bioadhesive polyvinylmethyl ether/maleic anhydride [PVM/MA] copolymer (Gantrez™) compared to a commercial dentifrice without polymer but containing the same concentration of potassium ions. They concluded that the increase in potassium transport was derived from partial occlusion by PVM/MA. Clinical research has also reported efficacy for Gantrez-containing potassium dentifrice formulations in subjects with dentine hypersensitivity . Octadecene/maleic anhydride (O/MA) copolymer is a partially neutralised, hydrolyzed resin (PA-18) with alternating hydrophilic/hydrophobic monomeric subunits, similar in structure to Gantrez. It is hypothesised that O/MA may act similarly to enhance transport of potassium ions across dentine and thereby enhance the efficacy of potassium-containing dentifrice for the relief of dentine hypersensitivity.

The aim of this exploratory clinical study was to investigate whether the modification of a 5% w/w KNO 3 dentifrice formulation to include 3% w/w O/MA copolymer could enhance its anti-sensitivity efficacy compared to a 5% w/w KNO 3 dentifrice without the polymer excipient (active comparator), a 0% KNO 3 /3% w/w O/MA dentifrice (placebo) and a regular fluoride dentifrice with no known anti-sensitivity properties (negative control). Efficacy and safety were assessed at baseline and following 1, 2, 4 and 8 weeks twice daily brushing with assigned study dentifrice.

Subjects and methods

Study design

This was a randomised, controlled, examiner blind, four treatment arm, parallel group study to investigate and compare the anti-sensitivity efficacy of four study dentifrices in volunteer subjects, stratified by maximum baseline Schiff sensitivity score of two selected test teeth, over an 8 week treatment period. In line with published recommendations , two independent stimulus-based efficacy measures, evaporative (air) and tactile stimuli, were used to assess dentine hypersensitivity at baseline and after 1, 2, 4 and 8 weeks of treatment. A single dental examiner, experienced in the assessment of dentine hypersensitivity, performed the clinical assessments in all subjects for the duration of the study. To help minimise the potential impact of the ‘Hawthorne’ effect (i.e., a change in subject behavior in response to being observed) or placebo response and to standardise oral hygiene practices across the study population, an acclimatisation period (minimum 4 weeks) was included ahead of baseline assessments and randomisation.

The study was approved by an FDA-approved institutional review board prior to initiation and conducted at BioSci Research, Inc., Las Vegas, NV, USA in accordance with all laws and local regulations, the principles of Good Clinical Practice , and the Declaration of Helsinki . Study funding was provided by GSK Consumer Healthcare.

Study population

Healthy subjects aged 18–65 years with a minimum of 20 natural teeth and self-reported dentine hypersensitivity lasting at least 6 months but no longer than 10 years were recruited. Subjects were required to have a minimum of two accessible, non-adjacent teeth (incisors, canines or pre-molars) with signs of erosion, abrasion or facial/cervical gingival recession (EAR), a Löe and Silness Gingival Index (GI) score of ≤1 , clinical mobility of ≤1 , and signs of sensitivity as measured by a qualifying evaporative (air) assessment.

General exclusion criteria included women who were pregnant (including those who fell pregnant during the study) or breast feeding; subjects with an intolerance to any of the study materials; subjects with a chronic debilitating disease that could have affected study outcomes; daily doses of a medication that could have interfered with the perception of pain or any condition/medication that was causing xerostomia. Subjects who had participated in another tooth desensitising treatment study within 8 weeks of the screening visit were also excluded. Dental exclusion criteria included tongue or lip piercing or presence of dental implants; dental prophylaxis within 4 weeks of screening; teeth bleaching or desensitizing treatment within 8 weeks of screening; scaling or root planing within 3 months of screening and gross periodontal disease or treatment of periodontal disease within 12 months of screening. Specific exclusions for test teeth included evidence of current/recent caries or reported treatment of decay in 12 months of screening; any tooth with exposed dentine but with deep, defective or facial restorations; teeth used as abutments for fixed/removable partial dentures; teeth with full crowns or veneers, orthodontic bands or cracked enamel, and sensitive teeth with contributing aetiologies other than EAR of exposed dentine.

Study treatments

The study evaluated four treatments.

  • Experimental dentifrice: 5% w/w KNO 3 , 3% w/w O/MA, 1150 ppm fluoride as sodium fluoride (NaF)

  • Active comparator dentifrice: 5% w/w KNO 3 , 0% O/MA,1150 ppm fluoride as NaF

  • Placebo dentifrice: 0% w/w KNO 3 , 3% w/w O/MA, 1150 ppm fluoride as NaF

  • Negative control dentifrice: 1000 ppm fluoride as sodium monofluorophosphate (SMFP) (Colgate Cavity Protection ® , US marketed dentifrice, Colgate-Palmolive Co., New York, NY)

Subjects were instructed to brush for 1 timed minute twice daily (morning and evening) using a brush head of their assigned study dentifrice on each brushing occasion, in line with typical consumer habit and common practice within dental clinical trials.

Clinical procedures

At the screening visit, subjects gave their written informed consent to participate in the study. Demography, medical history and concomitant medications were recorded, followed by an oral soft tissue (OST) examination. The teeth were then assessed sequentially for dentition exclusions; evidence of EAR; gingival health status (using the GI); mobility and sensitivity to a simple air blast stimulus applied to the facial surface of the tooth (where a ‘yes’ response from the subject indicated sensitivity) to determine their clinical eligibility for assessment of dentine hypersensitivity at subsequent visits. Eligible subjects were supplied with a regular fluoride dentifrice (Crest ® Cavity Protection, US marketed dentifrice, Procter & Gamble, Cincinnati, OH, USA; 1100 ppm fluoride as NaF) to use twice-daily (morning and evening) for a minimum of 4 weeks (acclimatisation period) prior to their baseline visit.

At baseline, subjects underwent an OST examination followed by clinical assessment of dentine hypersensitivity for all clinically eligible teeth identified at screening, first to a tactile stimulus using a Yeaple probe and then to an evaporative air stimulus (evaluated using the Schiff Sensitivity Scale and a visual analogue scale [VAS]). The Yeaple probe allows the examiner to apply a known force to the dentine surface, beginning at 10 g (g) and increasing in 10 g intervals. The tactile threshold (g) is the maximum force applied without the subject reporting pain or discomfort (the greater the tactile threshold, the less sensitive the tooth). At baseline, the maximum force was set at 20 g; at all subsequent visits it was 80 g.

Sensitivity to an evaporative (air) stimulus was assessed by directing an 1-s air blast from a triple air dental syringe onto the exposed dentine surface from a distance of approximately 1 cm, with the surface of the tooth isolated to prevent adjacent teeth or surrounding soft tissue being exposed to the stimulus . The examiner’s assessment of the subject’s response to the air stimulus was rated on the Schiff Sensitivity Scale as: 0, subject does not respond to air stimulation; 1, subject responds to air stimulus but does not request discontinuation of stimulus; 2, subject responds to air stimulus and requests discontinuation or moves from stimulus; 3, subject responds to air stimulus, considers stimulus painful and requests discontinuation of the stimulus . Study subjects also rated the intensity of their response to the evaporative air stimulus using a standard 100 mm VAS (0 mm = no pain to 100 mm = worst pain imaginable).

Clinical assessments of sensitivity were followed by a review of the inclusion/exclusion criteria. Eligible subjects were randomised (according to a schedule provided by the Biostatistics Department of GSK Consumer Healthcare) to treatment, stratified by maximum baseline Schiff sensitivity score of the two test teeth selected by the examiner (to give two strata with maximum Schiff 2 or 3) and assigned their study dentifrice for twice-daily use over the next 8 weeks. Adherence to twice-daily brushing was recorded in a subject diary. Dentine hypersensitivity was re-assessed after 1, 2, 4 and 8 weeks treatment. Safety was evaluated in terms of treatment-emergent adverse events (TEAEs) and OST abnormalities.

Statistical methods

This was an exploratory study not formally powered to detect statistically significant differences between treatments; thus, trends in the data were used to investigate treatment differences. It was planned that approximately 145 subjects would be randomised to have approximately 120 completers (30 subjects per treatment group). Efficacy variables were calculated at subject level as mean change from baseline across two selected test teeth. Change from baseline of Schiff sensitivity score at each time-point was assessed by analysis of covariance (ANCOVA) with treatment group included as a fixed effect factor and baseline Schiff sensitivity score as covariate. Because of this, baseline Schiff stratification was not included in the model. Changes from baseline of tactile threshold and VAS at each time-point were assessed by ANCOVA with treatment group and baseline Schiff stratification as fixed effect factors and baseline tactile threshold or VAS as covariate. The assumption of normality of residuals and homogeneity of variance were investigated and found to be acceptable. Adjusted mean treatment effects and intergroup differences (pairwise comparisons), 95% confidence intervals (95% CIs) and p-values are presented. All tests were performed at the 5% significance level with no adjustments for multiplicity. All analyses were conducted with SAS version 9.2 software (SAS Institute Inc., Cary, NC, USA).

Subjects and methods

Study design

This was a randomised, controlled, examiner blind, four treatment arm, parallel group study to investigate and compare the anti-sensitivity efficacy of four study dentifrices in volunteer subjects, stratified by maximum baseline Schiff sensitivity score of two selected test teeth, over an 8 week treatment period. In line with published recommendations , two independent stimulus-based efficacy measures, evaporative (air) and tactile stimuli, were used to assess dentine hypersensitivity at baseline and after 1, 2, 4 and 8 weeks of treatment. A single dental examiner, experienced in the assessment of dentine hypersensitivity, performed the clinical assessments in all subjects for the duration of the study. To help minimise the potential impact of the ‘Hawthorne’ effect (i.e., a change in subject behavior in response to being observed) or placebo response and to standardise oral hygiene practices across the study population, an acclimatisation period (minimum 4 weeks) was included ahead of baseline assessments and randomisation.

The study was approved by an FDA-approved institutional review board prior to initiation and conducted at BioSci Research, Inc., Las Vegas, NV, USA in accordance with all laws and local regulations, the principles of Good Clinical Practice , and the Declaration of Helsinki . Study funding was provided by GSK Consumer Healthcare.

Study population

Healthy subjects aged 18–65 years with a minimum of 20 natural teeth and self-reported dentine hypersensitivity lasting at least 6 months but no longer than 10 years were recruited. Subjects were required to have a minimum of two accessible, non-adjacent teeth (incisors, canines or pre-molars) with signs of erosion, abrasion or facial/cervical gingival recession (EAR), a Löe and Silness Gingival Index (GI) score of ≤1 , clinical mobility of ≤1 , and signs of sensitivity as measured by a qualifying evaporative (air) assessment.

General exclusion criteria included women who were pregnant (including those who fell pregnant during the study) or breast feeding; subjects with an intolerance to any of the study materials; subjects with a chronic debilitating disease that could have affected study outcomes; daily doses of a medication that could have interfered with the perception of pain or any condition/medication that was causing xerostomia. Subjects who had participated in another tooth desensitising treatment study within 8 weeks of the screening visit were also excluded. Dental exclusion criteria included tongue or lip piercing or presence of dental implants; dental prophylaxis within 4 weeks of screening; teeth bleaching or desensitizing treatment within 8 weeks of screening; scaling or root planing within 3 months of screening and gross periodontal disease or treatment of periodontal disease within 12 months of screening. Specific exclusions for test teeth included evidence of current/recent caries or reported treatment of decay in 12 months of screening; any tooth with exposed dentine but with deep, defective or facial restorations; teeth used as abutments for fixed/removable partial dentures; teeth with full crowns or veneers, orthodontic bands or cracked enamel, and sensitive teeth with contributing aetiologies other than EAR of exposed dentine.

Study treatments

The study evaluated four treatments.

  • Experimental dentifrice: 5% w/w KNO 3 , 3% w/w O/MA, 1150 ppm fluoride as sodium fluoride (NaF)

  • Active comparator dentifrice: 5% w/w KNO 3 , 0% O/MA,1150 ppm fluoride as NaF

  • Placebo dentifrice: 0% w/w KNO 3 , 3% w/w O/MA, 1150 ppm fluoride as NaF

  • Negative control dentifrice: 1000 ppm fluoride as sodium monofluorophosphate (SMFP) (Colgate Cavity Protection ® , US marketed dentifrice, Colgate-Palmolive Co., New York, NY)

Subjects were instructed to brush for 1 timed minute twice daily (morning and evening) using a brush head of their assigned study dentifrice on each brushing occasion, in line with typical consumer habit and common practice within dental clinical trials.

Clinical procedures

At the screening visit, subjects gave their written informed consent to participate in the study. Demography, medical history and concomitant medications were recorded, followed by an oral soft tissue (OST) examination. The teeth were then assessed sequentially for dentition exclusions; evidence of EAR; gingival health status (using the GI); mobility and sensitivity to a simple air blast stimulus applied to the facial surface of the tooth (where a ‘yes’ response from the subject indicated sensitivity) to determine their clinical eligibility for assessment of dentine hypersensitivity at subsequent visits. Eligible subjects were supplied with a regular fluoride dentifrice (Crest ® Cavity Protection, US marketed dentifrice, Procter & Gamble, Cincinnati, OH, USA; 1100 ppm fluoride as NaF) to use twice-daily (morning and evening) for a minimum of 4 weeks (acclimatisation period) prior to their baseline visit.

At baseline, subjects underwent an OST examination followed by clinical assessment of dentine hypersensitivity for all clinically eligible teeth identified at screening, first to a tactile stimulus using a Yeaple probe and then to an evaporative air stimulus (evaluated using the Schiff Sensitivity Scale and a visual analogue scale [VAS]). The Yeaple probe allows the examiner to apply a known force to the dentine surface, beginning at 10 g (g) and increasing in 10 g intervals. The tactile threshold (g) is the maximum force applied without the subject reporting pain or discomfort (the greater the tactile threshold, the less sensitive the tooth). At baseline, the maximum force was set at 20 g; at all subsequent visits it was 80 g.

Sensitivity to an evaporative (air) stimulus was assessed by directing an 1-s air blast from a triple air dental syringe onto the exposed dentine surface from a distance of approximately 1 cm, with the surface of the tooth isolated to prevent adjacent teeth or surrounding soft tissue being exposed to the stimulus . The examiner’s assessment of the subject’s response to the air stimulus was rated on the Schiff Sensitivity Scale as: 0, subject does not respond to air stimulation; 1, subject responds to air stimulus but does not request discontinuation of stimulus; 2, subject responds to air stimulus and requests discontinuation or moves from stimulus; 3, subject responds to air stimulus, considers stimulus painful and requests discontinuation of the stimulus . Study subjects also rated the intensity of their response to the evaporative air stimulus using a standard 100 mm VAS (0 mm = no pain to 100 mm = worst pain imaginable).

Clinical assessments of sensitivity were followed by a review of the inclusion/exclusion criteria. Eligible subjects were randomised (according to a schedule provided by the Biostatistics Department of GSK Consumer Healthcare) to treatment, stratified by maximum baseline Schiff sensitivity score of the two test teeth selected by the examiner (to give two strata with maximum Schiff 2 or 3) and assigned their study dentifrice for twice-daily use over the next 8 weeks. Adherence to twice-daily brushing was recorded in a subject diary. Dentine hypersensitivity was re-assessed after 1, 2, 4 and 8 weeks treatment. Safety was evaluated in terms of treatment-emergent adverse events (TEAEs) and OST abnormalities.

Statistical methods

This was an exploratory study not formally powered to detect statistically significant differences between treatments; thus, trends in the data were used to investigate treatment differences. It was planned that approximately 145 subjects would be randomised to have approximately 120 completers (30 subjects per treatment group). Efficacy variables were calculated at subject level as mean change from baseline across two selected test teeth. Change from baseline of Schiff sensitivity score at each time-point was assessed by analysis of covariance (ANCOVA) with treatment group included as a fixed effect factor and baseline Schiff sensitivity score as covariate. Because of this, baseline Schiff stratification was not included in the model. Changes from baseline of tactile threshold and VAS at each time-point were assessed by ANCOVA with treatment group and baseline Schiff stratification as fixed effect factors and baseline tactile threshold or VAS as covariate. The assumption of normality of residuals and homogeneity of variance were investigated and found to be acceptable. Adjusted mean treatment effects and intergroup differences (pairwise comparisons), 95% confidence intervals (95% CIs) and p-values are presented. All tests were performed at the 5% significance level with no adjustments for multiplicity. All analyses were conducted with SAS version 9.2 software (SAS Institute Inc., Cary, NC, USA).

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Jun 19, 2018 | Posted by in General Dentistry | Comments Off on An exploratory clinical trial to evaluate the efficacy of an experimental dentifrice formulation in the relief of dentine hypersensitivity
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