Salivary stimulation and substitution in patients with hyposalivation and xerostomia – Stimulation of saliva
Recognition of the key role of saliva in maintaining normal oral function has stimulated research on its protective properties against caries and on the treatment of xerostomia and salivary hypofunction. Salivary clearance, buffering power, and degree of saturation with respect to tooth mineral are the major protective properties (for review, see Sreebny et al, 1992; Tenuvuo, 1997), their effect increasing with salivary stimulation: The saliva stimulated by consumption of fermentable carbohydrates reduces the fall in plaque pH that could lead to demineralization and
increases the potential for remineralization. When saliva is stimulated after carbohydrate intake, acids produced in the plaque are neutralized, and experimental lesions in enamel are remineralized. The pH-raising effects are more easily explained by the buffering action of stimulated saliva than by clearance of carbohydrates.
Remineralization is dependent on the presence of fluoride.
These findings suggest that the protective properties of saliva can be potentiated by appropriate salivary stimulation. In addition to established procedures, such as diligent oral hygiene and fluoride regimens, general recommendations for caries prevention might therefore include eating patterns that stimulate secretion of saliva. There are now a number of management options for protecting the oral cavity from the devastating effect of inadequate salivary function and for relieving the patient’s discomfort. Treatment is determined by the degree of functional impairment. For the patient who has some remaining glandular function, stimulation of secretion is the optimal approach. Patients with negligible natural function can be offered symptomatic treatment to relieve oral dryness. For either patient category, selection of specific treatment measures is determined by a number of factors, including the patient’s medical status. The practitioner must also be able to manage the complications of salivary hypofunction: increased incidence of caries, oral candidiasis, altered oral function, and pain. Stimulation of secretion, locally or systemically, has the great advantage of providing the benefits of natural saliva.
Systemic. There has been increasing interest in systemic pharmacologic stimulation of salivary function. Three agents have been studied in some detail: bromhexine hydrochloride, anethole trithione, and pilocarpine hydrochloride. All three should be used only under specialist supervision and following medical examination.
Bromhexine is a mucolytic agent used in the management of chronic bronchitis. Its use in managing dryness of the eyes associated with Sjogren’s syndrome is controversial. No beneficial effects on salivary dysfunction have been demonstrated.
Anethole trithione has been proposed as a treatment for salivary hypofunction caused by psychotropic drugs, radiation, and Sjogren’s syndrome. Conflicting results have been reported on the efficiency of treatment. In one study, 74% of patients with Sjogren’s syndrome had increases in the output of unstimulated whole saliva, whereas Swedish studies, on patients with more pronounced salivary dysfunction, have failed to show any improvement in salivary function. Patients with postradiation xerostomia showed no improvement following drug treatment, compared to controls. Further trials are necessary to delimit the ability of this drug to improve salivary function(for review see Pearce, 1991; Edgar et al, 1994).
Pilocarpine hydrocholoride is a parasympathomimetic drug that functions primarily as a muscarinic-cholinergic agonist with mild b-adrenergic stimulatory properties. It has been used for more than 100 years as a potent stimulant of exocrine secretion. In the last decade, carefully controlled studies have shown that it can increase salivary output in normal volunteers and effectively relieve oral dryness in patients with salivary gland hypofunction. In a 6-month trial by Fox et al (1986) in patients with irradiation-induced salivary hypofunction and in patients with Sjogren’s syndrome, 5 mg of pilocarpine, three times a day, was effective; side effects were well tolerated; and there were no significant alterations in heart rate, blood pressure, or electrocardiographic parameters. Greenspan and Daniels (1987) reported that pilocarpine treatment resulted in subjective and objective improvement in about 80% of patients with postradiation xerostomia. A synergistic effect on salivary stimulation from a combination of pilocarpine and anethole trithione was reported by Epstein and Schubert (1987).
Although pilocarpine appears to be the most effective systemic sialagogue currently
available, it is of limited use in the management of salivary hypofunction. It is
ineffective if insufficient functional tissue remains, as in advanced stages of Sjogren’s
syndrome or following head and neck radiotherapy. Possible interactions with other
medications or potential adverse cardiovascular and pulmonary effects further limit
patient eligibility. Further clinical studies are necessary to determine optimal doses,
administration schedules, and systemic effects of pilocarpine. For the patient with an
irreversible condition requiring long-term or lifelong management of dry mouth, a
sustained-acting preparation would be ideal.
Local. Local stimulation is feasible, because the salivary glands are highly responsive
to stimulation from taste, masticatory activity, and the sensory nerves of the mucosa
and periodontium. Because the salivary secretion rate usually increases during meals
(a physiologic response), an important first step to potentiate salivary flow should be a
diet of fiber-rich, well-flavored aromatic food, such as fruit. In addition, finishing a
meal with matured cheese (for instance, cheddar) has been shown to increase SSR and
decrease plaque pH significantly (Imfeld, 1983).
In developed societies, the reduced masticatory activity required to chew highly
processed modern foods may favor a measure of salivary hypofunction, because of
disuse atrophy. Studies in both animals (Johnson and Sreebny, 1982) and humans
(Axelsson et al, 1997a; Dodds et al, 1991; Jenkins and Edgar, 1989) have indicated
that prolonged increases in levels of salivary stimulation after dietary changes result
in greater salivary output. Adequate water intake is another prerequisite for normal
salivation. For optimal prevention and control of dental caries, every meal containing
easily fermented carbohydrates, particularly sucrose, should be followed immediately
by supplementary local salivary stimulation to increase the sugar clearance, buffering
effect, plaque pH, and the access of calcium and phosphate ions. As described earlier,
demineralization is thereby decreased and remineralization is enhanced.
Local saliva-stimulating agents that contain fluoride will further enhance the
remineralization potential significantly and should therefore be recommended in
preference to similar agents without fluoride. Specially formulated lozenges and
chewing gum, both with and without fluoride, are available. Because frequent intake
is recommended (four to six times per day, directly after meals and snacks), it is
important that these agents not contain sugar and not be potentially erosive. The
sweetening agents commonly used in these products are sorbitol, xylitol, and
saccharin, separately or in combination.
Fluoride lozenges containing 0.25, 0.50, 0.75, and 1.00 mg of fluoride are also
commercially available. The 0.25-mg lozenges are recommended for children older
than 5 years and 0.25 to 1.00 mg lozenges are recommended for selected young adults
and adults, particularly in cases of hyposalivation, for combined salivary stimulation
and fluoride delivery directly after meals. A recent study by Sjogren et al (1995)
showed that in subjects with reduced SSR, fluoride lozenges and chewing gum not
only improved the SSR, but also significantly prolonged fluoride clearance time, an
important factor in prevention and control of caries in such patients, who are generally
at high caries risk.
To date, the most promising system for local salivary stimulation is the recently
introduced fluoride chewing gum (Fluorette and Fludent, used widely in Scandinavia).
It is sugarless and sweetened with xylitol and sorbitol. Each piece contains 0.25 mg of
fluoride. Chewing gum is unique because it is usually chewed for a prolonged
period¾around 30 minutes¾but its caloric value is almost negligible, both important
characteristics in the context of salivary stimulation. Chewing gum has been shown to
elicit a continued flow of saliva during prolonged mastication (Dawes and
Macpherson, 1992), but the level of stimulus gradually declines: As the flavoring
agents are released and swallowed, the gustatory stimulatory component is rapidly
depleted, and the intensity of the masticatory stimulus abates, because of softening of
the gum (Rosenhek et al, 1993). The effect of varying not only the duration of
chewing, but also the interval elapsing between the caries challenge (drop in pH) and
the subsequent gum chewing, has been studied. For maximum neutralization of the
plaque pH, the gum must be chewed for at least 15 minutes, immediately following
the caries challenge (Park et al, 1993).
Recently, Sjogren et al (1997) compared the effect of chewing fluoride gum for 5, 10,
15, 20, 30, or 45 minutes on approximal plaque pH and salivary fluoride
concentration on the chewing and nonchewing sides. The subjects had undisturbed
approximal plaque, 3 days old, and rinsed for 1 minute with 10 mL of 10% sucrose
solution. The resultant fluoride concentrations were two to three times higher on the
chewing side than on the nonchewing side (Fig 111). The best recovery in approximal
plaque pH was also noted on the chewing side, but the difference was not as
pronounced as for the salivary fluoride concentration. Significantly higher values of
plaque pH were found during prolonged chewing (Fig 112), while variations in
chewing duration caused only minor variations in salivary fluoride concentration.
This study showed that to attain optimal fluoride- and plaque pH-raising effects
throughout the entire dentition, the gum should be chewed for at least 20 minutes,
using both sides of the mouth.
Studies in patients with low salivary flow rates (Abelson et al, 1990; Markovic et al,
1988) also showed that use of a sorbitol-sweetened gum raised the pH of the plaque
on both enamel and root surfaces.
Two principal mechanisms are implicated in the plaque pH-raising effects of chewing
gum or foods such as cheese: clearance of carbohydrates and buffering of plaque
acids. For chewing gum, the relative contributions of these two factors were studied
by Dawson (1993). After a sucrose mouthrinse, the test subjects chewed sugar-free or
sucrose-sweetened gum; the control subjects did not chew any gum. Over 45 minutes,
SSRs, pH, sugar concentrations, and bicarbonate levels were measured. The results
were compared with plaque pH data noted under similar conditions (Manning and
Edgar, 1993).
Both gums had pH-raising effects on plaque. The sugar-free gum accelerated
clearance of the sucrose rinse, while the sugared gum released sugar, at potentially
acidogenic concentrations, throughout the 45-minute period. The gums had a similar
effect on salivary secretion rates, but the sugared gum resulted in lower levels for
salivary pH and bicarbonate, indicating active participation of salivary bicarbonate in
neutralizing and buffering acids produced in the mouth from the sugars released from
the gum. Thus, the buffering effect was capable of overwhelming the acids formed
from sugars derived from sucrose-sweetened gum.
If the bicarbonate level of saliva is thus paramount in eliciting the pH-raising action of
chewing gum (and, by analogy, other pH-raising foods), then it is important to note
that the relationship between salivary flow rate and bicarbonate concentration is not
linear, but approaches a maximum at an intermediate flow rate. Thus, increasing
salivary flow above this rate would not be expected to result in a comparable increase
in pH-raising action on plaque, contrary to what would be obtained if the major
plaque pH-controlling factor were salivary clearance of sugars or acids. This point
merits further study with various levels of stimulation of saliva and observation of the
effects on plaque pH.
Sugar-free chewing gum containing urea (V6) is available in Europe and Scandinavia,
and is claimed to exert plaque pH-raising effects superior to those of gum without
added urea, presumably because of the increased synthesis of ammonia in plaque
resulting from ureolysis. Recently, Imfeld et al (1995) used the telemetric technique to
compare the effect of chewing xylitol or xylitol-carbamide (urea) gum on approximal
plaque pH after a sucrose rinse. Figure 113 shows the extraordinary effect of the
carbamide-containing gum compared to the xylitol gum and no chewing gum.
Together, these studies offer convincing evidence that, following consumption of
fermentable carbohydrates, the chewing of sugarless gum rapidly elevates plaque pH
toward resting levels, where it persists for the duration of the experiment. In addition
to causing an increase in the buffering power by stimulating saliva, the chewing
increases bicarbonate levels leading to an increase in salivary pH and thus to the
degree of supersaturation of stimulated saliva with respect to calcium phosphate
solids, including hydroxyapatite. The increase in the degree of supersaturation with
calcium and phosphate leads to the conclusion that stimulated saliva can influence the
equilibrium between demineralization and remineralization in the development of
caries, not only by reducing the duration of demineralization resulting from the pH
changes in plaque but also by enhancing the potential for remineralization.
This hypothesis was tested by Leach et al (1989). An intraoral device carrying a piece
of partially demineralized human enamel, covered with gauze to encourage deposition
of plaque, was attached to a mandibular first molar tooth in volunteers. The subjects
used a sorbitol-sweetened chewing gum for 20 minutes after three meals and two
sugary snacks each day. After 3 weeks, the enamel particle was replaced, and the
subjects consumed the same meals and snacks but without using gum. The order (gum
versus no gum) was reversed in half the subjects. The subjects continued to use their
usual fluoride-containing dentifrice thoughout the study.
Analysis of the mineral content of the carieslike lesions after intraoral exposure
showed a significantly greater increase in the mineral content after gum chewing than
was found without gum chewing, indicating a potentially beneficial remineralizing
effect of the stimulated saliva. The increase in remineralization after the use of gum
could have occurred either because of a reduction in the degree of demineralization
via the effect of gum chewing on plaque pH or because of an increase in
remineralizing potential. These results should not be interpreted as indicating that
early white-spot lesions in enamel can necessarily be completely remineralized
through the use of sugar-free gum. Rather, the data indicate the possibility of
favorable alteration of the equilibrium between demineralization and remineralization,
preventing the development of an initial carious lesion.
In such studies of salivary stimulation, the environment in which remineralization of
the enamel lesion occurs is the fluid phase of plaque, which differs from saliva in pH
and concentration of calcium and phosphate ions. While an increase in the
supersaturation of saliva resulting from stimulation would be expected to have a direct
effect on the supersaturation of plaque fluid, to date no such effect has been
demonstrated. Sternberg et al (1992) found, however, that chewing of sorbitol and
xylitol gum, besides reducing plaque accumulation and gingival inflammation,
increased the concentration of acid-extractable calcium in plaque by more than one
third. This would be expected to increase the remineralizing potential of the plaque,
and it was suggested that the effect was due to complexing of calcium by both xylitol
and sorbitol, leading to their retention in plaque. Equally, it may be that the elevation
of plaque pH that would have followed gum chewing resulted in increased retention
of calcium in plaque in the form of insoluble calcium phosphate deposits. Fluoride
chewing gums should increase the reservoir of phosphate and protein-coated CaF2
crystals in the pellicle, as well as in any plaque that might remain.
In the remineralization studies already described, a therapeutic fluoride environment
was provided by the use of a fluoride dentifrice. The essential role of fluoride in the
remineralizing potential of sugared gum was shown in preliminary data. Subjects
chewed sucrose gum for 20 minutes after meals and snacks for successive 21-day
periods, during which the fluoride content of the dentifrice was varied between 0 and
1,000 ppm. In the presence of fluoride, some remineralization was observed, although
it was statistically insignificant; with the nonfluoridated dentifrice, significant
demineralization occurred (Manning and Edgar 1993). In caries-susceptible patients
with impaired salivary secretion, use of the new sugarless fluoride chewing gum
directly after meals is therefore a promising adjunctive measure. Compared to
subjects with normal salivary flow, patients with reduced salivary flow have a
fluoride clearance time that is fortuitously prolonged, as shown in the aforementioned
study by Sjogren et al (1993).
The effect of a fluoride sugar-free chewing gum on stimulated salivary secretion rate,
Plaque Index, Gingival Index, and Plaque Formation Rate Index, as well as on
salivary mutans streptococci scores, was recently evaluated. The selected group of
patients (n = 53) had less than 0.7 mL/min stimulated SSR (mean = 0.4 mL/min). The
subjects were instructed to chew a stick of fluoride chewing gum (0.25 mg of
fluoride) for 15 to 20 minutes after every meal (four to six times per day) for 6
months (Axelsson et al, 1997a).
The results showed an increase in the mean stimulated salivary secretion rate from 0.4
to 0.6 mL/min. This finding is important because it shows that through regular
salivary stimulation with chewing gum after every meal, a gradual increase in salivary
secretion is possible. An average reduction of about 35% was achieved for Plaque
Index, Gingival Index, and Plaque Formation Rate Index (Fig 114). The percentage of
subjects with salivary mutans streptococci scores of 0 to 3 at baseline and after 6
months is shown in Fig 115. There was a pronounced shift from high scores to low; in
particular a decline in score 2 and an increase in score 1 (Axelsson et al, 1997a).
These results indicate that regular use of a fluoride chewing gum after every meal
would have a very significant caries-controlling effect in patients with hyposalivation,
over and above the primary effect of the fluoride release from the chewing gum.
In two recent studies on experimentally induced caries (enamel and root lesions), the
remineralizating effect of fluoride chewing gum (0.1 mg of fluoride) used five times
per day for 21 days was compared with an in situ slow-release fluoride device that
released 0.5 mg of fluoride/day. A nonfluoride toothpaste was used for oral hygiene
three times a day during the test period. The degree of remineralization of enamel
lesions was 35.5% for the chewing gum and 34.0% for the slow-release device (Wang
et al, 1993). On root lesions, De los Santos et al (1994) achieved similar results
(36.0% and 35.8% for the gum and the device, respectively) for remineralization.
However, the chewing gum resulted in higher stimulated SSR than did the fluoridereleasing
device and the control (2.1, 1.8, and 1.7 mL/min, respectively) and higher
mean salivary fluoride concentration during stimulation (3.0, 0.2, and less than 0.02
ppm of fluoride, respectively).
The potential clinical effect of saliva stimulation per se has not been tested in a
clinical trial, although it is possible to interpret results from certain clinical studies as
effects of salivary stimulation. Thus, the caries-preventive effects of
xylitol¾including apparent reversals of carious lesions (remineralization) shown in
the Turku chewing gum trial, when sucrose- or xylitol-sweetened gum was chewed ad
libitum over a 12-month period (Scheinin et al, 1975)¾could be due to the enhanced
remineralizing potential, although inhibition of plaque acidogenicity and other effects
of xylitol cannot be excluded.
More conclusive indications of a beneficial effect of salivary stimulation are disclosed
in studies by Moller and Poulsen (1973) in which chewing of sorbitol gum was
associated with a small but significant reduction in caries incidence; by Isokangas et
al (1989), in which significant long-term benefits of xylitol gum, used two or three
times daily were shown; and by Kandelman and Gagnon (1990), in which a decrease
of 65% in caries progression was found in children who chewed xylitol gum as part of
a preventive program. It should be noted that the study designs did not stipulate
routine postprandial chewing for 20 minutes, which would have maximized the
influence on saliva.
The only direct comparison of xylitol and sorbitol gums appears to be the recently
published 2-year study by Makinen et al (1996), in which South American children
chewed sorbitol or xylitol gum daily. Compared with controls not using any gum, the
observed reduction in caries incidence was greater for xylitol than for sorbitol gum,
while an increase in caries incidence occurred in the children using sucrose gum. The
caries onset risks for xylitol and sorbitol pellet chewing gum were 35% and 44%,
respectively of that in the non-gum group. The effects were greater with pellet gums
than with stick gums and with increasing frequency of gum chewing. Both xylitol and
sorbitol mixtures in pellet form were associated with a caries onset rate comparable
with that of the xylitol stick gum. The largest reduction in caries risk was observed in
the group receiving xylitol pellet gum.
Thus, the protective action of saliva, essential for normal dental health, can be
enhanced by stimulation through appropriate dietary manipulation and selection.
Sugar-free chewing gum may be of particular value in stimulating salivation over a
prolonged period without increasing the energy content or acidogenicity of the diet.
With the use of such gum after meals and snacks, for normal gum-chewing periods of
20 minutes or more, the effects of fluoride in favoring remineralization may be
enhanced, and the benefits of salivary neutralization, buffering, and sugar clearance in
opposing demineralization may be mobilized, as part of a program of prevention
against caries.
The use of gum not only as a salivary stimulant but also as a vehicle for preventive
agents may further extend its potential applications. Recently, a new chewing gum
containing chlorhexidine (10 mg per stick, available in Scandinavia) has shown
significant antiplaque effects (Smith et al, 1996; Tellefsen et al, 1996) comparable to
0.2% chlorhexidine mouthrinse. It seems possible that in the near future a combined
chlorhexidine-fluoride chewing gum will become available. Meanwhile, concurrent
chewing of one stick each of the fluoride and the chlorhexidine chewing gum for 20
minutes directly after every meal could be recommended for high-caries-risk patients
with reduced salivary secretion rate, high or very high Plaque Formation Rate Index
(score 4 or 5) and high salivary mutans streptococci levels. In this way, chemical
plaque control, fluoride, and salivary stimulation will act synergistically at the crucial
time; during the acid attack. In addition, because the stimulatory effect is related to
the volume of the stimulating agent, an even greater effect on salivary stimulation
should be achieved if twice the amount of gum is chewed.
