Formulations of desensitizing toothpastes for dentin hypersensitivity: a scoping review

Abstract Objective: This study aimed to review evidence from randomized controlled trials (RCTs) to describe: 1) the active ingredients and desensitizing toothpaste brands; 2) the evaluation of these active ingredients over time, and 3) the fluoride and abrasive content in the formulations designed to treat dentin hypersensitivity (DH). Methodology: In total, 138 RCTs and their tested toothpastes were included. Searches were updated up to August 19, 2021. Formulations, reported brands, active ingredients over time, and type of fluoride (ionizable or ionic fluoride) and abrasive (calcium or silica-based) were analyzed (PROSPERO #CRD42018086815). Results: Our trials assessed 368 toothpaste formulations, including 34 placebo (9%), 98 control toothpastes with fluoride (27%), and 236 (64%) with active ingredients to treat DH. We tested the following active ingredients: potassium compounds (n=68, 19%), calcium sodium phosphosilicate (CSP) (n=37, 10%), strontium compounds (n=28, 8%), arginine (n=29, 8%), stannous fluoride (SnF2) (n=21, 6%), hydroxyapatite (n=9, 2%), potassium combined with another active ingredient (n=19, 5%), inorganic salt compounds (n=11, 3%), citrate (n=5, 1%), formaldehyde (n=3, 1%), herbal (n=4, 1%), copolymer (n=1, 0.5%), and trichlorophosphate (TCP) (n=1, 0.5%). The number of toothpaste formulations increased since 1968, with the greatest increment after 2010. Most toothpastes described their type of fluoride as sodium monofluorphosphate (MFP) (n=105, 29%) and NaF (n=82, 22%), with silica-based (n=84, 23%) and calcium-based (n=64, 17%) abrasives. Conclusion: Patients and dentists enjoy an increasing number of brands and active ingredients to decide what desensitizing toothpaste to use. The most common types of fluoride are MFP and NaF.


Introduction
Over time, toothpaste brands have added several active ingredients to their products, depending on their purpose: anti-caries, antiplaque, antigingivitis, anti-malodor, antitartar, and whitening agents. 1 Other purposes include, among others, adding more efficacious active ingredients to decrease pain from dentin hypersensitivity (DH). Systematic reviews have compared desensitizing toothpastes to treat DH with varying results. 2-5 A recent systematic review of 125 randomized clinical trials (RCTs), which included a network meta-analysis (NMA) of 90 RCTs, concluded that calcium sodium phosphosilicate (CSP), stannous fluoride (SnF 2 ) and potassium compounds in combination with hydroxyapatite or SnF 2 were the most effective active ingredients against tactile and air stimuli with a high to moderate certainty of evidence. 2 CSP was also effective against cold stimuli. Arginine was effective against air stimuli, and potassium and strontium compounds, for tactile stimuli (with moderate certainty of evidence). The following active ingredients showed from large to small beneficial effects when compared to fluoride with low or very low certainty and, for this reason, were considered ineffective: herbal, hydroxyapatite, inorganic salts, copolymer, and trichlorophosphate (TCP). 2 Over-thecounter fluoride toothpastes were the most common comparator since they serve general purposes.
Our first systematic review evaluated how industry funding influenced desensitizing toothpastes trials, finding that, though the industry funded 58% of them, the funding failed to affect the directionality of results. 6 Our second publication focused on the effectiveness of several active ingredients via an NMA. 2 However, dentists might ask which are the brands and active ingredients available in these formulations. To our knowledge, no scoping review has described the spectrum of formulations and brands of desensitizing toothpastes. Thus, this study aimed to describe the toothpaste formulations reported by 125 included trials. Moreover, we aimed to describe: 1) active ingredients and toothpaste brands; 2) active ingredients evaluated over the years, and 3) the types of fluoride and abrasives in their formulations.

Methodology Protocol and registration
This study is reported according to PRISMA for scoping reviews, 7  Decades were categorized as follows: prior to 1979, 1980-1989, 1990-1999, 2000-2009, and from 2010 onwards. Lastly, the type of fluoride and abrasive was descriptively analyzed. Fluorides were categorized into: 1) ionizable: sodium monofluorphosphate   Arginine is effective in reducing air stimuli, 2 and can transport calcium and phosphate into dentin tubules, forming a protective salivary glycoprotein with calcium and phosphate. 10 Trials have tested much fewer formulations with both these new active ingredients, such as CSP and arginine, than those with potassium and strontium compounds, among the oldest active ingredients in use and with more types, brands, and concentrations available. Strontium compounds were one of the first active ingredients to be introduced in the early 1900s, known to strengthen teeth and to reduce sensitivity, 1 at a time lacking strong available scientific evidence. Trials still study both these active ingredients.
So far, we lack a clear rationale to why some toothpastes are more effective for one stimulus over others, but we can consider a few of them. Each patient may respond differently to different stimuli. Formulations of active ingredients and brands described by trials*

Effectiveness ‡ in reducing pain via a VAS scale (compared to fluoride toothpaste):
Most effective toothpastescompared to fluoride ‡

Calcium sodium phosphosilicate (CSP)
CSP (BioMin-F) 2.5% CSP (Schott UK Ltd. (United Kingdom)) 5% CSP (Sensodyne Repair & Protect, GlaxoSmithKline, GSK). 5% CSP (Shy-NM, Group Pharmaceutics (India)) 5% CSP (Vantej, Dr. Reddy's laboratories (India)) 5% CSP (Group Pharmaceutical Ltd.) 7.5% CSP (Novamin, Novamin Technology, Alachua) 7.5% CSP (Shy-NM Pharmaceuticaus) CSP was highly effective in reducing pain from air stimulus (3.4 VAS points); and moderately for tactile (2.5 points ) and cold stimuli (  Also, air stimuli are the most common outcome used in clinical trials, as it is easily used in dental offices via triple syringes. 16 As confirmed in our previous NMA, trials most often measured air stimuli (85 trials for air stimuli compared to 71 for tactile stimuli and 16 for cold stimuli). 2 Moreover, air stimuli can affect a larger area of the dentin and thereby cause more pain. 16 Conversely, cold stimuli are the most common pain trigger for patients, 10 though they may be more difficult to measure in clinical trials. Tactile stimuli often relies on the use of a Yeaple or Jay probe to apply increasing force to an exposed area of the tooth 17 or a constant manual force to probe the dental surface. 2 We postulate that the first probe method is more accurate than the second, which depends upon the operator's manual pressure. Overall, dentin hypersensitivity is difficult to objectively measure and evaluate since reports of pain are subjective and clinical responses to the stimuli measured in diverse ways could lead to heterogeneity. 18 As expected, all toothpastes had fluoride (except the placebo) since it is important to prevent caries. 19 In general, NaF or SnF 2 were combined with silica-based formulations and we found some SnF 2 toothpastes combined with calcium-based formulations. If ionic fluoride (e.g., NaF) is combined to calcium-based formulations, the free Fion reacts with Ca +2 forming calcium fluoride (CaF 2 ) which is a insoluble fluoride for caries prevention. Also, calcium-based formulations are combined with ionizable fluoride (MFP), although fluoride can hydrolyze and release free Fto form inactive CaF 2 over time. 8,20 However, we observed no Potassium + SnF2 moderately reducted the pain from tactile (VAS 3.5 points) and air stimuli (3.9 points). We found no results for cold stimulus.
Potassium + hydroxyapatite moderately reduced the pain from tactile (2.8 VAS points) and air stimuli (4.2 points). We found no result for cold stimulus.
There is uncertain evidence of effectiveness of reduction of pain for potassium + herbal for cold and air stimuli. We found no results for tactile stimulus.
Least effective toothpastes compared to fluoride ‡ We found uncertain evidence of how effective potassium + strontium are in reducing the pain from tactile and air stimuli. We found no result for cold stimulus.
We found uncertain evidence of its effectiveness against the pain from tactile, cold, and air stimuli.
We found uncertain evidence of its effectiveness against the pain from air stimulus. We found no results for tactile and cold stimuli. We found uncertain evidence of its effectiveness against the pain for tactile, cold and air stimuli.
Herbal herbal (Wheezal dental cream, Wheezal Labs (India)) herbal (HiOra-K Herbal, The Himalaya Drug Company (India)) herbal (Sensodyne, Block Drug Co.) We found uncertain evidence of its effectiveness against the pain from tactile and cold stimuli. We found no results for air stimulus.

Citrate
2% citrate (Protect, JO Butler Co.) We found no results for citrate.

Trichlorophasphate (TCP)
TCP (Clinpro Tooth Creme, 3M) We found uncertain evidence of its effectiveness against the pain for tactile stimulus. We found no results for cold and air stimuli.
* Not all RCTs reported all information (e.g. concentration, manufacturer). ‡ Toothpastes were ordered by effectiveness based on the previous systematic review.2 Pain was measured by Visual Analogue Scale (VAS) that varies from 0 (no pain) to 10 cm (maximum pain) and was reported by patients before and after the follow up treatment. The evidence reported in this table was published in the supplementary material of Martins, et al. 2 (2020) and it is based on the results of the network meta-analysis. The evidence takes into account the type of active ingredient independent of the brand. improper combinations of fluoride with abrasives in the sample of toothpastes analyzed. Based on this information and on our results, we assume that these toothpastes are stable and effective in also preventing dental caries.
We previously described that the most effective toothpastes, compared to fluoride toothpastes (moderate to high certainty of evidence), were: CSP, SnF 2 , and potassium compounds combined with SnF 2 or hydroxyapatite. 2 We found few options for the combined active ingredients, possibly because the trials were testing future combinations. Dental companies funded 58% of trials but industry funding was unrelated to positive results. 6 Many factors likely influence how consumers make choices for or against a toothpaste brand. One study reported that patients choose toothpastes mainly due to the brand name and to their dentists' advice. 21 Advertisement is likely to play a role as well.

Strengths and limitations
This is the first review that used a scoping methodology to describe the active ingredients, formulations, and brands of desensitizing toothpastes.
We found no other study in the literature describing the spectrum of desensitizing toothpaste formulations. This study lacks a chemical lab test to check the reported label formulations. However, as this is a scoping review, we had to rely on authors' information. Also, a high percentage of information was missing, such as concentration values and brand names. Moreover, 30% (n=112) of toothpastes lacked information on the specific type of fluoride used and 58% (n=213) on the particular type of the abrasive used. Only 32% (n=115) of toothpastes fully reported this information.
Due to the missing information, we were unable to perform a more rigorous statistical analysis of the combination of fluorides and abrasives, and to categorize toothpastes according to concentration values. In the future, we strongly suggest that trials report complete formulation breakdowns.

Implications for research and clinical practice
For future research, trials should report the full formulation (active ingredients and concentrations) of fluorides and abrasives. A recent NMA showed that combinations of two active ingredients, such as potassium compounds with hydroxyapatite or SnF 2 , were efficient against DH, though it included too few trials to base this evidence. 2 Thus, more studies testing the combination of the active ingredients of toothpastes may further clarify their effectiveness.
This review provides clinical dentists with a list of the most effective desensitizing toothpastes together with the best available evidence for patients and their dentists to make decisions together. The decision of which toothpaste to use should consider the type of pain patients report, the scientific evidence, the toothpastes available in their jurisdiction and the long-term cost for patients. We acknowledge that desensitizing toothpastes are more expensive than traditional fluoride ones. However, these products are still less expensive than in-office treatments for dentin hypersensitivity and the reported side effects of toothbrushing with them are very rare. 2 In summary, toothbrushing with desensitizing toothpastes offers more benefits than harms for patients with dentin hypersensitivity.

Conclusion
There are increasingly more brands of desensitizing toothpastes on the market. This study categorized the active ingredients in these formulations according to their effectiveness, and MFP and NaF were the most common types of fluoride desensitizing toothpastes .