Abstract
Objective
The purpose of this randomized controlled trial was to compare the efficacy of a toothpaste containing paeonol, potassium nitrate, and strontium chloride with control toothpaste on dentine hypersensitivity (DH).
Methods
DH patients who had at least two sensitive teeth and did not use desensitization toothpaste in the past 3 months were randomly allocated to either test or control group. The toothpaste containing paeonol, potassium nitrate, and strontium chloride was used in the test group, while the placebo toothpaste used in control group. The outcome measures included Yeaple probe score and Schiff Index score at 4 and 8 weeks. The patients, personnel and assessors were blinded to the allocation. The differences in Yeaple probe score and Schiff Index score between groups were analyzed with ANOVA.
Results
91 eligible subjects were randomized. 88 of them completed 8-week follow-up and were analyzed (45 in the test group and 43 in the control group). In both groups, the Yeaple probe score showed an upward trend, while the Schiff sensitivity score showed a downward trend. At week 8, the Yeaple probe score had increased by 30.22 g in the test group, and the Schiff Index score had decreased by 0.89. Compared with the control group, the Yeaple probe score in the test group increased by 286.85% from baseline, and the Schiff Index score decreased by 42.96%, showing a statistically significant difference. Five cases of adverse events were observed.
Conclusion
The toothpaste containing paeonol, potassium nitrate, and strontium chloride was effective against DH.
Clinical significance
This combination of paeonol, potassium nitrate and strontium chloride could be a novel functional ingredient choice for anti-hypersensitivity products in future.
Registration
The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2000041417).
Keywords: Paeonol, Potassium nitrate, Strontium chloride, Dentine hypersensitivity
1. Introduction
In China, approximately 30% of adults aged 20–60 years and 80% of those aged over 60 years have dentine hypersensitivity (DH) [1]. With population aging, the prevalence of DH has been rising. DH is characterized by a short, sharp pain arising from the exposed dentine in response to thermal, evaporative, tactile, osmotic or chemical stimuli, which cannot be ascribed to any other form of dental defect or pathology [2]. Management of DH is primarily based on over the counter dentifrices.
DH is caused by two factors: exposure of dentin and stimulation of dentin tubules by external factors. At present, one of well acknowledged mechanisms of DH is the hydrodynamic theory, which holds that external stimulation promote the fluid flowing in the dentin tubule, and in turn stimulates the peripheral nerves between the dental pulp and dentin, causing pain symptoms [3]. According to this theory, there are two effective ways to relieve DH clinically: one is to occlude exposed dentin tubules, which reduce the permeability of dentin and avoid the fluid flow in dentin; the other is to sedative pulp nerve, namely reduce the sensitivity of dentin and pulp nerve endings, thereby relieving the pain caused by DH [4].
In Traditional Chinese Medicine, the pharmaceutical drug paeonol has effects such as sedation, antipyretic, anti-inflammatory, immune regulation, antioxidant [5,6]. Some studies have shown that it also has antibacterial, anti-hypersensitivity, antihalitosis and analgesic effects when applied in dental clinical practice [[7], [8], [9]]. It is speculated that paeonol could inhibit the tissue permeability of hypersensitive area and reduce the fluid flow in dentin, and decrease the sensitivity of dentin and pulp nerve endings, so it has the potential to reducing dentin hypersensitivity [9,10]. As a typical potassium salt, potassium nitrate has been approved by FDA as an active ingredient in the treatment of DH, and has been widely used in various oral care products. Potassium ions depolarize the sensory nerve fiber membranes, leading to inactivation of the action potential generation mechanism [11]. Thus, the excitability of nerve fiber terminals in dental pulp is reduced and the pain caused by DH is relieved [12]. Strontium-based dentifrices were the first proposed tubule blocking agents, that has been clinically verified to relieve DH [13]. Some researchers believed that the desensitization effect of strontium was that Strontium-based products can enter the dentinal tubules and react with calcium in hard tissues, forming calcified strontium apatite and depositing on the dentinal tubules, which can alleviate symptoms of dentine hypersensitivity by blocking dentinal tubules [14,15]. Kun supported this conclusion using high-resolution microradiography, electron probe analysis, and X-ray diffraction [16].
The hypothesis for this clinical trial was that a dentifrice containing paeonol, potassium nitrate, and strontium chloride will reduce dentin hypersensitivity after 4 and 8weeks of use.
2. Methods
2.1. Study design
This was a single-center, placebo-controlled, randomized double-blind trial with two parallel groups. This study was approved by the Ethics Committee (WCHSIRB-D-2020-157). It was registered in the Chinese Clinical Trial Registry (ChiCTR2000041417). There were no changes to the method after trial commencement.
The trial was conducted from June 2020 to December 2020 in the Department of General Dentistry at West China Hospital of Stomatology, Sichuan University. It aimed to clinically compare the efficacy of the toothpaste containing paeonol, potassium nitrate, and strontium chloride with control toothpaste on dentine hypersensitivity.
2.2. Participants
Inclusion criteria were: 1)age, 18–65 years; 2)continued participation for 8 weeks; 3) hypersensitive area on facial surfaces of the teeth (incisors, cuspids and bicuspids with exposed cervical dentine) with at least two nonadjacent teeth scoring two or three at the airblast sensitivity test (Schiff Cold Air Scale) and scoring 10 g or 20 g at the tactile sensitivity test; 4) good periodontal health (no probing depth >4 mm) with no other conditions that might explain their apparent DH; 5) good physical health and not allergic to the research toothpaste; 6) no use of the desensitization toothpaste within three months before the study; 7) informed consent.
Exclusion criteria were: 1) oral mucosal or chronic disease or a history of allergy to any of the toothpaste ingredients; 2) periodontal disease progression or periodontal treatment in the past year, including periodontal surgery; 3) hypersensitive teeth with a mobility >1; 4) extensive tooth restoration, pulpitis, caries, enamel cracking, or abutment for a removable partial denture; 5) current anticonvulsants, antihistamines, antidepressants, sedatives, tranquilizers, anti-inflammatory agents, or daily analgesics; 6) participation in another study involving a desensitizing toothpaste in the past 3 months or daily use of desensitizing toothpaste; 7) participation in other clinical trials; 8) pregnancy or lactation; 9) a history of allergies to personal health products or their ingredients.
Before participation, the participants would sign a consent form after being informed in detail about the process, benefits and risks, and voluntary principles. Then the participants were initially assessed for eligibility in the study by the investigator.
2.3. Interventions
The eligible participants were randomly divided into two groups: the test and control groups. Each subject had equal chance to be assigned to either group. The test group used the experimental toothpaste containing active ingredients, while the control group used a blank placebo toothpaste, mainly composed of water, silica, polyethylene glycol, and sorbitol, without anti-hypersensitivity agent. For 8 weeks, the participants only used the given toothpaste and toothbrush and stopped other oral hygiene measures, such as flossing or using a mouthwash. The amount of toothpaste used was to cover the whole toothbrush hair. Brush their teeth twice a day with the toothpaste and toothbrush provided, at least 1 min each time. The brushing method was not specified. Diet or smoking was not restricted.
A series of inspections were carried out. After 4 weeks, the toothpaste was recycled and checked, and a new toothpaste of the same group was issued again. The toothpastes were recovered after 8 weeks, and the study was completed after relevant inspections. Other oral hygiene measures and chewing gums were stopped 8 h prior to each examination, and eating or drinking was stopped 2 h before. Participants were phoned to remind them of upcoming appointments 1–2 days ahead of time.
2.4. Efficacy evaluation index
Sensitive teeth respond differently to different stimuli; therefore, stimulation is used as an indicator to record dentine hypersensitivity. Based on Holland 's research, two independent stimuli methods were used for evaluation: airblast test and tactile test [17]. They are measurable and repeatable, and there was sufficient time (5–10 min) between the stimulations to restore dentinal responsiveness, thus preventing mutual interference. From the teeth that met the Schiff Index score (2 or 3) and Yeaple probe score (10–30 g) at baseline, the investigators selected two teeth for evaluation at subsequent visits. The two teeth were non-adjacent and were preferably in different quadrants. All assessors had received uniform training.
2.4.1. Airblast test: Schiff Index score
Airblast hypersensitivity was measured using a standard unit air syringe at 60 psi (±5 psi) and 20 °C (±2 °C). A blast of air directed onto the affected area of the tooth for 1 s from a distance of 10 mm, and the fingers were placed on the neighboring teeth to prevent the neighboring teeth from affecting the accuracy of the results. The Schiff Index score for cold air sensitivity was as follows:
0, no response of the tooth or subject to air stimulation; 1, response of the tooth or subject to air stimulation but without requesting to stop the stimulation; 2, response of the tooth and subject to air stimulation and a request to stop or remove the stimulation; 3, response of the tooth and subject to air stimulation, leading to pain and a request to stop.
A low score indicated mild dentine hypersensitivity, and a high score indicated severe dentine hypersensitivity.
2.4.2. Tactile test: Yeaple probe score
Tactile hypersensitivity was measured using an Electronic Force Sensing Probe (Yeaple Probe Model 200A; Xinix Research Inc., Portsmouth, New Hampshire), which was calibrated daily by the assessors.
All participants had been conformed a probe would pass their teeth repeatedly, and they should answer whether fell pain or discomfort.
The probe tip was placed perpendicular to the buccal surface and moved in a slow motion while drawn across the tooth surface in order to ensure application of the stimulus across the sensitive area of the exposed dentine. Initially, the force was set at 10 g; subsequently, it was increased by 10 g each time, up to 80 g. The test was repeated twice before a score was recorded. The high and low exploratory powers indicated low and high levels of dentine hypersensitivity, respectively.
2.4.3. Safety evaluation indicators
The mild and serious adverse events that occurred during the trial were recorded, and whether or not they were related to the test product was determined. The incidence of mild and serious adverse events was calculated. Vital signs before and after the test were recorded and statistically analyzed.
2.5. Sample size calculation
For the purposes of calculating a required sample size for this study, we referred to the relevant studies as well as Products for the Treatment of Dentinal Hypersensitivity published by American Dental Association [18,19]. To achieve 95% power, the trial included 40 patients per group (for Yeaple probe score width feature; standard deviation, 7.65; alpha level, 0.05; beta level, 0.05; differences between groups, 6.12). The number of participants was widened to 44 to account for a 10% loss to follow-up.
2.6. Randomization
A simple randomization was automatically generated by the SAS program. Each number was placed in a separate, opaque envelope kept by an independent investigator who was not involved in this trial. Each envelope contained the treatment allocation card (group 1 or 2). The independent investigator distributed envelope to eligible participant sequentially. According to the card information, the subjects went to the corresponding toothpaste group.
2.7. Blinding
The toothpaste was indistinguishable in appearance and packaging between the two groups. They were named BQ-1 and BQ-2 and provided by toothpaste manufacturers. Throughout the study, all dentists, assessors, participants were unaware of which group was the test group and which was the control group. The assessors were the same in both groups, and the assessors would not ask the subjects which group they were in before evaluation. Unblinding was carried out after the data statistics had been completed, and the manufacturer informed the toothpaste groups corresponding to BQ-1 and BQ-2.
2.8. Statistical analysis
Original observation records were appropriately entered for a statistical analysis. These included number, mean, and standard deviation. SAS 9.4(SAS Inc., North Carolina, USA), the statistical analysis software, was used for the analysis. Yeaple probe score and Schiff Index score between groups were analyzed with ANOVA. Unless otherwise specified, the testing level for all hypothesis testing was set to 0.05 bilaterally.
3. Results
3.1. Participant flow
A total of 91 eligible subjects were enrolled, including 47 in the test group and 44 in the control group. Of them, 88 completed the eight-week follow-up, whereas two were lost to follow-up and actively withdrew the informed consent. The overall number of analyzed participants was 88, with 45 participants in the test group and 43 participants in the control group. The CONSORT flowchart of the participants for this trial is shown in Fig. 1. No serious adverse reactions caused by the toothpaste was found in any subject.
Fig. 1.
Test procedure.
3.2. Baseline analysis
The 88 subjects who completed the trial were analyzed. Before treatment, the two groups showed no statistical differences in age, sex, Yeaple probe score, or Schiff Index score (p > 0.05). The baseline conditions of the two groups were consistent and comparable.
3.3. Toothpaste usage
A total of 260 g of toothpaste was distributed at the baseline and week 4, and the remaining toothpaste was recycled and weighed at weeks 4 and 8 (see Table 1). The weight of the toothpaste was then calculated. Table 2 shows the weight of the toothpaste. The weight used did not differ significantly between the two groups in the first 4 weeks and 8 weeks (p > 0.05).
Table 1.
Subject population data and baseline Yeaple probe and Schiff Index scores.
| Test group | Control group | P | |
|---|---|---|---|
| Gender: male/female, No. | 8/37 | 7/36 | 0.854 |
| Age in y, mean (SD) | 38.91 (7.56) | 40.37 (9.43) | 0.424 |
| Yeaple probe score, mean (SD) | 11.89 (5.38) | 12.79 (5.01) | 0.252 |
| Schiff Index score, mean (SD) | 2.06 (0.23) | 2.13 (0.34) | 0.096 |
Table 2.
Toothpaste weight at baseline, week 4, and week 8.
| Test group1 |
Control group2 |
P | |||||
|---|---|---|---|---|---|---|---|
| n | Mean | SD | n | Mean | SD | ||
| Total weight of distribution | 45 | 260.32 | 7.57 | 43 | 261.76 | 1.86 | 0.236 |
| Weight used in the first 4 weeks | 45 | 57.93 | 19.71 | 42 | 62.99 | 20.34 | 0.248 |
| Total weight used in 8 weeks | 42 | 151.42 | 35.18 | 37 | 152.57 | 31.45 | 0.880 |
1: Of the 45 subjects in the test group, 3 did not bring the toothpaste back at 8-week.
2: Of the 43 subjects in the control group, 1 did not bring the toothpaste back at 4-week; 6 did not bring back at 8-week.
3.4. Evaluation of efficacy
3.4.1. Dentine hypersensitivity scores
Sensitivity scores are shown in Table 3 for all measures (Schiff and Yeaple probe) at weeks 4 and 8. Compared to baseline, the Yeaple probe score showed an upward trend in both groups (Fig. 2), while the Schiff Index score showed a downward trend (Fig. 3). At week 4, compared to the control group, the Yeaple probe score was higher in the test group, while the Schiff score was lower. At week 8, the difference between the two groups had increased. Compared with baseline, the Yeaple probe score had increased by 30.22 g in the test group and 22.79 g in the control group, while the Schiff score had decreased by 0.89 in the test group and 0.72 in the control group.
Table 3.
The Yeaple probe and Schiff Index scores at weeks 4 and 8.
| Week 4 |
Week 8 |
||||||
|---|---|---|---|---|---|---|---|
| Mean | SD | 95% CI | Mean | SD | 95% CI | ||
| Yeaple | Test Group | 31.33 | 22.12 | 26.67 to 35.99 | 42.11 | 25.41 | 36.76 to 47.46 |
| Control Group | 28.72 | 18.97 | 24.63 to 32.81 | 35.58 | 24.85 | 30.22 to 40.94 | |
| Schiff | Test Group | 1.41 | 0.49 | 1.31 to 1.51 | 1.17 | 0.37 | 1.09 to 1.25 |
| Control Group | 1.55 | 0.54 | 1.44 to 1.67 | 1.41 | 0.49 | 1.30 to 1.51 | |
Fig. 2.
Yeaple probe Fig. 3 Schiff Index.
Fig. 3.
Schiff Index.
3.4.2. Clinical efficacy of the test toothpaste
Given the inconsistent baseline data for each participants, the rate of change was used to measure the improvement in dentin hypersensitivity. At week 4, there was no statistical difference between the two groups in either Yeaple or Schiff score changes. As the trial progressed, at week 8, the gap between the two groups became larger, and rates of change in both Yeaple and Schiff scores were statistically significant (Table 4). According to the data of week 8, the test group was better than the control group in reducing dentine hypersensitivity after continuous use of the toothpastes.
Table 4.
Rate of change from baseline in Schiff and Yeaple score.
| Week 4 |
Week 8 |
||||||
|---|---|---|---|---|---|---|---|
| Mean | SD | p | Mean | SD | p | ||
| Yeaple | Test Group | 187.59 | 217.46 | 0.230 | 286.85 | 251.96 | 0.022 |
| Control Group | 15.58 | 185.44 | >0.05 | 203.29 | 225.99 | <0.05 | |
| Schiff | Test Group | −30.93 | 24.41 | 0.243 | −42.96 | 18.08 | 0.003 |
| Control Group | −26.55 | 24.82 | >0.05 | −33.72 | 22.30 | <0.05 | |
Formula for the rate of change: (Week 4 or 8 − baseline)/baseline × 100%.
3.5. Safety evaluation
Five cases of adverse events were observed, including two cases of lip bleeding, one case of toothache, one case of a gingival fistula, and one case of white spots the on tongue and cheek. Of all cases of adverse events, two were in the trial group, whereas three in the control group. Table 5 shows the severity and correlation evaluation of adverse events in both groups. The two groups did not differ significantly in adverse events.
Table 5.
Summary of adverse events.
| Test group | Control group | Total | |
|---|---|---|---|
| Number of adverse events | 2 | 3 | 5 |
| Number of events related to the toothpaste | 0 | 2 | 2 |
| Number of events unrelated to the toothpaste | 2 | 1 | 3 |
| Mild adverse events | 2 | 2 | 4 |
| Moderate adverse events | 0 | 1 | 1 |
| Serious adverse events | 0 | 0 | 0 |
4. Discussion
With the development of society, the demands for toothpaste are getting higher, especially for functional toothpastes. By adding active ingredients to make toothpaste has the effect of preventing or treating oral diseases, has be the priority of enterprise research and development. At present, various functional products have been introduced to the market, including anti-hypersensitivity, whitening, anti-caries, inhibition of dental plaque, and alleviation of gingivitis. Dentin hypersensitivity is one of the most common oral diseases, with an average prevalence of 33.5%. Among young adults, this figure even rises to 43.9% [20]. The sales of over-the-counter toothpaste used to relieve DH has been one of the few areas of commercial growth in the oral care industry [3].
The dentin of healthy teeth is covered by the enamel and gums. The enamel wears down over time, reducing protection to the teeth. The gums shrink with age, exposing the dentin at the root [21]. Consequently, cold and hot temperatures, sour and sweet tastes, and other stimuli are transmitted to the dental pulp via the exposed dentin tubules, causing various discomforting symptoms, such as soreness, resulting in dentine hypersensitivity [2]. The effective treatment for dentine hypersensitivity is to seal the dentin tubules or reduce nerve sensitivity [4,22]. Commonly used drugs for sealing the dentinal tubules include fluorides, calcium salt, strontium salt, colloidal metal, and resin, and commonly used neuro-desensitizing drugs include potassium salt and formaldehyde drugs [22,23].
Paeonol, as a traditional Chinese medicine, has been proved to have anti-inflammatory, analgesic, neuroprotection effects in many studies. Anti-inflammatory is the basic pharmacological effect, which acts by blocking the lipopolysaccharides stimulated inflammatory responses in BV-2 and RAW264.7 inflammatory cells model [24]. Anti-inflammatory effects include osteoarthritis and rheumatoid arthritis, skin inflammation, colitis, etc. Pain is one of the main symptoms of inflammatory, and studies have confirmed the analgesic effect of paeonol. Chou found that paeonol inhibited carrageenan-evoked thermal hyperalgesia in a dose-dependent manner in a rat model of carrageenan-evoked thermal hyperalgesia. The analgesic mechanism may be reduced the production of proinflammatory cytokines NO and PGE [25]. Chen showed that paeonol exerted analgesic effects by inhibiting HMGB1/TLR4/NF-κB p65 pathway and subsequently producing cytokines TNF-α and IL-1β in the anterior cingulate cortex [26]. In the nervous system, paeonol exerts neuroprotective effect by inhibiting neuroinflammation in microglia cells [27,28], and plays remarkable roles in central nervous system disorders such as cerebral ischemic injury, diabetic encephalopathy, Alzheimer's disease. Other effects of paeonol include anti-tumor, anti-cardiovascular disease, anti-allergy and so on.
Paeonol also presents many advantages when used in the treatment of oral disease. Chang illustrated that paeonol had a consistent ameliorative effect on ligature- or LPS-induced periodontal destruction and gingival inflammation, and also can inhibit the formation of LPS-induced osteoclasts on alveolar bone surface [29]. Hu extracted paeonol from cortex moutan and developed paeonol gargle. The gargle had antibacterial activity against Porphyromonas gingivalis and Streptococcus mutans in vitro, and the antibacterial effect on Porphyromonas gingivalis was better than that on Streptococcus mutans [8]. Zhao prepared paeonol gargle with supercritical extraction, and in vivo study found the gargle had auxiliary therapeutic effects on oral diseases such as halitosis and periodontitis, and also protect probiotics in the mouth [7]. Based on the effects of paeonol, it can be further developed and applied in more fields in the future.
The toothpaste used in the test group of this trial was supplemented with three active ingredients: paeonol, potassium nitrate, and strontium chloride, while the control group was negative blank placebo. From Fig. 2, Fig. 3, the DH status of subjects in both groups was improved during the study period. The Yeaple probe score increased by over 20 g, and the Schiff Index score decreased by over 0.7. The figure shows that the improvement in the first 4 weeks was better than that in the next 4 weeks. At week 8 of the end point, compared with baseline, the test group outperformed the control group on both measures. Although an improvement in DH scores from baseline was observed in control group, the test group were significantly better than the control group at each time point after baseline. In addition, it should be considered that subjects may be affected by the Hawthorne effect, and control group may be also affected by the placebo effect [30].
This study preliminarily verified the effect of compound toothpaste containing paeonol, potassium nitrate and strontium chloride on reducing dentin sensitivity. The limitation of this study is that it is impossible to demonstrate which of the three ingredients plays a leading role, or whether there is a better prescription. More research is needed to understand the effect of different components, especially paeonol, on dentin hypersensitivity, and then select the best proportion.
5. Conclusion
According to Schiff and Yeaple score changes, the toothpaste containing paeonol, potassium nitrate and strontium chloride was statistically more effective than the blank control toothpaste in alleviating dentine hypersensitivity after 8 weeks of continuous use, and no subject experienced serious adverse events in the study period. This combination of paeonol, potassium nitrate and strontium chloride could be a novel functional ingredient choice for anti-hypersensitivity products in future. We will carry out further research to optimize the prescription.
Author contribution statement
Yisi Zhong: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper.
Jia Li: Analyzed and interpreted the data; Wrote the paper.
Qi Han: Analyzed and interpreted the data; Contributed materials, analysis tools; Wrote the paper.
Li Zhang ang Jing Zhang: Performed the experiments; Wrote the paper.
Funding statement
Jia Li was supported by West China Hospital of Stomatology, Sichuan University [RD-01-202105].
Data availability statement
Data included in article/supp. material/referenced in article.
Declaration of interest's statement
The authors declare no competing interests.
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