journal of dentistry 41s (2013) s1–s11

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A new treatment alternative for sensitive teeth:

A desensitizing oral rinse

Kenneth Markowitz *
Department of Oral Biology, New Jersey Dental School, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave,
Newark, NJ 07103, USA

article info abstract

Article history: Objective: Tooth sensitivity is a common, painful dental condition. Consumer dental pro-
Received 29 May 2012 ducts, mostly dentifrices, play an important role in sensitivity treatment. The objective of
Received in revised form this review is to describe a new mouthwash-based desensitizing technology.
21 August 2012 Data: Background literature concerning desensitizing products is reviewed. Potassium salts
Accepted 12 September 2012 are the most commonly used active ingredients in desensitizing dentifrices. Clinical studies
show that while potassium salt dentifrices are generally effective; most formulations
require several weeks to exert their desensitizing effect. Recently, a new desensitizing
Keywords: dentifrice containing the amino acid arginine was introduced. This dentifrice acts to occlude
Tooth sensitivity the dentinal tubules, and has been shown to be highly effective in multiple clinical studies.
Mouthwash This arginine-containing dentifrice has also been shown to provide instant relief of sensi-
Arginine tivity pain when applied directly to the sensitive tooth surface.
Clinical study In contrast to dentifrices, there are few desensitizing mouthwashes available. Building
Dentine on the success of the arginine-based dentifrice, an arginine-based mouthwash formula was
Tubule occlusion developed and tested.
Sources: Published studies in peer-reviewed publications.
Study selection: Controlled and blinded clinical studies to provide evidence of efficacy. In
vitro studies are included to indicate the mechanism of action. This review includes studies
testing the new arginine-based desensitizing mouthwash.
Conclusion: Clinical findings indicate that this new desensitizing mouthwash, based on the
Pro-ArginTM mouthwash technology effectively reduces sensitivity symptoms and can be
used alone or as a adjunct to the use of the arginine-containing dentifrice in the home
treatment of tooth sensitivity.
# 2012 Elsevier Ltd. Open access under CC BY-NC-ND license.

1. Introduction sensitivity were dentifrices that exerted their effectiveness

1.1. Approaches to the treatment of sensitive teeth
Consumer dental products targeting tooth sensitivity consti-
tutes a segment of the oral care market where the application
of biotechnologies promise innovation and the opportunity for
growth.1 In the past, most consumer products for tooth
following multiple weeks of twice-daily use.2 Although some
clinical studies have examined the effectiveness of desensi-
tizing mouthwashes, the use of desensitizing mouthwashes as
a supplement to dentifrice use has not been thoroughly
evaluated or embraced. Recent advances in the treatment of
sensitivity may allow the dental community to think outside
the toothpaste-box in terms of the way consumers can

* Tel.: +1 973 972 2788; fax: +1 973 972 4500.

E-mail address: markowkj@umdnj.edu.
0300-5712 # 2012 Elsevier Ltd. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.jdent.2012.09.007
S2 journal of dentistry 41s (2013) s1–s11
Fig. 1 – Clinical images of sensitive canine and premolar
teeth. Areas of gingival recession and cervical tooth
structure loss can be subtle (A) or extensive (B).
successfully use desensitizing products. As will be reviewed in
this paper, the introduction of efficacious new actives has
allowed investigators to consider alternative methods of
applying desensitizing agents and a reassessment of the
desensitizing mouthwash concept.
The teeth are richly innervated structures.3 In healthy
intact teeth, intense cold can activate these nerves resulting in
a sensation of sharp pain. When dentine is exposed the teeth
can become markedly more sensitive to normally innocuous
stimuli such as air currents, temperature changes and probing
with a sharp instrument (Fig. 1).4 Although preventable to a
degree, gingival recession and tooth wear, conditions that
predispose teeth to becoming sensitive, are almost inevitable
consequences of keeping our teeth throughout our increasing
life span. This is particularly true since aggressive oral hygiene
practices and healthy diets rich in acidic fruits accelerate tooth
structure loss.5,6 Dental cleanings and periodontal procedures
can also result in dentine exposure and can leave teeth
sensitive.5 In light of these facts it is no wonder that tooth
sensitivity is a common problem.
Unlike enamel, dentine is a permeable tissue traversed by
fluid-filled dentinal tubules.7 Nerve fibres are not found in the
superficial parts of the dentine but are restricted to the deep
areas of the tubules and superficial pulp tissue.8 When stimuli
activate these nerve fibres a sensation of pain may be
experienced. Peroxides used in tooth whitening diffuse
through the enamel and dentine, activating nerve fibres
resulting in the characteristic ‘‘zinger’’ pain described as
accompanying whitening treatments.9
Air blasts and controlled tactile stimulation applied with a
sharp probe are two methods used to evoke pain in clinical trials
examining the efficacy of tooth sensitivity treatments. When
applied to intact teeth, little discomfort results from either of
these two stimuli. In contrast, these same two stimuli often
evoke pain when they are applied to teeth with exposed
dentine. When air blasts are applied to exposed dentine
evaporation of dentine fluid occurs, causing fluid shifts to
occur in the dentine tubules. These fluid movements mechani-
cally activate nerve endings located in deeper areas.10 Probing
dentine with a sharp instrument indents the surface slightly.
When the probe tip is moved, the dentine surface rebounds
causing a localized outward fluid shift in the tubules.11,12
Although the intradental nerves appear to respond to these
dentine fluid shifts directly, the odontoblasts may also
respond to dentine stimulation activating the intradental
nerve endings indirectly.13,14 In understanding the aetiology
and potential therapies to treat dentine sensitivity, one
important clue obtained from clinical research is the observa-
tion that not all exposed dentine is sensitive. Nature has
solved the sensitivity problem by evolving several mecha-
nisms where dentine permeability gets reduced by reactionary
dentine formation and the formation of intratubular mineral
deposits.15,16
Based on our understanding of the physiological mecha-
nisms linking dentine stimulation with pain, there are two
ways in which tooth sensitivity treatments can act on
sensitive teeth to reduce sensitivity symptoms (Fig. 2):
(1) Treatments can reduce dentine permeability to the extent
that stimuli such as air blasts and probing do not cause
dentinal fluid shifts that activate the intradental nerves.
This can be accomplished by treatments that deliver
materials such as particulates that occlude the tubules.
Alternatively, agents that interact with the oral environ-
ment to encourage the formation of mineral in the dentinal
tubules can reduce dentine permeability.17 The effect of
prospective tubule-occluding agents on dentine can be
assessed using in vitro studies where dentine permeability
is measured and by studies that examine the impact of
treatments on dentine structure.18,19
(2) Agents in dental products can act to reduce the excitability
of the intradental nerves, making them less likely to
respond to dentinal fluid shifts.20 Potassium salts such as
potassium nitrate, potassium chloride and potassium
citrate are used as theraputic agents in desensitizing
products. In experiments where the responses of intra-
dental nerve fibres are recorded, potassium salts depolar-
ize nerves resulting in transient excitation.21,22 Following
this transient activation the excitability of the nerves
becomes depressed, making the nerves unresponsive to
stimulus. When normally pain evoking stimuli such as air
blasts and tactile stimulation are applied to human
dentine, the pain responses can be reduced by potassium
salt application to the exposed dentine.23 When potassium
salts are applied to dentine in human teeth, the desensi-
tizing effects are transient and modest in magnitude.24
These and other results raise questions concerning the
ability of potassium salts to reduce nerve excitability when
used clinically.25
 journal of dentistry 41s (2013) s1–s11
Fig. 2 – Diagram of a sensitive dentine surface showing
areas of abrasion or erosion that expose the dentinal
tubules. Stimuli such as air blasts directed towards the
dentine surface, induce fluid shifts in the tubules which
activate nerve ending located in the deep dentine and
pulp. The odontoblasts appear to respond to various forms
of pain producing stimuli but it is not clear if they activate
the intradental nerve fibres. Treatments for sensitive teeth
can act by reducing the dentine permeability or by
reducing the excitability of the intradental nerves.
Reprinted with permission from: Markowitz K. Pretty
painful: Why does tooth bleaching hurt? Medical
Hypotheses 2010;74:835–840.
2. Desensitizing dentifrices based upon
arginine and calcium carbonate
2.1. Scope of the technology
To date, the majority of consumer products for tooth
sensitivity are dentifrices containing potassium salts. Howev-
er, other dentifrice-based ingredients such as stannous
fluoride and strontium salts are reported to act by tubule
occlusion.26,27 Several recently introduced desensitizing
agents are designed to encourage the formation of calcium
and phosphate containing mineral on the dentine surface and
inside the tubules.28 The goal of these treatments is to reduce
stimulus-evoked pain and to reverse some of the effects of
mechanical and acid damage on the dentine surface. Ongoing
treatment with agents that occlude the tubules and enhance
the mineral content of the surface would also make the surface
less susceptible to further damage. Many of these products,
such as a varnish containing calcium fluoride,29 deliver
calcium directly; others in addition to releasing calcium,
provide a surface that can encourage mineral formation.30 It
was hypothesized that arginine particularly when combined
with a source of calcium may exert an anti-sensitivity action by
a mineral forming – occlusion mechanism.
Kleinberg and co-workers developed the first generation of
desensitizing products containing an arginine-calcium car-
bonate complex.31 Later, this technology was further devel-
oped and subjected to a series of in vitro and clinical
evaluations by the Colgate-Palmolive Company. Based on
S3
Kleinberg’s initial work, two types of products were developed
around this arginine based desensitizing technology17:
(1) A professional product containing 8% arginine and calcium
carbonate designed for application with a dental prophy-
laxis handpiece. This product was evaluated against a
negative control, for its ability to reduce tooth sensitivity
pain when applied during dental cleanings and to prevent
post-treatment sensitivity.32
(2) Dentifrices containing 8% arginine, calcium carbonate and
1450 parts per million (ppm) fluoride as sodium mono-
fluorophosphate (MFP).33 One variant of this dentifrice was
formulated to provide superior stain removal.34
2.2. Clinical evaluation of the arginine/calcium carbonate
technology as a tooth sensitivity treatment
In conducting clinical evaluations of the efficacy of tooth
sensitivity treatments, it is important to use multiple stimuli
to elicit pain since people with sensitive teeth frequently
complain that their teeth are sensitive to more than one type
of stimulation.35 The clinical studies evaluating this new
arginine-based technology used two methods of eliciting tooth
sensitivity pain, tactile and air blast stimulation. In the case of
tactile stimulation a control force probe was used to determine
the tactile threshold, the lowest force applied where the
subject reported pain.36 For air blasts, the intensity of
the stimulation is kept constant and the examiner rates the
patient’s response to the stimulation using a numerical
scale.37 These sensitivity-pain assessment methods have
been used in many recently published tooth sensitivity clinical
studies.37–39
In tooth sensitivity clinical studies, patients in the negative
control treated group frequently experience improvements in
their symptoms. This ‘‘placebo effect’’ is observed in many
types of clinical studies and pain therapy studies in particu-
lar.40 Several behavioural factors are hypothesized as contrib-
uting to the placebo effect in dental product studies. Patients
who are participating in oral care product trials may brush
their teeth better than they would normally. This is an
example of what is called the ‘‘Hawthorne effect’’ where
subjects will devote more effort to an activity that is being
observed by the study examiners.40 The placebo effect has an
impact on how data from tooth sensitivity trials is interpreted.
In order for a test treatment to be judged to be effective,
subjects treated with it must exhibit tooth sensitivity score
improvements that are better than that of a control by a
margin that is both statistically and clinically significant.35
Two clinical studies evaluated the desensitizing efficacy of
the professionally applied arginine/calcium carbonate con-
taining in-office desensitizing paste.41,42 The control treat-
ment in these studies was a pumice-containing dental
prophylaxis paste. In both of these studies, sensitive teeth
were identified and baseline sensitivity scores measured using
tactile and air blast stimuli. In one study, the test products
were applied to the sensitive teeth before a cleaning procedure
consisting of scaling and dental polishing. Immediately
following this cleaning procedure, the patient’s sensitivity
scores were assessed a second time.41 In a second study, the
test products were applied after the cleaning procedure and
S4 journal of dentistry 41s (2013) s1–s11
the post-treatment sensitivity measurements were conducted
immediately, then following 4 and 12 weeks during which
time the subjects brushed twice daily with a fluoride-
containing dentifrice.42 In both studies when measured
immediately post-treatment, subjects treated with the argi-
nine/calcium carbonate-containing paste exhibited statisti-
cally significantly superior improvements in both pain scores
compared to the pumice placebo-treated subjects. In the one
study where sensitivity was assessed at longer time points the
arginine/calcium carbonate-containing paste also induced
greater pain score reductions at 4 weeks but there was no
statistical difference in sensitivity scores between the treat-
ment groups, measured at 12 weeks. Based on these clinical
results, the arginine/calcium carbonate-containing profes-
sional paste is recommended for use in reducing sensitivity
both during and after professional tooth cleaning.43
Laboratory studies were conducted examining the effect of
simulated tooth cleaning with this professional paste on the
physical properties of commonly used dental restorative
materials. Repeated application cycles were not observed to
increase the surface roughness of these materials. This
experiment indicates that this arginine-containing paste is
safe for dental enamel and restorative materials.44
Dentifrices containing 8% arginine, calcium carbonate, and
1450 ppm fluoride as sodium monofluorophosphate (MFP) were
evaluated for desensitizing efficacy in a series of clinical studies.
In addition to these clinical studies, in vitro studies were
conducted in order to elucidate the ways that this formula could
interact with dentine to exert its desensitizing action. Three 8-
week clinical studies were performed comparing the desensi-
tizing efficacy of the arginine, calcium carbonate, and 1450 ppm
MFP formula to a 2% potassium ion-containing dentifrice (KCl in
two studies, KNO3 in a third study) with fluoride.45–47 In each of
these studies, sensitivity evoked by tactile and air blast
stimulation was assessed following 2, 4 and 8 weeks of twice
daily brushing with the assigned dentifrice. Subjects using the
potassium ion-containing formulas experienced improve-
ments in sensitivity scores at 2, 4 and 8 weeks. Comparison
between the degrees of improvements experience by the two
treatment groups revealed that at these time points, the
subjects using the arginine, calcium carbonate and 1450 ppm
MFP-containing dentifrice had statistically greater pain score
improvements than the subjects using the potassium ion-
containing products.
An 8-week study comparing the desensitizing performance
of the 8% arginine, calcium carbonate, and 1450 ppm MFP-
containing dentifrice, a second high cleaning variant of this
dentifrice, and a negative control demonstrated that there was
no significant difference in efficacy of the two arginine,
calcium carbonate-containing formulas. Users of both argi-
nine formulas experienced superior sensitivity relief relative
to negative control users at 2, 4 and 8 weeks.48 A separate
clinical study confirmed that this high cleaning variant
removed significantly more extrinsic stain and reduced the
stained tooth area more than the original formula.49
Taken together these four clinical studies clearly show the
superiority of 8% arginine, calcium carbonate and 1450 ppm
MFP dentifrices to a benchmark 2% potassium ion-containing
dentifrices in treating sensitivity when applied to teeth by
twice daily brushing.
2.3. Instant relief studies
As is typically the case with desensitizing dentifrices, the
results of the twice-daily brushing studies indicated that while
the desensitizing efficacy of the 8% arginine, calcium carbon-
ate, and 1450 ppm MFP-containing products is superior to
dentifrices delivering 2% potassium ion, time was required for
arginine to exert its effect when applied using typical tooth
brushing practices. This is not surprising since even in these
clinical trials where subject compliance was monitored, the
participants brushed their entire dentition for one-minute. In
contrast, during the clinical studies evaluating the desensitiz-
ing efficacy of the professionally applied 8% arginine and
calcium carbonate containing paste, the test materials were
applied with a rubber prophylaxis cup as opposed to a
toothbrush and material was applied to each sensitive tooth
forcefully for a period of time. The increased application time
and force exerted would be expected to result in superior
tubule occlusion resulting from prophylaxis cup application as
compared to application by tooth brushing.
By instructing subjects to perform a focused topical
application of the desensitizing agent to sensitive tooth sites,
the benefits of professional application could possibly be
obtained with home treatment. If this idea was substantiated,
it should be possible to demonstrate some degree of instant
relief in treated subjects. Three clinical trials were conducted
to assess the ability of the 8% arginine, calcium carbonate,
and 1450 ppm MFP-containing dentifrices to provide instant
relief when applied directly for one minute to sensitive tooth
surfaces. In these three studies the tactile and air blast scores
of sensitive teeth, were assessed before then immediately
following one minute of direct finger application of the test
agent to each of the sensitive teeth. The subjects were then
instructed to brush twice daily with their assigned toothpaste
for three days and return to have a final tooth sensitivity score
determination. In two of these trials, the immediate and
three-day efficacy of the 8% arginine, calcium carbonate and
1450 ppm MFP-containing dentifrice was compared to that of
a benchmark fluoride-containing 2% potassium ion deliver-
ing dentifrice (5% KNO3), and also to a MFP-containing
negative control dentifrice.50,51 In the third trial the immedi-
ate and three-day efficacy of the 8% arginine, calcium
carbonate and 1450 ppm MFP-containing dentifrice was
compared to a high cleaning variant of this formula and a
negative control.52
When compared to subjects using the negative control,
subjects using the 8% arginine, calcium carbonate and
1450 ppm MFP dentifrices experienced large, statistically
significant improvements in pain scores immediately follow-
ing product application and further improvements following 3
days of twice daily brushing. In the study comparing two
formula variants no significant difference was observed
between their performances in providing instant relief. In
clear contrast to the efficacy of the 8% arginine, calcium
carbonate and 1450 ppm MFP-containing dentifrices, subjects
using the 5% KNO3-containing dentifrice failed to obtain
immediate relief when their post-application pain scores were
compared to those of subjects using the negative control
dentifrice. Following three days of product use, potassium
product users obtained a low but statistically significant level
 journal of dentistry 41s (2013) s1–s11
of relief on one of the two sensitivity scores in one of the two
clinical trials.51
In a separate study, the effect of application method on
desensitizing efficacy was examined. Either a finger or a cotton
applicator can be used to obtain instant relief with the 8%
arginine, calcium carbonate, and 1450 ppm MFP dentifrice.53
This study indicates that consumers can choose the method of
application that fits their oral hygiene practices.
These results are noteworthy in that they are the first
documentation of the capacity of a direct to the consumer,
home use desensitizing agent; providing clinically significant
immediate relief of sensitivity pain in multiple, peer reviewed
studies. These results also show the value of the 8% arginine/
calcium carbonate technology to be effective in treating tooth
sensitivity when administered in a manner other than by
twice daily brushing.
3. A new desensitizing mouthwash
3.1. Mouthwashes as oral care delivery vehicles
Mouthwashes have a long history of use in dental care as a
means of delivering anti-microbial agents and fluoride.54,55
The experience with antimicrobial use is instructive since it
highlights the potential of mouthwashes to be an adjunct
rather that a replacement for tooth brushing and other
forms of mechanical plaque control.56 Oral rinses expose
the entire oral cavity to the therapeutic agent. In dentifrice
use, exposure of non-dental oral sites to the formulation is
limited. The disadvantage of mouthwashes is the necessity to
deliver lower concentrations of a therapeutic agent than
would normally be delivered with a dentifrice. This is dictated
by safety considerations since if products are inadvertently
swallowed, a greater volume of mouthwash would be
swallowed compared to a dentifrice. This may be balanced
though by the normal consumer behaviour of rinsing follow-
ing tooth brushing and not rinsing after mouthwash use, this
would allow mouthwash ingredients to remain in the oral
cavity following use.
The use of mouthwashes as fluoride delivery agents has
been examined as a means of remineralizing acid damaged
tooth surfaces and protecting tooth surfaces from mineral loss
resulting from dietary acid exposure.57 Tooth structure
fluoride uptake and anti-erosive effects can be improved by
delivering higher concentrations of fluoride.58 Experiments
have also been performed using polymers to enhance the
interaction between tooth surfaces and the fluoride source.59
Experiments utilizing enamel specimens worn in intra-oral
appliances indicate that the use of a regimen consisting of a
fluoride-containing dentifrice together with a fluoride-con-
taining mouthwash can provide greater hardness gains to
acid-softened enamel and better protection against subse-
quent acid damage than the use of a fluoridated dentifrice or
mouthwash alone.58
Few studies have been conducted examining the effective-
ness of desensitizing agents in mouthwash formulations. An
eight-week study compared the desensitizing efficacy of a
mouthwash containing, 2% potassium citrate, fluoride and
cetylpyridinium chloride with a fluoride-containing control
S5
mouthwash. There was no significant difference in the post-
treatment sensitivity scores of the subjects using either
mouthwash.60 Two six-week studies compared the effective-
ness of a fluoridated, 3% KNO3-containing mouthwash and a
fluoride control mouthwash.61,62 In terms of treatment effects
on air blast pain score and tactile threshold, the results of one
study,61 showed that the KNO3-containing mouthwash per-
formed significantly better than the control mouthwash in
improving these sensitivity scores. In the second study,62 the
advantage of using the potassium ion-containing mouthwash
was less clear. Subjects using the KNO3-containing mouth-
wash had significantly lower air blast pain scores at six weeks
but there was no significant difference at two weeks. In this
same study, the tactile scores did not differ significantly
between the two treatment groups at either time point.
Taken together, these studies fail to provide strong or
consistent evidence establishing potassium ion-containing
mouthwashes as being effective in reducing tooth sensitivity
symptoms. Other studies have examined the effectiveness of
low levels of potassium ion (as potassium fluoride) in
combination with other agents.63,64
3.2. Arginine-containing mouthwash
In view of the manifest high efficacy and versatility of the 8%
arginine/calcium carbonate based desensitizing products;
there has been strong interest in developing a companion
mouthwash utilizing arginine as a key ingredient. The three
clinical studies, reported in this special issue, were conducted
examining the desensitizing efficacy of twice daily mouth
rinsing with a product containing the Pro-ArginTM mouthwash
technology. This 0.8% arginine mouthwash also contains the
substantivity-promoting polymer polymethylvinyl ether/
maleic acid (PVM/MA), 0.05% sodium fluoride, pyrophosphates
and mouthwash excipients. In addition to the clinical studies,
two reports also found in this special issue, describe laboratory
studies investigating the actions of this arginine mouthwash
on dentine structure and function. These studies will be
considered in a separate section below along with similar
studies conducted using the 8% arginine/calcium carbonate-
containing products.
The clinical studies examining the sensitivity-reducing
effectiveness of this new mouthwash had several goals:
(1) To establish the efficacy of the mouthwash containing
0.8% arginine, PVM/MA copolymer, pyrophosphates, and
0.05% sodium fluoride compared to a negative control
mouthwash.65
(2) To establish the efficacy of the mouthwash containing
0.8% arginine, PVM/MA copolymer, pyrophosphates, and
0.05% sodium fluoride compared to a commercial mouth-
wash containing potassium nitrate and fluoride and to a
negative control fluoride-containing formulation.66
(3) Since mouthwashes are typically used along with denti-
frices as part of an oral hygiene regimen, to establish the
efficacy of a regimen comprising the 8% arginine, calcium
carbonate, and 1450 ppm MFP dentifrice and the mouth-
wash containing 0.8% arginine, PVM/MA copolymer,
pyrophosphates, and 0.05% sodium fluoride compared to
S6 journal of dentistry 41s (2013) s1–s11
a regimen comprising a potassium nitrate based dentifrice
and mouthwash and to a Negative Control regimen
comprising a non-desensitizing dentifrice and mouth-
wash.67
These studies used the same widely accepted methods of
assessing sensitivity to air blast and tactile stimuli as were
used in the clinical studies establishing the efficacy of the 8%
arginine and calcium carbonate-containing products.
The desensitizing efficacy of a mouthwash containing 0.8%
arginine, PVM/MA copolymer, pyrophosphate and 0.05%
sodium fluoride was compared to a negative control mouth-
wash in a two-cell clinical study. Tactile and air blast
sensitivity assessments were made prior to use and following
2, 4 and 8 weeks of twice daily use of the assigned mouthwash.
For tactile sensitivity, subjects using the mouthwash contain-
ing 0.8% arginine, PVM/MA copolymer, pyrophosphate and
0.05% sodium fluoride had statistically significant 22.1%, 37.1%
and 24.0% improved tactile scores, compared to the negative
control group, at 2, 4 and 8 weeks, respectively. When the air
blast sensitivity scores of the two subject groups were
compared, the subjects using the mouthwash containing
0.8% arginine, PVM/MA copolymer, pyrophosphate and 0.05%
sodium fluoride had scores that were lower than the negative
control group by margins of 14.2%, 24.1% and 24% at 2, 4 and 8
weeks, respectively. This study shows that when compared to
a negative control, the mouthwash containing 0.8% arginine,
PVM/MA copolymer, pyrophosphate and 0.05% sodium fluo-
ride is effective in reducing tooth sensitivity.65
In order to determine if the 0.8% arginine-containing
mouthwash possess superior desensitizing efficacy to a
potassium salt-containing mouthwash a three-cell study
was conducted comparing the desensitizing efficacy of three
mouthwashes:
(1) A mouthwash with 0.8% arginine, PVM/MA copolymer,
pyrophosphates, and 0.05% sodium fluoride.
(2) A commercially available mouthwash containing 2.4%
potassium nitrate and 0.022% sodium fluoride.
(3) A negative control mouthwash containing 0.05% sodium
fluoride.
In this study, sensitivity determinations were made prior to
use (baseline), one-half hour after first use and then following
2, 4 and 6 weeks of twice daily rinsing. When assessed 30-min
after first use none of the mouthwash users experienced
significant reductions in pain scores. By two weeks of use,
significant differences were observed in the sensitivity scores
between subjects in the three experimental groups. At 2
weeks, subjects using the mouthwash containing 0.8%
arginine, PVM/MA copolymer, pyrophosphate and 0.05%
sodium fluoride had tactile scores that were 125.3% improved
compared to the negative control using subjects and 86.3%
improved compared to those measured in the potassium salt
mouthwash users. Both of these tactile score differences were
statistically significant. At 2 weeks there was no significant
difference between the tactile scores of the subjects using the
potassium salt and negative control users. At 2 weeks subjects
using the mouthwash containing 0.8% arginine, PVM/MA
copolymer, pyrophosphate and 0.05% sodium fluoride
experienced air blast scores that were 51.2% lower than those
of the negative control using subjects and 37.6% lower than
those measured in the potassium salt mouthwash-using
group. Both of these air blast pain score differences were
statistically significant. At 2 weeks subjects using the
potassium ion mouthwash had air blast sensitivity scores
that were 21.9% lower than those measured in the negative
control group, a significant difference.
As was the case at two weeks, the data collected on the
fourth week of the study demonstrated that there were large,
significant improvements observed using both measures, in
sensitivity scores experienced by the subjects using the
mouthwash containing 0.8% arginine, PVM/MA copolymer,
pyrophosphate and 0.05% sodium fluoride compared to both
the negative control and potassium salt-using subjects. At 4
weeks there was a significant improvement in air blast (but not
tactile) scores in subjects using the potassium salt mouthwash
compared to the negative control subjects. The 6-weeks
results continued to show higher, significantly better improve-
ments for the subjects using the arginine-containing mouth-
wash. This study shows that the 0.8% arginine-containing
mouthwash containing 0.8% arginine, PVM/MA copolymer,
pyrophosphate and 0.05% sodium fluoride was more effective
in reducing sensitivity than a marketed potassium salt
containing mouthwash.66
In the study where the combined effect of brushing and
mouthwash use was investigated, subjects were assigned to
one of three regimens to be used twice daily:
(1) PRO-ARGINTM Technology regimen – Assigned subjects
brushed with the 8% arginine, calcium carbonate dentifrice
with 1450 ppm fluoride as MFP using a special sensitivity
toothbrush. Following brushing the subjects rinsed with a
mouthwash containing 0.8% arginine, PVM/MA copolymer,
pyrophosphates, and 0.05% sodium fluoride.
(2) Potassium regimen – Assigned subjects brushed with a
marketed 5% KNO3-containing dentifrice with 1450 ppm
sodium fluoride using a sensitivity toothbrush. Following
brushing the subjects were instructed to rinse with a
mouthwash containing 0.51% potassium chloride and
230 ppm fluoride as sodium fluoride.
(3) Negative Control regimen – Assigned subjects brushed with a
1450 ppm fluoride as MFP dentifrice using a soft tooth-
brush. The subjects than rinsed with a mouthwash that did
not contain fluoride, potassium salt or arginine.
Assessments of tactile and air blast sensitivity scores were
made before the subjects started the assigned regimen as well
as after 2, 4 and 8 weeks of regimen adherence.
Following 2 weeks on the PRO-ARGINTM technology
regimen, subjects had tactile sensitivity scores that were
92.5% improved over the scores measured from followers of
the Negative Control regimen and 61.2% improved over the
scores of the subjects using the Potassium regimen. These
differences were statistically significant. At the 4 and 8-week
tactile sensitivity assessments the users of the PRO-ARGINTM
Technology regimen continued to experience significantly
greater improvements in tactile sensitivity than users of the
two other regimens. There was no significant difference in the
sensitivity score improvements obtained by the Potassium
 journal of dentistry 41s (2013) s1–s11
regimen users relative to Negative Control regimen subjects
for tactile scores at any time point in the study.
Following 2 weeks of regimen adherence, subjects using
the PRO-ARGINTM Technology regimen achieved air blast
sensitivity scores that were 44.4% lower than the scores
measured in Negative Control regimen users and 32.4% lower
than the scores obtained from Potassium regimen users.
These air blast pain score differences were statistically
significant. The Potassium regimen users had significantly
(17.8%) lower air blast sensitivity score, compared to Negative
Control users. The air blast pain assessments performed at 4
and 8 weeks continued to significantly favour the PRO-
ARGINTM Technology regimen over the Potassium regimen
and the Potassium regimen over the Negative Control
regimen.
The data from this study was analysed so that the time
course of symptom improvement could be monitored. This
was accomplished using a form of survival analysis called
time-to-improvement (TTI). In this study, the time it took
subjects on the PRO-ARGINTM Technology regimen to reach
50% symptom improvement was faster than the time it
took subjects on the Potassium regimen to reach 50%
improvement.67
These three clinical studies demonstrate that the new
mouthwash containing 0.8% arginine, PVM/MA copolymer,
pyrophosphate and 0.05% sodium fluoride reduces tooth
sensitivity either when used alone or when used as part of a
regimen programme that includes use of the 8% arginine,
calcium carbonate, and 1450 ppm MFP containing dentifrice.
These studies also show that the mouthwash containing 0.8%
arginine, PVM/MA copolymer, pyrophosphate and 0.05%
sodium fluoride performs better than a negative control
mouthwash and better than a commercially available
potassium-based mouthwash. The results of the regimen
study are consistent with previously reported findings,
reviewed above, that demonstrate the superiority of the 8%
arginine, calcium carbonate, and 1450 ppm MFP-containing
dentifrice in improving dentine hypersensitivity compared to
the efficacy of a 2% potassium ion-containing dentifrice. As
expected, use of the potassium ion-based mouthwash alone
and in combination with potassium dentifrice did afford
subjects some improvements in sensitivity scores. Although
most studies indicate that twice daily brushing with a 2%
potassium ion-containing dentifrices induces significant
sensitivity score reduction relative to a negative control,
subjects using the Potassium regimen did not experience
significant tactile score reductions at any of the study’s time
points, relative to negative control. This is not entirely
unexpected since the desensitizing performance of 2%
potassium ion containing dentifrices in tooth sensitivity
clinical trials can be inconsistent.25
3.3. How do arginine-containing products interact with
the tooth dentine to relive sensitivity?
Although clinical studies are the only way to establish the
efficacy of therapeutic agents, laboratory studies have added
critical knowledge to our understanding of tooth sensitivity
and the methods used to treat it. A direct corollary to the
hydrodynamic hypothesis of dentine sensitivity is that agents
S7
that have affinity for dentine and occlude the tubules may be
effective tooth sensitivity treatments.17,28 Various forms of
microscopy can assess the ability of materials to adhere to
dentine and physically lodge in the tubules.68
The potential of the arginine and calcium carbonate-
containing formulas to interact with the dentine surface and
occlude the tubules has been investigated.69,70 Several high-
resolution microscopic methods including scanning electron
microscopy (SEM), confocal laser scanning microscopy (CLSM)
and atomic force microscopy (AFM) were used to study this
effect. CLSM and AFM are noteworthy in that these techniques
are non-destructive and can be used to visualize surface films.
Imaging of dentine surfaces treated with 8% arginine and
calcium carbonate compositions reveals surface coverage and
coverage of the tubule orifices. Examination of treated speci-
mens fractured perpendicular to the surface reveals material
filling the entrances of the tubules. CLSM imaging of the
dentine following treatment with experimental dentifrice
formulations where either the arginine or the calcium
carbonate were removed from the formulation (in the case
of calcium carbonate replaced with another calcium contain-
ing particulate) revealed that both arginine and calcium
carbonate are needed for tubule occlusion. This observation
confirms Kleinberg’s original hypothesis that these agents
form a complex on the tooth surface.31 AFM examination of
untreated dentine reveals fine surface details such as the
banding pattern of dentine collagen fibres. Following treat-
ment with 8% arginine and calcium carbonate compositions,
this banding pattern is covered, as are the tubule orifices.70
The in vitro deposition of material on the dentine surface
can be evaluated by performing an elemental analysis of the
surface. Dentine has a characteristic elemental composition
resulting from its mixed mineral and protein composition.27
Following dentifrice or mouthwash treatment, the elemental
composition of the dentine surface may change; treatments
that lead to mineral formation/deposition may result in the
representation of calcium and phosphate to increase and the
representation of elements typical of proteins such as nitrogen
and carbon to decline. If treatments contain elements that are
not native to dentine such as silica or strontium, these
elements may also be evident in a post-treatment elemental
analysis. Higher resolution elemental mapping techniques
can be used to visualize treatment related deposits inside the
dentinal tubules.27
Significant changes in the elemental composition of the
dentine surface were observed following treatment with 8%
arginine and calcium carbonate compositions. This treatment
resulted in coverage of the dentine protein and addition to the
surface of a calcium and phosphate-containing mineral rich
layer. High-resolution elemental mapping indicates that these
mineral deposits can be observed in the dentinal tubules.70
Being a high-resolution form of light microscopy, CLSM is
frequently used to image the structural localization of
fluorescent compounds. Fluorescein is a fluorescent dye that
binds to the amino groups such as those present in arginine.
Fluorescein does not stain dentine itself (personal observa-
tion). When fluorescein is applied to dentine treated with a 8%
arginine and calcium carbonate formulation, the presence of
fluorescence at the fluorescein wavelength demonstrates the
presence of arginine on the dentine surface.70
S8 journal of dentistry 41s (2013) s1–s11
Being a porous, permeable tooth tissue; the fluid flow
through dentine slices can be measured in the laboratory. This
testing methodology has been used to evaluate several
desensitizing technologies.18 If experimental treatments
occlude the dentinal tubules in vivo, they should be able to
reduce dentine permeability in vitro.71 In addition to having an
impact on dentine surface structure, treatment with 8%
arginine and calcium carbonate formulations leads to a
reduction in dentine fluid flow. Repeated applications increase
the flow reductions observed.70 The results of these dentine
fluid flow and structural analysis studies demonstrate that
arginine/calcium carbonate has an affinity for dentine and can
occlude tubules.
Following the treatment of dentine surfaces with a tubule
occluding desensitizing agent the dentine surface should have
increased resistance to acid. Several experiments using both
microscopy and dentine fluid flow testing have indicated that
the tubule occlusion induced by 8% arginine and calcium
carbonate treatments resists exposure of the dentine to a low
pH cola beverage.70 Other experiments where dentine was
treated with 8% arginine and calcium carbonate-containing
compositions agree with the studies described above in that
that this treatment caused tubule occlusion. The occlusion
was observed to be partially lost following prolonged immer-
sion in a citric acid solution.72,73 This partial acid liability of the
arginine calcium carbonate tubule plug is not unexpected;
since calcium phosphate based mineral substances are acid
soluble. When treating tooth sensitivity, patients should be
advised to reduce the ingestion of acid-rich foods in order to
prevent the recurrence of sensitivity symptoms.74
As reported in this special issue, CLSM and AFM imaging of
dentine treated with the 0.8% arginine and PVM/MA mouth-
wash revealed the presence of material coating the surface
and extending into the tubules. Near infrared spectroscopy
was used to examine untreated and mouthwash treated
dentine specimens for the presence of arginine. Following
treatment the presence of arginine on the dentine surface was
verified.75
The new 0.8% arginine-containing mouthwash does not
contain calcium carbonate, which is a solid but does contain
the film-forming polymer PVM/MA. Dentine fluid flow
experiments demonstrated how in the mouthwash system,
arginine and the PVM/MA polymer work in concert to provide
a degree of tubule occlusion. In contrast to dentine perme-
ability experiments conducted with dentifrices, agents in the
mouthwash experiments were applied to the dentine without
brushing. Application of arginine alone reduced dentine fluid
flow by an average of 11.7%. Application of PVM/MA itself
reduced dentine fluid flow by an average value of 28.7%. When
these two materials were combined the combined treatment
induced a mean flow reduction of 39.5%. In other experiments,
treatment of dentine with the a mouthwash containing 0.8%
arginine, PVM/MA copolymer, pyrophosphates, and 0.05%
sodium fluoride induced significant higher dentine flow
reductions than did treatment with a placebo mouthwash.76
Taken together the results of the laboratory studies reported in
this special issue demonstrate that the 0.8% arginine, PVM/MA
copolymer, pyrophosphates, and 0.05% sodium fluoride
mouthwash is able to interact with the dentine surface
resulting in reduced dentine fluid flow.
The amino acid arginine has several properties that help
explain its effectiveness as a tooth sensitivity treatment.
Firstly, arginine has the capacity to interact directly and
rapidly with the dentine surface. Arginine contains several
nitrogen atoms that can carry positive charges making this
amino acid cationic over the range of physiological pH
values.77 Cationic molecules have a high affinity for dentine,
since dentine has a negative surface charge.78 Cationic agents
can also facilitate the attachment of other materials to the
dentine surface by charge interactions and hydrogen bond-
ing.78 This is the proposed mechanism that explains the
combined effects of arginine with calcium carbonate in
the toothpaste, and of arginine with the polymer PVM/MA
in the mouthwash, each of which promote the formation of
surface structures on dentine that occludes the tubules. Many
of the microscopic and surface analysis studies reviewed
above demonstrate the presence of arginine on dentine
surfaces treated with either the paste or mouthwash for-
mulations. This observation indicates that arginine has an
affinity for dentine and may act to promote the adhesion of
materials to the dentine surface.
4. Conclusion
As the technologies used to treat tooth sensitivity improve,
consumers will have more choices in terms of the types of
products available to them. The arginine technology has lent
itself to three distinct types of professional and consumer
products. In using this technology at home, consumers may
perform twice daily tooth brushing, direct topical application
to the sensitive surface with the same toothpaste, and oral
rinsing with the mouthwash formulation, the latter of which is
discussed in this issue of the Journal of Dentistry.
Conflict of Interest Statement
Preparation of this article was sponsored by the Colgate-
Palmolive Company.
Acknowledgement
Preparation of this article was sponsored by the Colgate-
Palmolive Company.
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