Saudi Journal of Oral Sciences

REVIEW ARTICLE
Year
: 2021  |  Volume : 8  |  Issue : 3  |  Page : 122--128

Nano hydroxyapatite toothpaste as a treatment for dentine hypersensitivity: A systematic review


Hanan Oubenyahya 
 Department of Dentistry, Military Hospital, Agadir, Morocco

Correspondence Address:
Dr. Hanan Oubenyahya
Department of Dentistry, Military Hospital, Agadir 80000
Morocco

Abstract

Introduction: Dentin hypersensitivity (DH) is a common and painful clinical occurrence that can negatively impact patients' quality of life. An arsenal of different desensitizing molecules is available on the market, but no gold standard has yet to be set.Aim: The aim of this study was to perform a review on the potential of nano-hydroxyapatite (n-HA) as a desensitizing toothpaste agent as opposed to placebo or other desensitizing molecules. Materials and Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, an electronic search of the PubMed database was conducted from inception up until May 2021. Seven English written randomized controlled trials about the use of n-HA toothpaste in treating adults with DH were assessed for quality via the modified Jadad scale, and included in the review. Non-English studies, publications involving lasers, and studies researching the effect of n-HA on gingival inflammation or postwhitening sensitivity were all excluded. Results and Discussion: Available evidence suggests that n-HA is a promising addition to the growing arsenal of desensitizing treatments available on the market. Conclusion: n-HA remains a viable everyday option that dentists should strongly consider for their patients' pain relief. However, due to the heterogeneity of pain studies and the lack of standardization in trial protocols, no evidence of superiority to other desensitizing agents can be ascertained, thus far.



How to cite this article:
Oubenyahya H. Nano hydroxyapatite toothpaste as a treatment for dentine hypersensitivity: A systematic review.Saudi J Oral Sci 2021;8:122-128


How to cite this URL:
Oubenyahya H. Nano hydroxyapatite toothpaste as a treatment for dentine hypersensitivity: A systematic review. Saudi J Oral Sci [serial online] 2021 [cited 2022 Jan 25 ];8:122-128
Available from: https://www.saudijos.org/text.asp?2021/8/3/122/334294


Full Text



 Introduction



Dentin hypersensitivity (DH) is a common clinical condition characterized by a sharp pain of short duration. This condition is a result of exposed dentin that reacts to various stimuli (thermal, evaporative, tactile, osmotic, or chemical). Gingival recession and/or loss of enamel structure by attrition, abrasion, abfraction, erosion, or inadequate brushing techniques are often behind the dentinal exposure. Microscopic examination from multiple studies has demonstrated that individuals who suffer from this condition often exhibit more and wider dentinal tubules in sensitive dentin than in nonsensitive dentin.[1],[2]

The hydrodynamic theory from Brännström is still the most widely accepted explanation of this painful phenomenon. According to this theory, pain results when a stimulus in contact with the exposed dentin triggers rapid dentinal fluid flow, which in turn excites pulpal nerve terminals.[3] The philosophy behind most proposed treatments is therefore to focus on limiting the fluid movement within the tubules to prevent neural discharge.

A precise etiological diagnosis is of utmost importance before considering a suitable treatment plan. DH, being mainly a diagnosis of exclusion, a differential diagnosis with other conditions causing similar short bouts of pain, should be established.[1] Patients should be checked for predisposing conditions such as improper brushing techniques, high acidic diets, premature occlusal contacts, xerostomia, eating disorders, periodontal disease, and tobacco use.[4]

There is no gold standard for treatment. However, the least invasive options should always be proposed first to the patient, before considering any invasive approach. The goal of noninvasive treatment is to alleviate pain via two known methods. The first one is by blocking the nerve response via chemical agents that can penetrate the dentinal tubules and depolarize the nerve synapse. The second one is by blocking the hydrodynamic mechanism via chemical or physical tubule-occluding agents that can create a mechanical layer, thus preventing the dentinal fluid flow.[5]

In search of both short-term and long-term therapeutic effects, these approaches have been vectored both as home treatments and in-office treatments.

Due to daily occurrence of stimuli in a person's life, this is a condition that cannot be noninvasively treated in one go. Toothpastes have therefore established themselves as the most practical and cost-effective in-home vectors of active desensitizing compounds. Their formulations have benefitted a great deal from the advances of nanotechnology, with nano-hydroxyapatite (n-HA) being the latest addition to the arsenal of pain-fighting molecules. n-HA is the synthesized version of HA applied in microcluster or nanocrystalline forms and it is chemically similar to enamel apatite crystals.[6] Its biocompatibility has led to explore its biomimetic potential for remineralization purposes. Studies have shown that n-HA can promote crystallite deposition and growth, thus leading to remineralization of the superficial layer of enamel surfaces.[7],[8] These results prompted in vitro studies investigating the occlusion of dentin tubules; n-HA could provide a useful protective layer on the dentin surface against acid erosion and DH.[9],[10] However, in vitro models cannot replicate the conditions inside the oral cavity, so in situ studies followed. The latter confirmed the ability of n-HA crystals to deposit precipitate layers over and within dentin tubules.[11],[12] Following these results, n-HA has since been incorporated in treatments involving postbleaching sensitivity, DH, and caries prevention.[13] The aim of this paper is to systematically evaluate the existing evidence on the effect of n-HA as the newest desensitizing agent in toothpastes and how it faired in this therapeutical goal as opposed to established molecules or placebo treatments.

 Materials and Methods



The current systematic review methodology is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The ethical committee approval is exempted from the review.

Research question

The research question followed the PICOS framework:

Population: Adult patients (≥18 years) presenting with DH in noncarious cervical lesionsIntervention: Treatment of DH through toothpaste containing HA nanocrystalsComparison: DH treatment through a toothpaste containing other desensitizing agents or a placeboOutcome: Dentin-desensitizing effect.

Study design

This was a randomized controlled trial (RCT).

Search strategies

A Medline search was conducted on May 2021 via PubMed using the following MeSH keywords:

([dentine hypersensitivity] OR [dentinal hypersensitivity] OR [dentine sensitivity] OR [dentinal sensitivity]) AND ([hydroxyapatite dentifrice] OR [hydroxyapatite toothpaste] OR [hydroxyapatite paste]) AND ([dentifrice] OR [toothpaste] OR [paste]) AND ([reduction] OR [efficacy] OR [evidence] OR [treatment]).

Eligibility criteria

The search was performed on PubMed from the first available literature on the topic inception until May 2021.

Inclusion criteria: Double-blind RCTs published in the English language and in vivo use of n-HA toothpaste for DHExclusion criteria: Non-English studies, clinical studies, studies about the effect of HA on gingival inflammation or postbleaching sensitivity, and RCTs comparing lasers to HA toothpastes.

Quality assessment

The potentially relevant studies were assessed for quality through the modified Jadad scale. This is an eight-item scale designed to assess randomization, blinding, withdrawals and dropouts, inclusion and exclusion criteria, adverse effects, and statistical analysis. A score below 3 denotes low quality. No additional tool for risk of bias was used for our study [Table 1].{Table 1}

Ethics and data

The study did not involve contact with humans, so the need for ethical approval was waived. This systematic review was not registered.

 Results



The initial results yielded 44 references using an English-only filter. After careful title and abstract studying to ascertain relevance, only double-blind RCTs about in vivo use of n-HA toothpastes were retained as RCTs are regarded as the “gold standard” for curative effect evaluation of new treatments.[14] Holland et al. in their guidelines for the design and conduct of clinical trials on DH agreed on RCTs as a benchmark for future testing.[15]

The remaining seven papers all achieved robust quality based on the modified Jadad rating system and were thus all retained [Table 2]. Due to the variations in active agents, chemical formulations, observation period, and negative and positive control groups, there was insufficient ground to conduct a meta-analysis. The currently available evidence for the efficacy of n-HA as a desensitizing agent has been, of necessity, gathered as a narrative review.{Table 2}

Orsini et al. carried out a randomized double-blind controlled trial comparing an in-home new treatment of zinc carbonate nano-HA toothpaste (BioRepair® Plus, Coswell S. p. A., Funo, Bologna, Italy) to an active control group using potassium nitrate sodium fluoride (Sensodyne ProNamel™, GlaxoSmithKline Consumer Healthcare, Brentford, UK). Subjects were visited at baseline, after 4 weeks, and after 8 weeks. Significant improvement was noticed from all tests (air blast, tactile, cold water, and subjective) in both groups, thus comforting the potential of the newest dentifrice formulation. The latter even showed significantly better benefits in air blast and subjective tests. Between baseline and week 8, the air blast test score had a mean percentage reduction of 46.0% on average in experimental subjects versus 29.4% in controls, and there was a 47.5% decrease in the subjective score in the experimental group, versus a 28.1% mean reduction among controls (all P < 0.01).

To investigate short-term effects, Orsini et al. tested the same toothpaste (zinc carbonate n-HA, BioRepair® Plus) against 8% arginine monofluorophosphate toothpaste (Colgate Sensitive Pro-Relief, Colgate-Palmolive, New York, NY, USA) and 8% strontium acetate sodium fluoride (Sensodyne Rapid Relief, GlaxoSmithKline Consumer Healthcare, Brentford, UK) for a duration of 3 days. Even after a follow-up as short as this, all dentifrices induced an improvement in DH scores, with a higher response rate for cold water stimuli in the n-HA group (96%) than the arginine group (79.3%) although it was ruled of borderline significance. The response rates in the subjective test were significantly more frequent in n-HA and arginine groups than the strontium group. However, at 8 weeks, the three dentifrices did not show any significant difference in any score.

Vano et al. performed a randomized double-blind study to evaluate a 15% fluoride-free n-HA toothpaste against a fluoride toothpaste (positive control group) and a placebo toothpaste (negative control group). Results were collected at baseline, 2 weeks, and then 4 weeks. For all tests (cold air sensitivity, tactile sensitivity, and subjective evaluation), significantly lower values were recorded for the experimental group compared to the positive and negative control groups. No statistical difference was noted between the two control groups.

Gopinath et al. evaluated the effect of a n-HA dentifrice (Aclaim™, Group Pharmaceuticals, Bangalore, India) by means of a double-blind RCT involving a widely used benchmark 5% calcium sodium phosphosilicate toothpaste (Novamin® Shy-NM™, Group Pharmaceuticals, Bangalore, India). There was a statistically significant reduction of sensitivity in both groups from baseline to 4 weeks. However, no superiority in efficacy could be observed between the two products, suggesting n-HA is as effective as Novamin.

Wang et al. conducted the longest clinical trial in the selected studies. For duration of 3 months, they evaluated the hypersensitivity management of n-HA pastes. Wang et al. raised the threshold of sensitivity in inclusion criteria, selecting a minimal hypersensitivity of 4 on the visual analog scale (VAS). Four groups were formed:

In-office desensibilize nano-P paste (20% HA potassium nitrate and NaF, 9000 ppm F; desensibilize nano-P, FGM Dentscare, Joinville, Brazil)Desensibilize nano-P, associated with home care paste with 10% HA, potassium nitrate, and NaF, 900 ppm F (experimental home care paste, FGM Dentscare)Pro-Relief professional paste with 8% arginine (Pro-Relief Colgate, Sao Bernardo do Campo, Brazil), associated with home care toothpaste with 8% arginine and sodium monofluorophosphate, 1450 ppm F (Pro-Relief, Colgate)Duraphat professional varnish (NaF varnish, 22.600 ppm F) (Duraphat, Colgate).

Professional treatment was applied over a 3-week period and the home care one over a 3-month period. Data were collected at baseline, 1 month, and 3 months, through a VAS evaluation of air blast stimulation. All treatments proved effective (>3.0 in VAS difference), and they obtained no statistically significant differences among them at 1 month and at 3 months. This study showed an important contribution of dental chair n-HA treatment, as it was able to offer good results in three appointments with no need for home compliance for a duration of 3 months.

A clinical trial performed by Anand et al. evaluated the capacity of hypersensitivity management of n-HA (Aclaim™)- and arginine (Colgate Sensitive Pro-Relief)-based toothpastes. Patients were selected based on a VAS score higher than 2 and then randomized into two groups. The assessment consisted in measuring an electrical stimulus capable of eliciting a VAS score of 2, then comparing these values before and after treatment. Measurements were taken after 5 min, 1 week, and 4 weeks. Both pastes proved to be efficient in managing DH with the mention that the amperage value required to produce a VAS score of 2 for n-HA-based dentifrice was higher than the one for arginine-containing toothpaste, although the difference was judged not statistically significant.

Vano et al. in 2017 redid the same experiment from 2014, under the same conditions but with a lower concentration of n-HA (2%), and found the same results previously reported.

None of the studies have reported any adverse effects as per the Grossman requirements for an ideal dentin-desensitizing agent.[23]

 Discussion



DH is a complex condition, be it in terms of diagnosis or treatment. It was once described as “an enigma being often encountered yet poorly understood.”[24] It has been established that it has a negative influence on oral health-related quality of life, as the parameter of pain takes central stage throughout the management of this condition.[25]

One of the major challenges encountered when conducting this review was the large heterogeneity among the included studies in terms of eligibility criteria, sample size, follow-up period, concentration of n-HA, methodology of pain assessment, and use of control groups. It may be argued that a comparison of studies is thus futile. However, the rationale behind this review is to determine if n-HA delivers on its promise of reduction of DH, as claimed by various toothpaste manufacturers. We will therefore be discussing these claims in light of these variables.

When it comes to RCTs in dentistry, their quality has only been assessed in a few disciplines and it has so far been variable.[26] Moreover, the use of a control group has been controversial in clinical trials, with the inclusion of a placebo group (negative control) sometimes regarded as unethical, as mentioned by Orsini et al. and Wang et al.[17],[20] In DH trials, a negative control group is most often defined as toothpaste that does not contain the active ingredient object of the study. This might often be vague, as even fluoride toothpaste can have a certain effect on pain relief.[27] In studies where equivalence or superiority claims are anticipated, a formulation that has already proved effective might be used as an additional positive control group, as advanced by the majority of the studies in this review.[16],[17],[19],[20],[21]

In daily life, a patient is susceptible to all kinds of painful stimulation. Hence, clinically, combined measurements of tacticle, cold and airblast stimuli are all advisable. However, airblast stimuli remain the more reliable because they involve a wider area of dentin and are generally the most commonly used in clinical trials.[28]

Vano et al. tested different toothpaste concentrations of n-HA (15% and 2%) and found the same results, which is a statistically significant decrease in cold air sensitivity between the n-HA toothpaste group and the negative and positive groups. This statistical significance could be due to the nature of the control group in both studies, as they used lowly concentrated fluoride toothpaste (0.15%) as a positive control group, which might be too low to induce any desensitizing effect. However, in their second study, Vano et al. showed that even a concentration of n-HA as low as 2% can still provide a significant reduction of DH through both progressive closure of tubular openings and a remineralization effect.

Except for both Vano et al. studies that used fluoride and placebo toothpastes, all the other studies compared the effect of the newer n-HA dentifrices to commercially available desensitizing toothpaste formulations.

The most compared chemical agent by authors to n-HA was arginine associated with calcium carbonate (Colgate Pro-Relief, three studies). In fact, this combination has been introduced in 2002 and its efficacy in occluding dentinal tubules supported by in vitro[29],[30] and clinical studies.[31],[32] Comparing n-HA toothpaste to arginine should give an idea about the former's measure of efficacy. Anand et al. found that the n-HA group showed a consistently higher reduction of DH at each appointment, accumulating at 85% less DH versus 79% less for the arginine group. Orsini et al. found similar efficacy in a span as short as 3 days, for both n-HA and arginine groups. The Wang et al.'s study raised the threshold of sensitivity and still obtained comparable results for the experimental nano-HA group and the arginine one; even finding out that three in-office applications of n-HA paste were enough to achieve good control of DH for 3 months.

Gopinath et al. compared the efficacy of n-HA with another established toothpaste, Novamin® (calcium sodium phosphosilicate), and found no significant difference. The Novamin technology was introduced in 2004 and is reliant on an aqueous environment provoking the deposition of calcium sodium phosphosilicate particles onto the surface of the dentin, thus mechanically blocking the tubules.[33] Amaechi et al. evidenced these results in situ, as they found equal effectiveness in occluding dentinal tubules between n-HA toothpaste and a Novamin®-containing toothpaste.[34] Amaechi et al. in a recent study compared four groups of toothpastes (10% n-HA, 15% n-HA, 10% n-HA with potassium nitrate, and finally, Novamin). While all tested toothpastes gave way to similar DH reduction for all sensitive stimuli, it was suggested that a 15% concentration yielded better results in cold air and evaporative stimuli than 10%. Adjunction of potassium nitrate, known for targeting nerve receptors, to the 10% formulation slightly enhanced its efficacy.[35]

Orsini et al. in their two studies used a formulation presenting a zinc substitution of carbonate hydroxyapatite (CHA). Zinc has been reported to reduce the demineralization of enamel and dentin and inhibit dentin collagen degradation, plaque growth, and biofilm formation, which might offer an additional advantage in nano-HA toothpaste formulations.[36]

However, since pain studies usually carry a very powerful placebo effect, it is important to confront their results with in vitro examinations of the products.[37]

Through scanning electron microscope (SEM) study, Shetty et al. compared a fluoride dentifrice to an n-HA-containing paste and found the latter superior in terms of surface remineralization and formation of biomimetic apatite coating on the enamel and dentin surface.[38] Similarly, Kulal et al. compared n-HA paste to Novamin and arginine dentifrices, and while all three desensitizing agents were able to achieve dentinal occlusion, the n-HA group had the highest percentage of closed tubules (98.1%).[39] Bologa et al., Tschoppe et al., and Pei et al. all compared different brands of n-HA dentifrices with different concentrations and concluded through SEM images that all of them had similar capacities of tubule closure by mineral deposition.[40],[41],[42]

The concentration of n-HA was not standardized between studies (it ranged from 1% to 30%); it was also not disclosed in two studies.[16],[19] While all reported a measure of efficacy, Shetty et al. and Amaechi et al. suggested that higher concentrations of n-HA enhanced better penetration of the particles in the tubules.[35],[38]

In-office use of n-HA was only reported by one study,[20] which substantiated previous results by Shetty et al. The latter found that most patients obtained relief within the first or second appointment, with SEM study corroborating these results in showing effective tubule occlusion.[38]

The follow-up period showed variability between studies, from 3 days to 3 months. The nature of toothpaste as a daily treatment might explain studying short periods of time, as proving an immediate pain relief effect is also an objective. Again, there is no standard due to the different mode of action of each agent, and n-HA produced a relief of pain in both instances, immediate and cumulative for up to 3 months. Due to the low number of studies that might not be representative, a longer follow-up period might be needed to study potential effects in case of sensitivity resistance.

Pain studies in general, and by inclusion DH studies, have always been plagued by a high value of heterogeneity from selection to diagnosis and treatment. To give a measure of control to this heterogeneity, a meta-analysis search including n-HA as a desensitizing toothpaste agent was conducted in PubMed. The search only returned three relevant results. Hu et al. in 2018 analyzed 53 RCTs and concluded that nano-HA is effective in reducing DH compared to negative groups.[43] Hu et al. in 2019 included 30 RCTs and, while citing sample limitation, selection bias, and the need for placebo groups, concluded that nano-HA toothpaste might be the best desensitizing compound, followed by arginine.[44] To the best of our knowledge, only de Melo Alencar et al. conducted a meta-analysis with strictly n-HA RCTs. While acknowledging that their results stemmed from a low number of studies (only 6), they still concluded that the n-HA-containing treatment showed greater DH relief when compared to other desensitizing agents, placebo, or negative control.[45] These conclusions support the results of our review regarding the efficacy of n-HA in treating DH, even though the limited number of studies is a common denominator. This could be due to the relatively new mainstream introduction of n-HA as it was once considered too expensive and very few daily use products were patented.[46]

Finally, our study has some limitations that should be discussed. First, because the search was limited to the English language across only one literature database, selection bias might have occurred. Second, the small number of studies and limited population samples might be insufficient to draw definitive conclusions. An increase in subjects would allow the elimination of variance tied to the nonreproducibility of pain recording methods. Third, the nonstandardization of RCT protocols and scarcity of placebo groups might increase the risk of heterogeneity.

 Conclusion



The evidence behind n-HA as a desensitizing agent is very promising both in situ and in vivo. In the face of multiple heterogeneity issues in pain research, no conclusion of superiority of n-HA can be ascertained when compared to other desensitizing molecules. Clinically, the therapeutic choice for DH is the responsibility of the dentists, and they should always strive to offer the best noninvasive treatment available to their patients while taking into consideration that toothpastes remain the most practical and low cost. Therefore, n-HA remains an effective desensitizing agent to consider as a therapeutic option in everyday practice. In future, RCTs of standardized design with larger samples are required to allow for more conclusive data analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Liu XX, Tenenbaum HC, Wilder RS, Quock R, Hewlett ER, Ren YF. Pathogenesis, diagnosis and management of dentin hypersensitivity: An evidence-based overview for dental practitioners. BMC Oral Health 2020;20:220.
2Saini N, Mathur S, Saini V, Kapoor A, Vijay S, Gurjar S. Effect of commercially available nano-hydroxy apatite containing desensitizing mouthwash on dentinal tubular occlusion: An in vitro FESEM analysis. Med Pharm Rep 2020;93:396-404.
3Brännström M. A hydrodynamic mechanism in the transmission of pain-produced stimuli through the dentine. In: Anderson DJ, editor. Sensory Mechanisms in Dentine. Pergamon: Oxford; 1963. p. 73-9.
4Bahşi E, Dalli M, Uzgur R, Turkal M, Hamidi MM, Colak H. An analysis of the aetiology, prevalence and clinical features of dentine hypersensitivity in a general dental population. Eur Rev Med Pharmacol Sci 2012;16:1107-16.
5Clark D, Levin L. Non-surgical management of tooth hypersensitivity. Int Dent J 2016;66:249-56.
6Balhuc S, Campian R, Labunet A, Negucioiu M, Buduru S, Kui A. Dental applications of systems based on hydroxyapatite nanoparticle: An evidence-based update. Crystals 2021;11:674.
7Amaechi BT, AbdulAzees PA, Alshareif DO, Shehata MA, Lima PP, Abdollahi A, et al. Comparative efficacy of a hydroxyapatite and a fluoride toothpaste for prevention and remineralization of dental caries in children. BDJ Open 2019;5:18.
8Hannig M, Hannig C. Nanotechnology and its role in caries therapy. Adv Dent Res 2012;24:53-7.
9Kawamata H, Ohta K, Saito T, Hayman R. Investigation of dentinal surface coating by nano-hydroxyapatite. J Dent Res 2010;89:2988.
10Ohta K, Kawamata H, Ishizaki T, Hayman R. Occlusion of dentinal tubules by nano-hydroxyapatite. J Dent Res 2007;86 (Sp Is A):(Abstr 1759).
11Kensche A, Holder C, Basche S, Tahan N, Hannig C, Hannig M. Efficacy of a mouthrinse based on hydroxyapatite to reduce initial bacterial colonisation in situ. Arch Oral Biol 2017;80:18-26.
12Najibfard K, Ramalingam K, Chedjieu I, Amaechi BT. Remineralization of early caries by a nano-hydroxyapatite dentifrice. J Clin Dent 2011;22:139-43.
13Bordea IR, Candrea S, Alexescu GT, Bran S, Băciuț M, Băciuț G, et al. Nano-hydroxyapatite use in dentistry: A systematic review. Drug Metab Rev 2020;52:319-32.
14Ovosi JO, Ibrahim MS, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Ann Afr Med 2017;16:97-100.
15Holland GR, Narhi MN, Addy M, Gangarosa L, Orchardson R. Guidelines for the design and conduct of clinical trials on dentine hypersensitivity. J Clin Periodontol 1997;24:808-13.
16Orsini G, Procaccini M, Manzoli L, Giuliodori F, Lorenzini A, Putignano A. A double-blind randomized-controlled trial comparing the desensitizing efficacy of a new dentifrice containing carbonate/hydroxyapatite nanocrystals and a sodium fluoride/potassium nitrate dentifrice. J Clin Periodontol 2010;37:510-7.
17Orsini G, Procaccini M, Manzoli L, Sparabombe S, Tiriduzzi P, Bambini F, et al. A 3-day randomized clinical trial to investigate the desensitizing properties of three dentifrices. J Periodontol 2013;84:e65-73.
18Vano M, Derchi G, Barone A, Covani U. Effectiveness of nano-hydroxyapatite toothpaste in reducing dentin hypersensitivity: A double-blind randomized controlled trial. Quintessence Int 2014;45:703-11.
19Gopinath NM, John J, Nagappan N, Prabhu S, Kumar ES. Evaluation of dentifrice containing nano-hydroxyapatite for dentinal hypersensitivity: A randomized controlled trial. J Int Oral Health 2015;7:118-22.
20Wang L, Magalhães AC, Francisconi-Dos-Rios LF, Calabria MP, Araújo D, Buzalaf M, et al. Treatment of dentin hypersensitivity using nanohydroxyapatite pastes: A randomized three-month clinical trial. Oper Dent 2016;41:E93-101.
21Anand S, Rejula F, Sam JV, Christaline R, Nair MG, Dinakaran S. Comparative evaluation of effect of nano-hydroxyapatite and 8% arginine containing toothpastes in managing dentin hypersensitivity: Double blind randomized clinical trial. Acta Medica (Hradec Kralove) 2017;60:114-9.
22Vano M, Derchi G, Barone A, Pinna R, Usai P, Covani U. Reducing dentine hypersensitivity with nano-hydroxyapatite toothpaste: A double-blind randomized controlled trial. Clin Oral Investig 2018;22:313-20.
23Grossman L. A systematic method for the treatment of hypersensitive dentine. J Am Dent Assoc 1935;22:592-602.
24Dababneh RH, Khouri AT, Addy M. Dentine hypersensitivity-An enigma? A review of terminology, mechanisms, aetiology and management. Br Dent J 1999;187:606-11.
25Soares AR, Chalub LL, Barbosa RS, Campos DE, Moreira AN, Ferreira RC. Prevalence and severity of non-carious cervical lesions and dentin hypersensitivity: Association with oral-health related quality of life among Brazilian adults. Heliyon 2021;7:e06492.
26Cioffi I, Farella M. Quality of randomised controlled trials in dentistry. Int Dent J 2011;61:37-42.
27Corneli R, Kolakemar A, Damda A, Naik R. An in vitro evaluation of dentinal tubule occlusion using three desensitizing methods: A scanning electron microscopic study. J Conserv Dent 2020;23:86-90.
28Lin PY, Cheng YW, Chu CY, Chien KL, Lin CP, Tu YK. In-office treatment for dentin hypersensitivity: A systematic review and network meta-analysis. J Clin Periodontol 2013;40:53-64.
29Yuan P, Lu W, Xu H, Yang J, Liu C, Xu P. In vitro dentin tubule occlusion by an arginine-containing dentifrice. Am J Dent 2019;32:133-7.
30Midha V, Midha V, Kochhar AS, Kochhar GK, Bhasin R, Dadlani H. Evaluating the efficacy of desensitizing dentifrices on dentinal hypersensitivity management: A scanning electron microscopic analysis. J Indian Soc Periodontol 2021;25:283-7.
31Ongphichetmetha N, Lertpimonchai A, Champaiboon C. Bioactive glass and arginine dentifrices immediately relieved dentine hypersensitivity following non-surgical periodontal therapy: A randomized controlled trial. J Periodontol 2021. [Epub ahead of print].
32Hirsiger C, Schmidlin PR, Michaelis M, Hirsch C, Attin T, Heumann C, et al. Efficacy of 8% arginine on dentin hypersensitivity: A multicenter clinical trial in 273 patients over 24 weeks. J Dent 2019;83:1-6.
33Khijmatgar S, Reddy U, John S, Badavannavar AN, D Souza T. Is there evidence for Novamin application in remineralization? A systematic review. J Oral Biol Craniofac Res 2020;10:87-92.
34Amaechi BT, Mathews SM, Ramalingam K, Mensinkai PK. Evaluation of nanohydroxyapatite-containing toothpaste for occluding dentin tubules. Am J Dent 2015;28:33-9.
35Amaechi BT, Lemke KC, Saha S, Luong MN, Gelfond J. Clinical efficacy of nanohydroxyapatite-containing toothpaste at relieving dentin hypersensitivity: An 8 weeks randomized control trial. BDJ Open 2021;7:23.
36Saad A, Nikaido T, Abdou A, Matin K, Burrow MF, Tagami J. Inhibitory effect of zinc-containing desensitizer on bacterial biofilm formation and root dentin demineralization. Dent Mater J 2019;38:940-6.
37Vase L, Wartolowska K. Pain, placebo, and test of treatment efficacy: A narrative review. Br J Anaesth 2019;123:e254-62.
38Shetty S, Kohad R, Yeltiwar R. Hydroxyapatite as an in-office agent for tooth hypersensitivity: A clinical and scanning electron microscopic study. J Periodontol 2010;81:1781-9.
39Kulal R, Jayanti I, Sambashivaiah S, Bilchodmath S. An in-vitro comparison of nano hydroxyapatite, novamin and proargin desensitizing toothpastes – A SEM study. J Clin Diagn Res 2016;10:C51-4.
40Bologa E, Stoleriu S, Iovan G, Ghiorghe CA, Nica I, Andrian S, et al. Effects of dentifrices containing nanohydroxyapatite on dentinal tubule occlusion – A scanning electron microscopy and EDX study. Appl Sci 2020;10:6513.
41Tschoppe P, Zandim DL, Martus P, Kielbassa AM. Enamel and dentine remineralization by nano-hydroxyapatite toothpastes. J Dent 2011;39:430-7.
42Pei D, Meng Y, Li Y, Liu J, Lu Y. Influence of nano-hydroxyapatite containing desensitizing toothpastes on the sealing ability of dentinal tubules and bonding performance of self-etch adhesives. J Mech Behav Biomed Mater 2019;91:38-44.
43Hu ML, Zheng G, Zhang YD, Yan X, Li XC, Lin H. Effect of desensitizing toothpastes on dentine hypersensitivity: A systematic review and meta-analysis. J Dent 2018;75:12-21.
44Hu ML, Zheng G, Lin H, Yang M, Zhang YD, Han JM. Network meta-analysis on the effect of desensitizing toothpastes on dentine hypersensitivity. J Dent 2019;88:103170.
45de Melo Alencar C, de Paula BL, Guanipa Ortiz MI, Baraúna Magno M, Martins Silva C, Cople Maia L. Clinical efficacy of nano-hydroxyapatite in dentin hypersensitivity: A systematic review and meta-analysis. J Dent 2019;82:11-21.
46Roveri N, Foresti E, Lelli M, Lesci IG. Recent advancements in preventing teeth health hazard: The daily use of hydroxyapatite instead of fluoride. Recent Pat Biomed 2009;2:197-215.