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Pilocarpine and Artificial Saliva for the Treatment of Xerostomia and

Xerophthalmia of Sjögren's Syndrome: A double blind control trial

Article  in  British Journal of Dermatology · February 2018

DOI: 10.1111/bjd.16442

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Article type : Original Article

Accepted Article
Pilocarpine and Artificial Saliva for the Treatment of Xerostomia and

Xerophthalmia of Sjögren’s Syndrome: A double blind control trial.

2
M. Cifuentes1; P. Del Barrio-Díaz1; C. Vera-Kellet1,
1
Department of Dermatology, Facultad de Medicina, Pontificia Universidad Católica de Chile,

Santiago, Chile.
2
Connective Tissue Diseases Unit, Department of Dermatology, Facultad de Medicina, Pontificia

Universidad Católica de Chile, Santiago, Chile.

Corresponding Author

Cristián Vera-Kellet, MD

Assistant Professor of Dermatology

Department of Dermatology, Facultad de Medicina,

Pontificia Universidad Católica de Chile, Santiago, Chile.

Address: Av. Vicuña Mackenna 4686. Macul, Santiago, Chile. Zip code 7810000

E-mail: cristianverakellet@gmail.com.

Phone: (56 2) 2354 8659. Fax: (56 2) 2552 9974.

IRB status: The Ethics Committee of Pontificia Universidad Católica de Chile

approved this study protocol.

Funding source: This article has no funding source.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/bjd.16442
This article is protected by copyright. All rights reserved.
 Conflicts of interest: All of the authors declare no conflicts of interest. Keywords:

Pilocarpine, artificial saliva, xerostomia, xerophthalmia, Sjögren’s syndrome.

Accepted Article
Abstract:

Background: Sjögren’s Syndrome (SS) is associated with xerostomia and

xerophthalmia. Pilocarpine stimulates the secretion of saliva.

Objectives: Investigate and compare the efficacy of pilocarpine and artificial saliva

as symptomatic treatments for xerostomia and xerophthalmia in patients with SS.

Patients and Methods: A double-blind, randomized, controlled study was

performed. 72 patients with SS were assigned randomly to receive ten drops of

pilocarpine (5 mg) or 10 drops of artificial saliva, orally, t.i.d.for 12 weeks. Patients

were evaluated at baseline and periodically throughout the study by whole saliva and

tear flow for global assessment of their dryness as well as for any adverse effects.

Results: Patients receiving pilocarpine had a statistically significant improvement in

their salivary flow (p< 0.0001), lachrymal flow (p< 0.0001), and their subjective global

assessment (p< 0.0001), compared with patients on artificial saliva. The most

common side effects were sialorrhea and nausea. Limitations: As the pilocarpine

was in solution (drops), it was possible for the dosage to become inaccurate.

Conclusions: Pilocarpine is more effective than artificial saliva for enhancing

salivary and lachrymal secretion in patients with SS. This is the first study comparing

the efficacy of pilocarpine and artificial saliva as treatments for xerostomia and

xerophthalmia in SS.

Keywords: Pilocarpine; artificial saliva; xerostomia; xerophthalmia; Sjögren’s

Syndrome.

This article is protected by copyright. All rights reserved.

 Trial Registration: clinicaltrials.gov Identifier: NCT 00438048
Accepted Article
Introduction

Sjögren’s Syndrome (SS) is a systemic, chronic, autoimmune disease produced by

a progressive and destructive inflammatory lymphocytic infiltration of salivary and

lacrimal exocrine glands with sicca symptoms following, such as xerostomia (dry

mouth), xerophthalmia (dry eyes) and parotid gland enlargement (1). It may occur in

the absence of an underlying rheumatic disorder (primary SS) or be associated with

another rheumatic disease, such as systemic lupus erythematosus, scleroderma,

rheumatoid arthritis, dermatomyositis, or primary biliary cirrhosis (secondary SS).

Untreated patients can present with burning mouth syndrome, oral ulcers,

malnutrition, weight loss, oral candidiasis, sialadenitis, sleep disruption, dental

caries, periodontal disease, corneal perforation, and/or conjunctivitis. The role of

immunosuppressive therapy is limited. Biologic agents, such as rituximab,

epratuzumab, and belimumab have shown promising results, but further studies are

needed to validate the findings (2).

There are many treatments for xerostomia, among them artificial saliva, topical

cyclosporine, and sialogogues (drugs or substances that increase salivary flow).

Sialogogues include chewing gums, malic and ascorbic acid (very effective, but not

used because they cause demineralization of tooth enamel), and the

parasympathomimetic drugs. The last include pilocarpine and cevimeline, which

bind to cholinergic (muscarinic) receptors and increase the secretion of the exocrine

glands, (salivary and lacrimal glands)(3)(4)(5).

This article is protected by copyright. All rights reserved.

 Pilocarpine impels M1 and M3 receptors, producing stimulation of exocrine glands in

humans, that produces diaphoresis, salivation, lacrimation, and gastric and

Accepted Article
pancreatic secretion. Pilocarpine is an alkaloid found in the leaves of two of the

jaborandi plants, Pilocarpus microphyllus and Pilocarpus jaborandi (6). Many studies

have demonstrated the utility of pilocarpine for the treatment of xerostomia

secondary to radiation (6)(7), to SS (8)(9), to graft-versus-host disease (10), and for

opioid-induced oral dryness (11).

The usual recommended dose is 2.5 to 10 mg administered orally 3 or 4 times daily.

The sialogenic effect is observed 30 minutes after its intake, and has a terminal half-

life of 9 hours (6).

Mouth rinsing with pilocarpine solutions at concentrations of 1 to 2% has

demonstrated in the past to induce a significant objective and subjective dose-

dependent increase in salivary flow (12).

When comparing the discontinuation rates and side-effect profiles of pilocarpine and

cevimeline for the treatment of xerostomia in patients with primary SS, patients were

more likely to continue cevimeline than pilocarpine long-term due to fewer reported

side effects with cevimeline (13).

In Chile and other developing countries, original pilocarpine tablets are not available

for the treatment of xerostomia, which is why patients usually receive artificial saliva

as a symptomatic treatment. Previous studies have shown that artificial saliva is

more efficient than placebo in regard to the subjective improvement of sicca

symptoms, but the artificial saliva doesn’t affect salivary production or prevent

complications (14)(15). Some patients find it to be expensive, ineffective, and/or

irritating (16).

This article is protected by copyright. All rights reserved.

 There are only two reports in the literature that compare artificial saliva and

pilocarpine, but neither of them are studies of patients with SS, and both studies
Accepted Article
measure only subjective outcomes. The first one was a prospective, randomized,

crossover study that compared a pilocarpine mouthwash used three times a day

with artificial saliva, in 20 patients with radiation-induced xerostomia. Overall, the

patients found that the pilocarpine mouthwash was more effective than the artificial

saliva in relieving their symptoms, but only 47 percent of them wanted to continue

with this treatment after the study was finished (17). The second study was a

prospective, randomized, crossover study, in which pilocarpine in tablets was found

to be more effective than the artificial saliva with regard to the mean change in visual

analog scale scores for xerostomia. 50% of the patients preferred the artificial

saliva, stating that this was because it was a spray, rather than a tablet (18).

Neither of these studies used the salivary and lacrimal flows as primary

outcomes.

The aim of this current study has been to compare artificial saliva with pilocarpine for

the management of xerostomia and xerophthalmia in patients with SS. We decided

to compound pilocarpine as oral drops to compare it with artificial saliva using

exactly the same amount of each.

Patients and Methods

Patients were recruited from the Department of Dermatology and Rheumatology at

the Pontificia Universidad Católica de Chile. The inclusion criteria included adults

with symptomatic xerostomia (a subjective sensation of dryness of the mouth),

symptomatic xerophthalmia (dry eyes), and with a documented diagnosis of primary

This article is protected by copyright. All rights reserved.

 or secondary SS according to the American-European Consensus Group (19). The

exclusion criteria for the study were clinically significant cardiopulmonary, renal, or
Accepted Article
gastrointestinal tract disease; diabetes mellitus; multiple sclerosis; hypersensitivity to

pilocarpine use; or clinically significant ocular disease; pregnancy, or breastfeeding.

Females of childbearing potential enrolled in this protocol agreed to use two reliable

forms of contraception simultaneously. Participants gave their written informed

consent. The Ethics Committee of the Pontificia Universidad Católica de Chile

approved the study protocol. The Declaration of Helsinki regarding research

protocols was followed. This study was registered in clinicaltrials.gov Identifier: NCT

00438048.

Study Design

We performed a double-blind, randomized, controlled study. 72 patients with

symptomatic SS were assigned randomly groups receiving either ten drops of

pilocarpine (equivalent to 5 mg) orally, or ten drops of artificial saliva, three times a

day for 12 weeks. At the admission visit, patients were blindly and randomly

assigned to one of the two groups using randomization tables. Both treatment

containers were identical in appearance and were supplied by an external pharmacy.

The investigator instructed the patients to introduce 5 mg of pilocarpine (equivalent

to 10 drops) or the same number of drops of artificial saliva directly into the mouth

three times a day for 12-weeks, during or directly after meals. The subjects were

reviewed at the beginning of the study, and every four weeks during its duration, for

global assessment of their dryness (mouth, eyes) as well as their subjective

assessments of specific symptoms of dry mouth and dry eyes. Total saliva and tear

flow were measured.

This article is protected by copyright. All rights reserved.

 The primary outcome was the measurement of the non-stimulated salivary flow and

the non-stimulated lachrymal flow at week 12. The non-stimulated salivary flow was
Accepted Article
measured by the Whole Saliva Test (WST), also known as the Oral Schirmer Test.

This test was created in 1996 by López-Jornet, et al. (20). WST is a quantitative

method that measures the entire salivary gland production. It consists of a Whatman

paper strip introduced in a polyethylene bag, leaving the first five millimeters of the

strip out of one end of the bag. This end is then folded and placed under the patient’s

tongue to contact the mucosal surface of the floor of the mouth. The patients were

sitting, in the position known as the “coachman position” (the sitting subject lowers

his trunk vertically, the back is curved, and the head hangs slightly forwards, the

hands resting on the knees, and with the eyes closed). The paper strip is left in place

for five minutes, after which the patients open their mouths, and the strip is

extracted. The wet paper strip is then read in centimeters (cm) (Fig.1).

In order to avoid variations the WST was carried out by the same investigator in a

quiet environment, always at the same time of the day (in the afternoon al least one

hour after lunch). The temperature of the examination room was set at 20ºC (68ºF)

and patients rested there for at least 30 min. All patients were paired by sex and age,

and medications or psychiatric conditions were recorded.

The given value was divided by 5, and the result expressed in cm/minute. The

results of salivary gland production were expressed in centimeters, obtaining the

range, mean, and standard deviation (s.d.) for the study group. The non-stimulated

lachrymal flow was measured by the Schirmer Test using a Wathman paper strip for

5 minutes. Results were expressed in cm/min.

This article is protected by copyright. All rights reserved.

 The symptoms of our patients were assessed using a 10-cm long visual analog scale

(VAS) related to the patient’s symptoms, including xerostomia, dysphagia, dysgeusia

Accepted Article
(abnormal taste), and ocular symptoms. The scoring scale had 0 representing no

symptoms, and 10 indicating unbearable symptoms. The tolerability of the

treatments was assessed using a side-effect checklist, which contained the known

side effects of both treatments. The patients were asked to grade any side effects as

mild, moderate, or severe. The VAS and the side-effect checklist were completed at

the beginning and end of each 4-week treatment period.

Statistical Analyses

The sample calculation was based on the response to treatment measured by the

salivary flow. Assuming a 20% difference in salivary flow between the pilocarpine

and the artificial saliva groups, and αn error of 0.05, 36 persons per treatment would

result in a power potency of 80% for this comparison. Continuous variables were

presented as means with standard deviations and categorical variables represented

by numbers and percentages. The Student-T test was used to compare numeric

variables between the two groups. To compare categorical variables between the

two groups, we used the Chi-square Test or Fisher's Exact Test.

To compare the evolution of patients in the two groups, mixed models were adjusted

considering the random effects reported by the patients, and fixed effects (timing and

week of measurement). Data from the primary and secondary outcomes were

analyzed as intention to treat. For those subjects who abandoned the study before

the end of the survey, the last evaluation was used for the data analysis.

This article is protected by copyright. All rights reserved.

 Results

A total of 72 subjects were included in this study (69 women and three men) with a
Accepted Article
mean age of 52.5 years (ranging from 24 to 74 years). Table Nº1 shows the main

demographic characteristics of both study groups.

Extraglandular involvement was only seen in 10% of our patients at the time of the

study and included: arthralgia, arthritis, peripheral neuropathy, and cutaneous

vasculitis. 60% of the cohort had positive Anti-Ro/SSA antibodies, 30% positive Anti-

La/SSB antibodies, and 90% of them had positive Antinuclear Antibodies.

The flowchart of our study is shown in Figure Nº2.

The main results of changes in salivary flow (WST), lachrymal flows for each eye

(Schirmer test), and symptom intensities measured by the VAS are shown in Table

Nº2. The evolution of the WST each week for patients taking either Pilocarpine or

artificial saliva is displayed in Figure Nº 3.

36 patients received pilocarpine, and only two of them did not respond to pilocarpine.

Interestingly non-responder to pilocarpine were patients with the longer duration of

sicca symptoms, and both of them didn't show any lachrymal or salivary flow at the

beginning of the study.

When comparing the WST response to Pilocarpine and to artificial saliva in patients

with primary and secondary SS, both groups responded similarly to the treatment.

When we analyzed the symptoms described by patients at the start of the study they

included: “sticky” tongue (64%), burning sensation (6%), and pruritus (6%), among

the most important. These symptoms showed no significant difference between the

two groups, but, at 12 weeks, 97% of the patients using Pilocarpine had no

symptoms, compared to 51% of the group using artificial saliva (p <0.0001).

This article is protected by copyright. All rights reserved.

 Adverse effects occurred in both groups, but they were low in frequency, and well

tolerated by the patients (Table Nº3). None of the patients had to stop using
Accepted Article
pilocarpine or artificial saliva because of them.

Discussion

In this and other studies, (18)(21)(22), the percentage of patients who demonstrated

improvement with the use of pilocarpine, with regard to moisture sensation and other

subjective parameters, was sustained or even increased as treatment continued.

This could be related to gradual changes in the oral mucosa, secondary to increased

salivary production, and to the fact that SS patients may still have potential functional

glands compared to patients with xerostomia secondary to radiation, whose glands

are not functional. However, it is difficult to compare this study with others, since

most of the latter used Pilocarpine and a placebo, in tablets rather than in oral drops.

In addition, different methods of salivary flow measurement were used, making it

difficult to standardize the results.

One of the methodologically similar studies is the Mosqueda, et al. work (22) in

which the usefulness of 5 mg of Pilocarpine in tablets every 8 hours is corroborated

for the treatment of xerostomia secondary to head and neck radiation. In it, an

increase of 65% in salivary flow measured by the WST was verified. Although these

results are lower than ours, this could be explained by the underlying pathology of

the population studied.

One limitation of our study is that we only used the Whole Saliva Test to measured

non-stimulated salivary flow, and we didn´t used other test like Parotid Sialography

or Salivary Scintigraphy. Another aspect to emphasize is that the dose of Pilocarpine

in drops can sometimes be less than precise, since the patients must measure and

This article is protected by copyright. All rights reserved.

 ingest an exact number of drops to complete a particular dose. This is not an issue

when Pilocarpine is prescribed in tablet form.

Accepted Article
The fact that the group of patients given pilocarpine had a greater component of

primary Sjögren from the beginning could explain their worse dental state, and their

greater intensity and presence of symptoms than the artificial saliva group showed at

week 0. Therefore, and after seeing our results, we believe that pilocarpine is an

excellent therapeutic option for patients with SS. Pilocarpine is contraindicated in

patients with SS with uncontrolled asthma, known hypersensitivity to pilocarpine,

patients with acute iritis and in narrow-angle glaucoma.

Pilocarpine should be administered with caution in patients with SS with significant

cardiovascular disease (transient changes in hemodynamics or rhythm induced by

pilocarpine) and in patients with SS with a controlled pulmonary disease requiring

pharmacotherapy. In Patients with cholelithiasis or biliary tract disease, pilocarpine

could precipitate cholecystitis, cholangitis, and biliary obstruction.

Because pilocarpine is a cholinergic agonist, patients should be advised that

pilocarpine causes visual blurring and impairment of depth perception and that may

have dose-related central nervous system effects (underlying cognitive or psychiatric

disturbances).

Even though excess sweating is often cited as the most frequent and annoying side

effect of Pilocarpine, patients in our group didn’t complain at all. We believe that this

could be explained because most of the study was performed during summertime,

where temperatures could be as high as 40ºC (104ºF).

Current management of Sjögren’s Syndrome is aimed at relieving symptoms and

limiting the damage caused by chronic xerostomia and xerophthalmia. Treatments

This article is protected by copyright. All rights reserved.

 include the use of various topical agents such as artificial tears and artificial saliva.

Previous studies had shown that artificial saliva is more efficient than a placebo with
Accepted Article
regard to the subjective impression of improvement of sicca symptoms, but it doesn’t

affect salivary production objectively, or prevent complications.

After analyzing Figure Nº3, the group taking artificial saliva had a slight increase in

salivary flow. We believe that this could be a placebo effect or could be explained

because the major constituent of the artificial saliva was sorbitol, a sugar alcohol with

a sweet taste, which has demonstrated to increase salivary flow in the past (23).

Systemic corticosteroids may increase salivary and lachrymal flow, but they are

associated with long-term side effects. Other systemic agents, such as antimalarials,

cyclosporine, methotrexate, and azathioprine, are useful for extra-glandular

manifestations, but do not improve the salivary and lachrymal flow.

The evidence supports that oral pilocarpine stimulates salivary flow in patients with

xerostomia from Sjögren’s Syndrome, graft-versus-host disease, opioid-induced oral

dryness, and from radiation therapy for head and neck cancer. However, prior

studies had shown that there is a gap between objective measures of salivary flow

and the patients’ subjective reports of xerostomia, with the objective response being

greater than the subjective response (8). The feeling of wetness may be influenced

by factors other than flow from the major salivary glands, and might reflect the

functioning of the minor salivary glands, such as those close to the oral cavity during

head and neck irradiation (6)(10).

This article is protected by copyright. All rights reserved.

 It has been hypothesized that the subjective feeling of xerostomia arises from the

loss of mucosal wetness on the hard palate, secondary to a decrease in the function
Accepted Article
of the minor salivary glands in the hard and soft palates (24).

In Chile, as in most Latin American countries to date, Pilocarpine hydrochloride

tablets are not available for the treatment of xerostomia. Most patients receive only

artificial saliva as a symptom-relieving treatment that produces only temporary relief

of discomfort without the protective effects that the saliva exerts on the tissues of the

mouth. We believe that formulating oral pilocarpine in solution is an inexpensive and

easy way to treat xerostomia secondary to SS, in those few countries that do not

have the original presentation of pilocarpine.

This study demonstrated the clinical efficacy and safety of a 5 mg oral pilocarpine

solution given three times daily for the treatment of dry mouth in patients with SS in

Chile. In this study, patients experienced global improvement of xerostomia, and

xerophthalmia, with significant improvement in most of the symptoms associated

with dry mouth, including mouth dryness, the intensity of symptoms, experienced

increased ability to sleep, to speak clearly, and an increase in saliva and lachrymal

secretion from their baseline, without serious adverse effects. This is the first

multicentric double-blind, randomized, controlled study comparing the efficacy and

the safety of pilocarpine and artificial saliva as symptomatic treatments for

xerostomia and xerophthalmia in patients with primary and secondary SS.

This article is protected by copyright. All rights reserved.

 Abbreviation and acronym list

Sjögren’s syndrome: SS
Accepted Article
Three times a day: t.i.d.

Whole Saliva Test: WST

Centimeters: cm

Standard deviation: s.d.

Visual analog scale: VAS

NS: Not significant

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Accepted Article
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Figure Legends:

Figure Nº1: Xerostomia and Xerophthalmia in Sjögren’s Syndrome. The Whole

Saliva Test.

Figure Nº2: Xerostomia and Xerophthalmia in Sjögren’s Syndrome. Flow Diagram of

our Study (CONSORT guidelines).

Figure Nº3: Xerostomia and Xerophthalmia in Sjögren’s Syndrome. The Whole

Saliva Test Progression during the Study.

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 Tables:
Accepted Article
Table Nº1: Demographic characteristic and clinical features of the study.

Characteristic Pilocarpine (n=36) Artificial Saliva (n=36) p value*

Mean Age (years) 52 ± 11,15 53,17 ± 11,66 NS
Sex Female 34 (94,4%) 35 (97,2%) NS
Male 2 (5,5%) 1 (2,78%)
Sjögren Syndrome Primary: 24 (66,6%) Primary: 13 (36,11%) 0.009
Secondary 12 (33,3%) Secondary 23 (63,89%)
Duration of the 22,16 ± 16,24 23,28 ± 15,31 NS
disease (years)
*
NS: Not significant

Table Nº2: Main results of our study group.

Pilocarpine Artificial Saliva p-value*

WST week 0 0,115 ± 0,110 cm/min 0,133 ±0,140 cm/min NS
WST week 12 0,924 ± 0,289 cm/min 0,297 ±0,275 cm/min < 0.0001
Schirmer test right eye week 0 0,054 ± 0,036 cm/min 0,063 ± 0,052 cm/min NS
Schirmer test right eye week 0,260 ± 0,145 cm/min 0,060 ± 0,040 cm/min < 0.0001
12
Schirmer test left eye week 0 0,063 ± 0,045 cm/min 0,078 ± 0,053 cm/min NS
Schirmer test left eye week 12 0,281 ± 0,152 cm/min 0,080 ± 0,050 cm/min < 0.0001
Symptoms intensity week 0** 6,83 ± 1,84 5,50 ± 2,38 0.01
Symptoms intensity week 12 2,78 ± 1,49 4,56 ± 2,29 < 0.0001
*
NS: Not significant; ** VAS

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 Table Nº3: The total adverse effects of our study group (some patients had more
than one).
Accepted Article
Event Pilocarpine Artificial Saliva
Sialorrhea 6 0
Nauseas 4 0
Bitter taste 3 0
Diarrhea 0 3
Stomatodynia 2 3
Sickness 2 0
Sore Throat 2 2
Gastritis 2 1
Dyspnea 1 0
Herpes Simplex 1 0

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.

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