Download A comparison of salivary substitutes versus a natural sialogogue

A comparison of salivary substitutes versus a natural sialogogue
(citric acid) in patients complaining of dry mouth as an
adverse drug reaction: a clinical, randomized controlled
study
Felice Femiano, MDM, PhD,a Rosario Rullo, MDMDr,a Federica di Spirito, DDSDr,a
Alessandro Lanza, DDS, MScDr,a Vincenzo Maria Festa, DDS, MScDr,a and
Nicola Cirillo, DDS, PhD,b Naples, Italy; and Bristol, United Kingdom
SECOND UNIVERSITY OF MEDICINE AND SURGERY AND UNIVERSITY OF BRISTOL
Objective. We aimed to compare the efficacy of saliva substitutes and citric acid long-term therapy for oral dryness
relief and unstimulated salivary flow in patients reporting drug-induced xerostomia.
Study design. Fifty-four patients reporting drug-induced xerostomia were randomly subdivided into 3 groups and
respectively administered artificial saliva, 3% citric acid, or distilled water in mouthwash 4 times a day for 30 days.
Patients underwent measurement of unstimulated whole saliva before and after they finished therapy and were asked
to note in a daily diary any symptomatologic changes 15 minutes and 1 hour after each daily intake of test solution.
Results. Fifteen minutes after solution intake, 12 patients (67%) belonging to the artificial saliva group, 9 (50%) from
the citric acid group, and 2 (11%) from the water group reported significant symptomatologic improvement. One hour
after solution intake, 7 patients (39%) from the artificial saliva group, 10 (56%) from the citric acid group, and 0 from
the water group noted significant symptomatologic improvement. None of the drugs tested affected unstimulated
whole saliva flow.
Conclusions. Both artificial saliva and citric acid provided immediate relief from oral dryness. Citric acid also
provided a longer-lasting feeling of oral moistness at 1 hour after use owing to its protracted activity on salivary gland
function. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:e15-e20)
The word “xerostomia” is derived from Greek. It comes
from “xeros” (dry) and “stoma” (mouth), and is usually
used to indicate the condition of not having enough saliva
to keep the mouth moist. The term “xerostomia,” however, may properly be used to describe the subjective
sensation of dryness in the mouth reported by patients,
whereas the more accurate term for measurable and objectifiable changes in reduced salivary function is “salivary gland hypofunction” for a reduction in fluid output
and “salivary gland dysfunction” for a more general alteration in physiologic salivary gland function.1-3
This semantic distinction is important, because a feeling of dry mouth is not always accompanied by an objective decrease in the salivary flow. In fact, patients may
occasionally report feelings of oral dryness, similar to a
sticky or doughy sensation, without any objective clinical
reduction being found.4,5 This would indicate that other
a
Department of Stomatology, Second University of Medicine and
Surgery, Naples, Italy.
b
Department of Oral and Dental Science, University of Bristol, Bristol, UK.
Received for publication Dec 25, 2010; returned for revision Jan 22,
2011; accepted for publication Jan 27, 2011.
1079-2104/$ - see front matter
© 2011 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2011.01.039
factors can influence the feeling of moistness in the
mouth. Several short- and long-term conditions can disrupt salivary secretion, leading to hyposalivation. These
include psychologic problems (stress and anxiety), autoimmune disease (Sjögren syndrome), and chemotherapy
or radiotherapy of the head and neck.6-9 The feeling of dry
mouth is the most common oral adverse drug reaction in
the oral cavity. In fact, a large number of medications,
⬎500, list dry mouth as an adverse effect. Relatively few
drugs, however, have been demonstrated to affect salivary
function in controlled clinical studies. This apparent disparity may reflect the subjective sensation of oral dryness
due to qualitative alterations of saliva rather than actual
changes in the salivary flow rate.10-12 The drugs most
commonly reported to induce xerostomia are the tricyclic
antidepressants, antipsychotics, benzodiazepines, atropinics, beta-blockers, antihistaminics, H2-receptor antagonists, diuretics and angiotensin-converting enzyme inhibitors, anti-HIV protease inhibitors, and omeprazole.8,9
Dry mouth treatment requires an etiologic and/or
symptomatic therapy. Etiologic therapy requires causative recognition and management of conditions. In
cases of drug-induced xerostomia, the intake of the
drug causing the sensation of dryness should be interrupted and an alternative medication should be pree15
e16
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July 2011
Femiano et al.
scribed; when that is not possible, the dose should be
reduced.13,14 Alternatively, a symptomatic pharmacologic treatment of xerostomia, based on saliva substitutes (artificial saliva) in mouthwashes or in gel
formulations (containing carboxymethyl cellulose or
hydroxyethyl cellulose), oral moisturizers in sprays or
gels (xylitol, maltitol, sorbitol, mannitol, aspartame,
acesulfame K), and sialogogues (pharmacologic salivary production stimulants) should be considered.15
Which kind of symptomatic pharmacologic therapy
(saliva substitutes, oral moisturizers, or sialogogues) to
use essentially depends on the efficiency of the salivary
gland parenchyma. Therefore, sialogogue prescription
is justified only if functioning salivary tissue is available, whereas moisturizing agents are to be administered, exclusively, in cases of compromised and unresponsive salivary gland parenchyma (e.g., severe cases
of Sjogren syndrome).14
Sialogogue drugs, whether natural or artificial, stimulate the salivary glands by targeting the autonomic
nervous system pathways. Citric acid, a natural sialogogue that stimulates the taste buds through parasympathetic efferent pathways, and pilocarpine, bethanecol,
and cevimeline, which act directly on specific muscarinic cholinergic receptors within the salivary gland
parenchyma, all stimulate abundant saliva secretion.
Muscarinic agonists can be responsible for several systemic side effects, such as sweating, upset stomach,
runny nose, flushes, chills, dizziness, weakness, frequent urination, and perspiration, and are, therefore,
suitable only in the treatment of severe xerostomia (i.e.,
Sjögren syndrome and other serious diseases, chemotherapy, radiation treatment, etc.). In contrast, only
local but preventable side effects have been reported for
citric acid in mouthwash (e.g., erosion of tooth enamel),
which makes it potentially safer than treatment with
muscarinic agonist drugs.12,16-24
The aim of the present study was to compare the
efficacy of saliva substitutes that do not contain citric
acid with that of a solution of 3% citric acid on the
feeling of dry mouth and on unstimulated saliva flow
rates in patients taking drugs with documented negative
influence on salivary flow rate.
MATERIAL AND METHODS
Study design
For this trial, a group of physicians (group A) recruited patients, and different physicians (group B)
evaluated the therapy and study outcomes.
A total of 78 patients complaining of a sensation of
dry mouth were clinically evaluated and asked to abstain from smoking, eating, and drinking for 1 hour
before the measurement of their salivary flow. Unstimulated whole saliva (UWS) was collected for 5
minutes by means of the spitting method, and stimulated whole saliva (SWS) was collected for 1 minute
after using the paraffin stimulation technique for 5
minutes. The whole saliva flow rate is expressed in
mL/min. UWS flow ⱕ0.1 mL/min was considered salivary hypofunction. Values ⬎0.1 and ⱕ0.25 mL/min
were defined as slight dysfunction, and values ⬎0.25
mL/min were interpreted as a normal resting flow rate.
SWS flow ⬎0.7 mL/min indicated normal activity of
the salivary glands. All patients were also asked to
provide a subjective assessment of their feeling of
dryness using 2 ranking scales (RS), both based on a
scale of 0 to 4 points: one for the daily frequency of oral
dryness (RS-A), rated as “never” (0), “hardly ever”
(1),’“occasionally” (2), “fairly often” (3), and “very
often” (4); and the other for the perceived intensity of
the dry mouth sensation (RS-B), rated as being “absent” (0), “slight” (1), “moderate” (2), “rather severe”
(3), and of “maximum discomfort” (4). These values
represented the patients’ baseline conditions.
Eligibility criteria
Patients satisfying the following criteria were considered to be suitable for the study:
1. They had experienced feelings of dry mouth for ⱖ7
days with UWS values ⬎0.1 and ⱕ 0.25 mL/min.
2. For ⱖ1 week before the start of the study they had
been taking a minimum of 2 drugs with documented
induction of salivary gland hypofunction (e.g., anxiolytics, anorexiants, antiasthmatics, anticholinergics, antidepressants, antiemetics, antihistamines,
antihypertensives, antiparkinsonians, antipsychotics, decongestants, diuretics, and sedatives) and continued taking them for the duration of the study
(specialized consultation did not authorize any
change of drugs or modification of dose).
3. They complained of dry mouth with an RS score ⱕ3
for both frequency (mode A) and intensity (mode B).
Patients were excluded if:
1. They had a history of systemic diseases explaining the
diminished salivary flow (i.e., Sjogren syndrome, diabetes mellitus, infection of the salivary glands, cancer
patients irradiated for head and neck cancer, antecedents of maxillofacial surgery with total or partial removal of major salivary glands, etc.).
2. Their SWS was ⬍.7 mL/min, thus excluding patients with potentially undiagnosed systemic disease
that might influence salivary flow rates.
3. They complained of dry mouth with a normal salivary flow rate (UWS with values ⬎.25 mL/min).
On the basis of these criteria, 24 patients were excluded from the study.
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Volume 112, Number 1
Study population, protocol, and outcome
measures
Fifty-four patients were considered to be suitable for
our study (32 women and 22 men; aged 51-78 years,
mean 66 years). Each of the patients signed an informed consent form, and the procedures of this study
were in accordance with institutional and national ethical standards on human experimentation and the Helsinki Declaration of 1975 as revised in 2000. Possible
carious lesions or dental erosions for all enrolled patients were corrected before beginning the study.
Using random number– generator computer software, another operator (not a doctor) divided the patients into 3 groups of 18 subjects each according to
gender, age, and drug types. Before the groups were
randomly divided, a number was assigned to each therapeutic protocol as prearranged for the 3 patient groups.
This sequence of numbers was known only to investigator A, who administered the drugs for each group.
Investigator A provided patients with mouthwash in
identical white containers, marked with numbers 1, 2,
and 3, respectively, for the artificial saliva group (group
1: 10 women and 8 men; mean age 68 years), the citric
acid group (group 2: 11 women and 7 men; mean age
65 years), and the distilled water group (group 3: 11
women and 7 men; mean age 66 years).
All patients were given identical instructions, i.e., to
keep 5 mL of the administered solution in the mouth for
30 seconds, 4 times daily for 30 days, 1 hour after
eating meals and brushing teeth. The patients in group
1 received a salivary substitute (containing water, hydroxypropyl cellulose, sorbitol, dipotassium chloride,
sodium chloride, magnesium chloride, calcium chloride, and potassium phosphate) with a neutral pH (⬃7)
and were marked as the artificial saliva group. The
patients in group 2 received a solution of citric acid (3%
in essential water) with pH of ⬃3.5 and were marked as
the citric acid group. The patients in group 3 received
distilled water with a pH of 7 and were marked as the
water group. All patients were instructed to note in a
diary their sensations about the efficacy of the therapy
they had undergone; this was to be done 4 times a day
for 30 days, both 15 minutes and 1 hour after the 4 daily
drug intakes (giving a total of 8 daily records), using an
RS-C based on a scale of 0 to 3 points for any change
of baseline symptomatology related to sensations of dry
mouth, defined as “worsening” (0), “unchanged” (1),
“slight improvement” (2), and “significant improvement of dry mouth and feeling of oral moisture” (3). All
patients were also encouraged to note in the diary any
other sensations they felt after intake of liquid test.
At the end of the study (30 days), all patients were
evaluated by investigator B, who was blinded to the form
of therapy given to each group, and UWS was measured
Femiano et al. e17
1 hour after the last dose of therapy. Investigator B also
received all patients’ daily diaries and calculated 2 numeric values per subject per day, representing the mean
value of the 4 daily RS-C scores recorded by the patients
15 minutes and 1 hour after the treatment.
The highest daily RS-C score for every liquid treatment (both 15 minutes and 1 hour after treatment) was
calculated, obtaining only 1 score value from the mean
of 4 daily administrations and assigning, for 30 days, a
possible total score of 90 corresponding with oral comfort. A total score ⱖ70 was considered to be a significant symptomatologic improvement of oral dryness, a
total score ⱖ40 but ⬍70 a slight symptomatologic
improvement, a score ⱖ20 but ⬍40 an unchanged or
unmodified symptomatology, and a total score ⬍20 a
symptomatologic deterioration. At the end of the study,
all patients received a dental examination of the soft
and hard tissues to determine any potential adverse
effects from the study therapy.
Statistical analysis
The data were analyzed using the 2-way analysis of
variance test by GraphPad Software to gain an understanding of the efficacy of the solutions.
RESULTS
The medicaments used for our study were well tolerated, and no patient noted serious adverse effects in their
diaries. The final dental examination of all patients did not
reveal any soft or hard tissue lesions. Patients’ compliance
was optimal, and all 54 patients completed the study.
Table I reports the daily mean of RS-C scores of all the
patients, after 15 minutes and after 1 hour, and their
distribution in relationship to the total score of 30 days’
therapy.
After 15 minutes both salivary substitutes and 3%
citric acid induce early relief from dryness in the
mouth
Figure 1 shows that after 15 minutes the mean RS-C
score was highest in the artificial saliva group: 67.8
(tertile range 69.3-80.7). A slightly lower mean RS-C
score, 61.7 (tertile range 49.7-78.7), was observed for
the citric acid group, and the water group demonstrated
the lowest RS-C score, with a mean of 34.9 (tertile
range 26.7-36.7). Collectively, these data show a significant relief of oral dryness with the reappearance of
a feeling of oral moisture by both salivary substitutes
(artificial saliva group vs. water group: P ⬍ .0001) and
the 3% citric acid solution (citric acid group vs. water
group: P ⬍ .0001) at 15 minutes after the intake. No
significant difference was found between the artificial
saliva and the citric acid groups for overlapping efficacy in oral dryness (P ⫽ .1320) (Table I).
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Femiano et al.
Table I. Effectiveness of therapies on dry mouth feeling at the end of the study in relation to 30 days’ RS-C scores
of from the daily diaries of patients
Artificial saliva group (A)
Citric acid group (C)
Water group (W)
68 (⫾9.1)
10
100
65 (⫾8.5)
11
100
66 (⫾8.3)
11
100
Mean age, y
Female (n)
Caucasian (%)
No. of patients (%)
ⱖ70
ⱖ40 to ⬍70
ⱖ20 to ⬍40
⬍20
Overall mean
P value by 2-way analysis
of variance
After 15 min
After 1 h
After 15 min
After 1 h
After 15 min
After 1 h
12 (67%)
4 (22%)
2 (11%)
0
67.83
7 (39%)
4 (22%)
5 (28%)
2 (11%)
54
9 (50%)
5 (28%)
4 (22%)
0
61.67
10 (56%)
5 (28%)
3 (17%)
0
66.39
2 (11%)
2 (11%)
10 (56%)
4 (22%)
34.89
0
2 (11%)
12 (67%)
4 (22%)
30.94
15 min vs. 1 h ⫽ .0048
15 min vs. 1 h ⫽ .1761
15 min vs. 1 h ⫽ .1676
A vs. W
A vs. C
C vs. W
⬍.0001
.0004
.1320
.0047
⬍.0001
⬍.0001
RS-C, Rating scale of symptomatology change.
Fig. 1. Box plots of total rating scale scores of symptomatology change (RS-C) from the daily diaries of patients, with distribution
of data into tertiles (lower, middle, and upper).
After 1 hour of liquid therapy, citric acid exerts
more longstanding effects than do salivary
substitutes in dry mouth relief
Figure 1 shows that after 1 hour the mean RS-C score
was highest in the citric acid group: 66.4 (tertile range
64-80.7). A slightly lower mean RS-C score, 54 (tertile
range 31.7-73), was recorded for the artificial saliva
group, and the water group showed the lowest RS-C
score, with a mean of 30.9 (tertile range 28.7-34.7). These
data show that both salivary substitutes and citric acid
proved to be effective against dry mouth compared with
the placebo (P ⫽ .0004 and P ⬍ .001, respectively) and
demonstrated that 3% citric acid provided a longer-lasting
beneficial effect in relief of the dry mouth feeling compared with salivary substitutes 1 hour after use (citric acid
group vs. artificial saliva: P ⫽ .0047; Table I).
Effects of saliva substitutes and citric acid on
resting salivary flow
UWS flow rates were compared for each group and
analyzed using the 2-way analysis of variance test. The
overall mean of initial UWS value of the artificial saliva
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Volume 112, Number 1
group (0.14 mL/min) was compared with the final
UWS value (0.18 mL/min), showing P ⫽ .1100. The
overall mean of initial UWS value of the citric acid
group (0.15 mL/min) was compared with final UWS
value (0.16 mL/min), showing P ⫽ .1355. The overall
mean of initial UWS value of the water group (0.14
mL/min) was compared with final UWS value (0.15
mL/min), showing P ⫽ .5425. These results indicate, as
predicted, that neither the 3% citric acid nor the saliva
substitutes affect the UWS flow rate.
DISCUSSION
A recent clinical study conducted by Eliasson et al.
(2009)26 showed a strong association between minor palatal and labial salivary gland secretion rates and subjective
oral dryness. A decrease in the salivary film retained on,
and moistening, the oral surfaces appears to be an essential element in oral discomfort in this context, and its
reduction is related to a worsening of the feeling of dryness.15,25,26 This could explain the current conflicting reports, often leading to mistaking a dry mouth feeling for
hyposalivation due to a hypofunctioning salivary gland,
validating the hypothesis that the sensation of moistening
in the mouth is not so much related to the quantity of
liquid within the mouth but rather to the moistness of the
oral mucosal surfaces.27-36
We examined the efficacy of salivary substitutes
versus 3% citric acid in patients complaining of oral
dryness for slight salivary gland hypofunction (UWS
values ⬎0.1 and ⱕ0.25 mL/min) that was drug induced
without alteration in SWS (i.e., ⬎0.7 mL/min). In this
trial, participants with more severe salivary gland hypofunction (UWS values ⱕ0.1 mL/min) and with SWS
⬍0.7 mL/min, who may have prejudiced the sialogogue
efficacy of citric acid, were excluded. Our findings
show that both salivary substitutes and citric acid induce an immediate and significant symptomatologic
improvement in the feeling of dry mouth 15 minutes
after solution use (Fig. 1; Table I). This finding is in
accordance with data presented by Silvestre et al.
(2009),32 who administered artificial saliva as a spray to
37 patients complaining of dry mouth, 20 of whom
showed an almost immediate improvement after application. Moreover, we found that the use of 3% citric
acid provides a prolonged and significant symptomatologic improvement 1 hour after its intake (10 patients
(56%) with score ⱖ70) compared with the use of artificial saliva (7 patients (39%) with a score ⱖ70; P ⫽
.0047). This longer-lasting efficacy of 3% citric could
be the consequence of the stimulation of both major and
minor salivary glands and an increase in the rate of
whole salivary flow and the formation of salivary film
upon the oral mucosa.
Femiano et al. e19
UWS represented a second parameter evaluated after
the intake of the solutions. Comparison of the initial UWS
flow rate values (collected for each group before the start
of treatment) and the final UWS flow rate values (collected for each group 1 hour after the last tested drug
treatment) showed no significant difference in any group.
These overlapping initial and final UWS flow rate values,
reflecting the inefficacy of the tested liquids on UWS
enhancement, were predictable for water and artificial
saliva, and for patients in the citric acid group the inefficacy could be related to the negative influence of xerostomia-inducing drugs themselves on the salivary gland
parenchyma, which did not permit sufficient gland activation. Interestingly, drug-induced xerostomia is mainly
reported by elderly patients on polypharmacy therapy,
with a reduction of the baseline resting salivary flow rate
but not of the stimulated saliva secretion (i.e., food or
salivary flow rate testing with citric acid stimulation).15,37
Drug-induced xerostomia therapy requires replacement or
at least a reduced dosage of the responsible drug. If this is
not possible, symptomatic treatment based on salivary
production stimulants (sialogogues) or moisturizing
agents (saliva substitutes) are recommended. Because
cholinergic sialogogues are potentially responsible for
muscarinic adverse drug reactions, they are used selectively for advanced salivary gland hypofunction. In
contrast, natural sialogogues, such as 3% citric acid, are
preferred in less advanced cases or as supplemental
therapy because of their minor side effects.
Clinicians should be aware that long-term use of 3%
citric acid in mouthwash can cause oral adverse effects,
i.e., dental hypersensibility and erosion, due to the demineralization of dental hard tissues from salivary pH reduction (3.5-3.0). However, when an acid enters the mouth,
whether from an intrinsic or extrinsic source, salivary flow
rate normally increases, along with the pH and buffer
capacity. Within minutes, the acid is neutralized and
cleared from the oral cavity and the pH returns to normal.
In the presence of xerostomia the oral intake of citric acid,
when not counteracted, can lower salivary pH. Our research found no dental erosion among patients in the citric
acid group at the final appointment, which may be related
to both the short time of contact with citric acid in the
mouth (30 seconds) and insufficient study time (30 days).
The use of citric acid in mouthwash for long periods
requires continuous dental monitoring and some essential
behavioral recommendations, such as restricting the time
of contact with the tooth surface, not brushing teeth for at
least 1 hour after taking the citric acid, limiting or eliminating other substances responsible for dental erosion
from the diet (i.e., spicy or acidic foods, soft drinks,
alcoholic beverages, fizzy mineral water, fruit juice, etc.),
and rinsing with a mouthwash of sodium bicarbonate in
water to raise the oral pH. Additionally, we recommend
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Femiano et al.
the use of calcium phosphates and fluorides to promote
dental remineralization to counteract citric acid dental
erosion.38 On the basis of the results of our study, for
patients complaining of drug-induced xerostomia with
preservation of responsive salivary gland parenchyma, we
recommend a long-term therapy using a mouthwash containing both a salivary substitute and citric acid in solution
for combined immediate and long-lasting relief, in addition to the use of a remineralizing products and consistent
periodic dental monitoring.
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