Pilocarpine Tablets for the Treatment of Dry Mouth and Dry Eye ...

Pilocarpine Tablets for the Treatment of Dry Mouth and 

Dry Eye Symptoms in Patients With Sjögren Syndrome 

A Randomized, Placebo-Controlled, Fixed-Dose, Multicenter Trial 

Frederick B. Vivino, MD; Ibtisam Al-Hashimi, PhD; Zafrulla Khan, DDS; Francis G. LeVeque, DDS; 

Paul L. Salisbury III, DDS; Tram K. Tran-Johnson, PharmD, PsyD; Charles C. Muscoplat, PhD; 

Madhu Trivedi, PhD; Barry Goldlust, PhD; Susan C. Gallagher, MS; for the P92-01 Study Group 

Background: Patients with Sjögren syndrome (SS) experience 

slowly progressive infiltration of lacrimal and 

salivary glands by mononuclear cells. This leads to diminished 

secretions, with resultant symptoms of xerostomia 

and xerophthalmia. Although pilocarpine hydrochloride 

tablets are currently indicated for the treatment 

of radiation-induced xerostomia, their effects on dry 

mouth or dry eyes in patients with SS are unclear. 

Objective: To assess the safety and efficacy of pilocarpine 

(Salagen) tablets as symptomatic treatment for dry 

mouth and dry eyes caused by SS in a multicenter, doubleblind, 

placebo-controlled trial. 

Methods: After providing written informed consent, 373 

patients with primary or secondary SS and clinically significant 

dry mouth and dry eyes were randomized to receive 

2.5-mg pilocarpine, 5-mg pilocarpine, or placebo 

tablets 4 times daily for 12 weeks. Symptoms were assessed 

by questionnaires with visual analog scales or cat- 

The affiliations of the authors 

and the names of the members 

of the P92-01 Study Group 

appear in the acknowledgment 

section at the end of article. 

Downloaded From: http://173.193.11.201/ on 04/10/2013 

ORIGINAL INVESTIGATION 

SJÖGREN SYNDROME (SS) is a 

chronic, autoimmune, rheumatic 

disorder characterized 

by lymphocyte-mediated 

destruction of exocrine 

glands and internal organ involvement that 

occur in association with autoantibody 

production or as a complication of a preexisting 

connective tissue disorder. Over 

time, progressive infiltration of lacrimal 

and salivary glands by mononuclear cells 

leads to diminished secretions, with resultant 

xerostomia (dry mouth) and xerophthalmia 

(dry eyes) being the most 

prevalent symptoms. 1,2 

Morbidity from salivary and lacrimal 

gland hypofunction results from alteration 

of mucosal and ocular surfaces and 

breakdown of the normal host barriers to 

infection. In addition to significant discomfort 

from dryness, untreated dry 

mouth and dry eyes may also lead to complications, 

including stomatopyrosis 

(burning mouth), oral ulcers, malnutri- 

ARCH INTERN MED/ VOL 159, JAN 25, 1999 

174 

egorical checkboxes. Whole-mouth salivary flow rates 

were measured. 

Results: A significantly greater proportion of patients 

in the 5-mg pilocarpine group showed improvement compared 

with the placebo group (P.01) in global assessments 

of dry mouth, dry eyes, and other symptoms of 

dryness (P.05). Salivary flow was significantly increased 

2- to 3-fold (P.001) after administration of the 

first dose and was maintained throughout the 12-week 

study. The most common adverse effect was sweating, 

and no serious drug-related adverse experiences were reported. 

Conclusion: Administration of 5-mg pilocarpine tablets 

4 times daily (20 mg/d) was well tolerated and produced 

significant improvement in symptoms of dry mouth 

and dry eyes and other xeroses in patients with SS. 

Arch Intern Med. 1999;159:174-181 

©1999 American Medical Association. All rights reserved. 

tion, weight loss, oral candidiasis, bacterial 

sialadenitis, sleep disruption, accelerated 

dental caries, periodontal disease, 

corneal ulceration or perforation, and bacterial 

conjunctivitis. 3-5 Use of currently 

available treatments, including tear and saliva 

substitutes, provides transient relief 

at best and often fails to prevent complications. 

In addition, patients often find 

these over-the-counter remedies costly, ineffective, 

inconvenient, or irritating. 

Pilocarpine is a naturally occurring 

compound derived from the South American 

shrub Pilocarpus jaborandi. This plant 

alkaloid is a cholinergic parasympathomimetic 

agonist that binds to muscarinic-M3 

receptors and can cause pharmacological 

smooth muscle contraction in 

humans and stimulation of various exocrine 

glands. 6 Pilocarpine hydrochloride 

(Salagen) tablets are currently indicated 

for treatment of radiation-induced dry 

mouth. 7 In 2 previous multicenter, doubleblind, 

placebo-controlled trials, 8,9 use of

PATIENTS AND METHODS 

PATIENTS 

Written of informed consent was obtained from all potential 

study participants as the first stage of screening and before 

admission to the study. Study patients were older than 

18 years and had a diagnosis of primary or secondary SS 

consistent with the European Cooperative Community classification 

criteria for SS. 10 The diagnosis of SS was confirmed 

at screening by positive test results for at least 1 of 

the following: marker autoantibodies against SS-A or SS-B, 

rheumatoid factor or antinuclear antibodies at a titer of 1: 

160 or greater (or equivalent), or a positive labial minor 

salivary gland biopsy sample. If a lip biopsy sample was used 

to support admission to the study, a representative slide 

of the biopsy sample was read by an external evaluator 

(T. E. Daniels, DDS, MS, Oral Pathology Laboratory, School 

of Dentistry, University of California, San Francisco). Positive 

biopsy samples required a focus score of greater than 

1 focus per 4 mm 2 tissue area. 3,11 The presence of clinically 

significant dry mouth and dry eye symptoms was confirmed 

by screening questionnaires. Patients who indicated 

mild symptoms by responding in the upper quartile 

of the screening questionnaire (100-mm visual analog scale 

[VAS]) did not qualify for entry. Patients were required to 

discontinue, for at least 6 weeks before screening procedures, 

use of any electrical device for salivary stimulation. 

At screening, patients were required to demonstrate some 

residual salivary function by demonstrating any level of saliva 

production. In these analyses, an unstimulated wholemouth 

salivary flow rate of less than 0.4 mL/min was classified 

as salivary hypofunction. 12 Patients were instructed 

to discontinue, at least 7 days before admission, taking any 

medication reported to produce significant dry mouth. 13,14 

Schirmer tear test results and Rose Bengal staining 15 were 

also recorded during screening. A Schirmer score of 7 mm 

per 5 minutes and staining of 3 were each considered indicative 

of dry eyes. These screening requirements were 

modified from the European classification criteria for SS, 10 

which requires a patient to meet 4 of the following 6 criteria: 

ocular symptom, oral symptom, ocular sign, histopathologic 

feature, objective salivary gland involvement, 

and presence of autoantibodies. 

Prospective patients were excluded if they had clinically 

significant cardiopulmonary, renal, or gastrointestinal 

tract disease; diabetes mellitus; multiple sclerosis; hypersensitivity 

to pilocarpine use; or clinically significant 

ocular disease, including narrow-angle glaucoma, peripheral 

retinopathies, or other conditions in which ocular 

(topical) pilocarpine use would be contraindicated. Female 

patients of childbearing potential were required to 

pilocarpine tablets provided significant relief to patients 

with radiation-induced dry mouth. In these 2 studies, use 

of pilocarpine tablets significantly improved symptoms 

of intraoral dryness, oral discomfort, and dysphonia and 

patients’ global assessment of dry mouth as well as reduced 

the need for administration of oral comfort agents 

such as artificial saliva, water, and hard candy. Patients 

treated with pilocarpine tablets also demonstrated a statistically 

significant increase in saliva production, mea- 


use medically acceptable contraceptive methods throughout 

the study. 

TREATMENT PROTOCOL 

At the admission visit, patients were randomly assigned to 1 

of 3 treatment groups for the duration of the study:2.5-mg pilocarpine,5-mgpilocarpine,orplacebotablets.Alltabletswere 

identicalinappearanceandweresuppliedbyMGIPharmaInc, 

Minnetonka, Minn. Site personnel instructed patients to take 

1 tablet of the study drug with water 4 times a day at mealtimes 

and bedtime, with a minimum of 3 hours between doses for 

the duration of the 12-week study. In addition, patients were 

instructed to record missed doses and adverse experiences in 

a diary. Patients recorded their responses to the dryness questionnaires 

before receiving the first dose of the test drug. At 

this visit, patients who took nothing by mouth for at least 90 

minutes before the start of salivary procedures were given the 

first dose of test drug with 180 mL (6 oz) of water. They were 

then monitored for an additional 90 minutes, during which 

timesalivasampleswereobtained(seethe“Methods”section). 

All baseline measurements were recorded for each patient before 

administration of this first dose of test drug. Patients returnedtothestudysiteatweeks6and12forefficacyandsafety 

evaluations. 

METHODS 

Efficacy Assessment 

Efficacy was evaluated at each visit by (1) response to questionnaires 

and (2) measurement of salivary flow. Primary 

variables were the global assessments of dry mouth and dry 

eyes at study end point. End point was defined as the last 

available postdose observation for each patient. In addition, 

specific symptoms associated with dry mouth and dry 

eyes were assessed, as was change in dryness associated with 

extraoral and extraocular symptoms, such as dryness of the 

skin, vagina, and nasal passages. 

Questionnaires 


175 


Patients completed questionnaires at the admission (baseline), 

week 6, and week 12 visits. Questions were presented 

in 2 formats: (1) a 100-mm VAS, with responses ranging 

from the negative (0 mm = extremely dry) on the left 

to the positive on the right, and (2) 3-point categorical questions 

(increase in, no change, or decrease in symptoms). 8,9 

For assessment of primary measures of efficacy— 

global improvement of dry mouth and dry eyes—patients 

were asked at each week 6 and week 12 visit to indicate on 

Continued on next page 

sured as either whole-mouth or parotid salivary flow. It 

is through this mechanism that cholinergic stimulation 

of residual-functioning exocrine glandular tissue in patients 

with SS could potentially alleviate symptoms of dry 

mouth, dry eyes, or other symptoms associated with SS. 

Therefore, the present study was undertaken to investigate 

the efficacy and safety of pilocarpine tablets for the 

treatment of symptoms associated with dry mouth and 

dry eyes in patients with SS.

a VAS question their overall change in mouth and eye dryness 

compared with how they felt at study admission (baseline). 

Responses on the VAS were classified as follows: less 

than 45 mm indicates nonresponder (worsened); 45 to 55 

mm, nonresponder (no change); and greater than 55 mm, 

responder (improved). 

The remaining VAS questions, also recorded at each 

visit, were designed to measure the intensity of specific 

symptoms of dryness as of the study visit and included (1) 

mouth: dryness of the mouth and discomfort of the mouth; 

(2) eye: overall ocular problems, change in tear flow, eye 

discomfort, sensitivity to light, visual blurring, discharge 

or draining, itching, redness, matting, sense of foreign body, 

use of tear substitutes, difficulty focusing, and difficulty with 

night driving; and (3) other symptoms of xeroses: dryness 

of the skin, vagina, and nasal passage and ability to produce 

mucus. These questions were compared with baseline 

ratings and required an improvement of 25 mm or more 

above the baseline score to be defined as responders. 

There were 5 questions using a 3-point categorical format 

that measured an increase, no change, or a decrease 

in symptoms. The oral questions included ability to speak 

without using water, ability to sleep without awakening for 

water, and use of saliva substitutes. The ocular questions 

included difficulty focusing eyes after taking the study medication 

and difficulty driving after taking the study medication. 

For these 5 questions, patients with improvement 

in symptoms were classified as responders, and those with 

no change or worsening symptoms were classified as nonresponders. 

Saliva Collections 

As noted above with reference to patient screening, an unstimulated 

whole-mouth salivary flow rate of less than 0.4 

mL/min was classified as salivary hypofunction. 12 At admission, 

week 6, and week 12 visits, salivary flow was measured 

in patients who took nothing by mouth for 90 minutes 

or longer before initiation of saliva measurements. Fiveminute 

saliva samples were collected before dosing and 30, 

60, and 90 minutes after patients received 1 tablet of their 

assigned test drug with 180 mL (6 oz) of water. For the 

collection procedure, the patients kept their heads tilted 

forward and swallowed once to clear the mouth of excess 

saliva. At this point, the 5-minute collection period was initiated. 

Patients then expectorated, as needed, any saliva 

that accumulated in the mouth into a preweighed 50cm 

3 centrifuge tube. Samples were weighed on an analytical 

balance to determine the volume (1 g = 1 mL) of 

saliva obtained. During this collection period, patients 

continued not taking anything by mouth other than the 

prescribed test medication, leaving them without fluids 

for 180 minutes. 

RESULTS 

Of the 373 patients with SS enrolled in the study at 17 

sites, 125 were randomized to the placebo group, 121 to 

the 2.5-mg pilocarpine group, and 127 to the 5-mg pilocarpine 

group. Demographic characteristics were similar 

among the treatment groups (Table 1). Patients with 

SS are predominantly female, 11,17 which is consistent with 

enrollment in this study (95.7% women). Ninety-four per- 


Safety 

Safety evaluations were based on results of laboratory tests 

(liver and kidney function tests, urinalysis, and complete 

blood cell counts with differential and platelet counts) conducted 

at each visit, results of electrocardiograms and physical 

examinations conducted before study admission and at 

the end of the study, and all adverse experience reports. 

An adverse experience was defined as any clinically significant 

change in physical signs or symptoms or a significant 

laboratory test result change occurring in any phase 

of the study regardless of its relationship to study drug. Safety 

assessment was done for any patient who withdrew from 

the study before week 12. 

STATISTICAL ANALYSES 


176 


The sample of calculations was based on 1 of the 2 primary 

efficacy variables, particularly, response to treatment with respect 

to dryness of the mouth. A 2-sided 2 test, with = .05, 

was used. Assuming a 30% response rate in the placebo group 

and a 50% response rate in the high-dose pilocarpine group, 

100 persons per treatment would result in a power of 80% 

for this comparison. Efficacy results are presented for the intent-to-treat 

cohort. All patients who received at least 1 dose 

of the study drug and who had at least 1 efficacy assessment 

after administration of the first dose were included in this cohort. 

The safety cohort included all patients who took at least 

1 dose of the study drug. Analyses were performed using the 

end point observation, ie, the last-available postdose observation 

for a patient. Differences in the proportion of responders 

among treatment groups were evaluated using a logistic 

regression model. 

Based on the pharmacokinetic profile for this drug, 16 the 

peak salivary flow was anticipated to occur approximately 60 

minutes after administration of a single 5-mg pilocarpine tablet. 

Therefore, the comparison of changes in salivary flow focused 

on the 60-minute postdose collection. Statistical significance 

was defined at P.05 for the determination of an 

overalltreatmenteffect.Foranalysisofsymptomaticresponse, 

if there was an overall treatment effect, specific pairwise comparisonsbetweentheplaceboandthe5-mgpilocarpinegroups 

were made using a logistic regression model. For analysis of 

salivary flow, if there was an overall treatment effect, specific 

pairwise comparisons between placebo and 5-mg pilocarpine 

tablets, and comparison between placebo and 2.5-mg pilocarpine 

tablets, were made using a 2-sided t test. 

The demographic and safety results are presented using 

overall comparisons for all 3 groups. Pairwise comparisons 

of the placebo group vs the 5-mg pilocarpine group 

are presented for efficacy results. A software program (SAS 

version 6.09 or greater, SAS Institute Inc, Cary, NC) was 

used for statistical analyses. 

cent of patients met criteria similar to the European classification 

10 of SS (Table 2). Most patients (87%) completed 

this 3-month study (Table 3). Medications used 

by this patient population were monitored throughout 

the study. The most frequently used (10%) medications 

were consistent with those expected in this population, 

ie, analgesic or anti-inflammatory drugs (aspirin, 

ibuprofen, naproxen, acetaminophen, and 

prednisone), antirheumatic drugs (hydroxychloro

Table 1. Demographic Characteristics 

of the Study Population* 

Characteristic 

Placebo 

Tablets 

(n = 125) 

Pilocarpine Tablets 

(n = 248) 

2.5 mg 

(n = 121) 

quine sulfate and methotrexate), gastrointestinal tract 

agents (omeprazole), hormonal replacement drugs (conjugated 

estrogen and medroxyprogesterone acetate), and 

thyroid preparations (levothyroxine sodium). Use of these 

medications was balanced across treatment groups. 

CLINICAL OUTCOMES 

5mg 

(n = 127) 

Overall P 

Age, y 54.6 ± 13.6 54.0 ± 12.5 55.4 ± 13.6 .72 

Height, cm 162.3 ± 7.6 161.5 ± 7.4 162.0 ± 7.8 .75 

Weight, kg 

Sex 

65.2 ± 14.5 65.4 ± 15.1 66.6 ± 14.5 .64 

Female 

Male 

Race 

118 (94.4) 

7 (5.6) 

116 (95.9) 

5 (4.1) 

123 (96.9) 

4 (3.2) 

.63 

White 97 (77.6) 96 (79.3) 104 (81.9) 

Black 

Asian 

5 (4.0) 

18 (14.4) 

1 (0.8) 

20 (16.5) 

3 (2.4) 

14 (11.0) 

.62 

Other 5 (4.0) 4 (3.3) 6 (4.7) 

*Data are given as mean ± SD and number (percentage). 

Primary Outcomes—Dry Mouth and Dry Eyes 

The primary measures of efficacy were the assessments 

of the global, or overall, improvement in symptoms of 

dry mouth and dry eyes in the end-point analyses 

(Figure 1, left). For global improvement of dry mouth, 

a significantly (P.001) greater proportion of patients 

in the 5-mg pilocarpine group (61.3%) responded to 

therapy compared with the placebo group (31.1%). For 

global improvement of dry eyes, a statistically significant 

(P.009) benefit was also observed in the 5-mg pilocarpine 

group (42.0%) compared with the placebo group 

(26.1%). The 2.5-mg pilocarpine group did not demonstrate 

differences in symptomatic relief of oral or ocular 

symptoms compared with the placebo group. 

Supportive Outcomes—Dry Mouth and Dry Eyes 

Additional questions assessed posttreatment benefits for 

specific symptoms associated with SS. Responses to 4 of 

the 5 dry mouth questions showed a statistically significant 

increase in the proportion of responders in favor of 

5-mg pilocarpine tablets (Figure 1, right). In addition to 

improved mouth comfort (P.004) and mouth dryness 

(P.02), patients also experienced an improved ability 

to sleep because of reduced nocturnal fluid ingestion 

(P.04) and reduced use of saliva substitutes (P.02). 

The difference between the 5-mg pilocarpine group and 

the placebo group in the ability to speak without drinking 

water was not significant (P.06). For ocular symptoms, 

a significantly greater proportion of patients taking 

5-mg pilocarpine tablets also showed clinically 

significant improvement compared with those taking pla- 


Table 2. Patient Disease Characteristics* 

Variable 

Placebo 


(n = 125) 


(n = 248) 

2.5 mg 

(n = 121) 

5mg 

(n = 127) 

Symptomatic dry mouth 124 (99.2) 121 (100.0) 124 (97.6) 

Symptomatic dry eyes 121 (96.8) 119 (98.3) 117 (92.1) 

Positive serologic marker 117 (96.8) 114 (94.2) 118 (92.9) 

Patients with positive 

biopsy samples 

3 (2.4) 4 (3.3) 3 (2.4) 

Ocular signs 93 (74.4) 96 (79.3) 94 (74.0) 

Reduced salivary flow rate 117 (93.6) 111 (91.7) 113 (89.0) 

Patients meeting diagnosis 

of Sjögren syndrome† 

119 (95.2) 117 (96.7) 116 (91.3) 

*Data are given as number (percentage). 

†Patients meeting at least 4 of 6 diagnostic criteria listed above (see the 

“Methods” subsection of the “Patients and Methods” section). 

Table 3. Patient Disposition* 

Status 


177 


Placebo 


(n = 125) 


(n = 248) 

2.5 mg 

(n = 121) 

5mg 

(n = 127) 

Completed study 112 (89.6) 102 (84.3) 110 (86.6) 

Discontinued study 13 (10.4) 19 (15.7) 17 (13.4) 

Reason for discontinuation† 

Adverse experience 7 (5.6) 9 (7.4) 9 (7.1) 

Death 0 1 (1.0) 0 

Lost to follow-up 0 0 1 (1.0) 

Miscellaneous/compliance 6 (4.8) 9 (7.4) 7 (5.5) 


†Adverse event whether or not related to use of the study drug. As a 

subset of these numbers, withdrawals due to drug-related adverse events 

were 1% for the 2.5-mg group and 3.1% for the 5-mg group. 

cebo for overall improvement in ocular problems 

(P.004), ability to focus their eyes during reading 

(P.04), and reduced severity of blurred vision (P.02). 

No benefit was observed for the remaining ocular symptoms 

(sensitivity to light, severity of itching, tiredness, 

redness, difficulty with night driving, discharge or draining, 

difficulty focusing in general, foreign body sensation, 

discomfort, reduced use of artificial tears, matting, 

and change in tear flow). 

In addition to the responder analyses reported above, 

a statistical analysis of mean VAS scores in the placebo 

vs the 5-mg pilocarpine group indicated a significant benefit 

of pilocarpine treatment. Both primary end points— 

global improvement of dry mouth (P.001) and dry eyes 

(P.01)—were significant. In addition, for relief of specific 

dry mouth symptoms, both VAS questions (dryness 

of mouth and discomfort of mouth) were significant 

(P.01). For relief of dry eye symptoms, 2 of 3 VAS 

questions for specific dry eye symptoms (overall change 

in eye problems and severity of visual blurring) that were 

significant by the responder analyses were also significant 

(P.03) when measured by mean increase in VAS 

scores.

Responders, % 

70 

60 

50 

40 

30 

20 

10 

0 

P ≤ .001 

P ≤ .009 

0 

Dry Mouth Dry Eyes Mouth 

Comfort 

Extraoral and Extraocular Symptoms of Dryness 

A significantly higher proportion of patients in the 5-mg 

pilocarpine group showed a positive response to therapy 

compared with those in the placebo group for relief of 

symptoms of nasal dryness (P.002), skin dryness 

(P.01), ability to expectorate mucus (P.02), and vaginal 

dryness (P.02). 

SALIVARY FUNCTION 

The measure of salivary flow is presented in milliliters 

per minute. The change in predose salivary flow over 

time was evaluated to determine if there was a carryover 

effect of pilocarpine therapy. This was assessed by 

analyzing the mean predose salivary flow for each treat- 

60 

55 

50 

45 

40 

35 

30 

25 

20 

15 

10 

5 

∗ 

∗ 

Decreased 

Use of 

Saliva 

Substitutes 

∗ 

Mouth 

Dryness 

∗ 

Ability 

to Sleep 

∗ 

Ocular 

Problems 

∗ 

Visual 

Blurring 

∗ 

Ability to 

Focus Eyes 

Nasal 


Skin 


ment group at each clinic visit. By the end of the study, 

there was no change in predose salivary flow rates 

(P.10). Therefore, no adjustment to postdose flow 

rates was required for the remaining analyses. As early 

as administration of the first dose of test drug at the 

admission visit, the 5-mg pilocarpine group demonstrated 

a statistically significant increase (P.001) in 

salivary flow at all postdose collections (30, 60, and 90 

minutes) compared with the placebo group. This 

increase was maintained throughout the study. At 

admission, the mean (±SD) flow rates for placebo vs 

5-mg pilocarpine therapy, respectively, were 0.11 

(±0.14) vs 0.11 (±0.15) mL/min before dosing; 0.12 

(±0.14) vs 0.34 (±0.53) mL/min 30 minutes after dosing; 

0.13 (±0.15) vs 0.34 (±0.45) mL/min 60 minutes 

after dosing; and 0.13 (±0.15) vs 0.27 (±0.34) mL/min 

90 minutes after dosing. Throughout the study, the 

mean salivary flow rate 60 minutes after dosing was 

0.15 (±0.19) vs 0.33 (±0.41) mL/min (P.001) at week 

6, 0.17 (±0.13) vs 0.38 (±0.48) mL/min (P.001) at 

week 12, and 0.17 (±0.19) vs 0.37 (±0.46) mL/min at 

end point (P.001). Flow rates comparing the placebo 

and the 5-mg pilocarpine groups 60 minutes after dosing 

throughout the study are presented in Figure 2. 

At study end point, there was no statistically significant 

difference between the 2.5-mg pilocarpine and 

the placebo groups in 60-minute postdose mean salivary 

flow. 

ADVERSE EXPERIENCES 

Placebo Group 

5-mg Pilocarpine Group 

Ability to 

Expectorate 

Figure 1. Percentage of patients with Sjögren syndrome with clinically significant improvements in symptoms of dryness comparing treatment with 5-mg 

pilocarpine tablets 4 times daily (20 mg/d) vs placebo. No difference was noted for the 2.5-mg pilocarpine group vs the placebo group (data not shown). Left, 

Percentage of patients with Sjögren syndrome with a significant improvement in the global assessment of dry mouth and dry eyes (primary end points). Right, 

Percentage of patients with Sjögren syndrome with a clinically significant improvement in specific symptoms, including dry mouth, dry eyes, dry skin, dryness 

of the nasal passages, vaginal dryness, and ability to expectorate. Asterisk indicates P.04. 

Salivary Flow Rates, mL/min 

0.40 

0.35 

0.30 

0.25 

0.20 

0.15 

0.10 

0.05 

0.00 

Predose Placebo 

Postdose Placebo 

∗ 

∗ 

5-mg Pilocarpine Predose 

5-mg Pilocarpine Postdose 

Admission Visit Week 6 Visit Week 12 Visit End Point 

Figure 2. Comparison of mean salivary flow rates in patients receiving 5-mg 

pilocarpine tablets 4 times daily vs placebo. Predose flow rates across 

groups were not statistically different. All postdose saliva collections in the 

5-mg pilocarpine group were statistically significantly (P.003) greater at all 

points (30, 60, and 90 minutes after dosing) throughout the study. The 

60-minute postdose collections (P.001) are plotted. No statistically 

significant change was noted at end point (the last available postdose 

observation for each patient) for the 2.5-mg pilocarpine group vs the placebo 

group (data not shown). Asterisk indicates P.001. 


∗ 

∗ 


178 


Vaginal 


No serious drug-related adverse experiences were reported 

in this study. The most frequently reported adverse 

experiences (10% in any treatment group) are 

shown in Table 4. Sweating was the most frequently reported 

event. The assessment of a possible relationship 

between use of the study medication and the occurrence 

of an adverse experience was based on either the 

known pharmacologic properties of pilocarpine or a statistically 

significant increase in incidence in the 5-mg pi- 

∗ 

∗ 

∗ 

∗

Table 4. Incidence of Adverse Experiences 

(10% in Any Treatment Group)* 

Adverse 

Experience 

Placebo 


(n = 125) 


(n = 248) 

2.5 mg 

(n = 121) 

5mg 

(n = 127) 

Overall P 

Sweating† 9 (7.2) 13 (10.7) 55 (43.3) .001 

Headache 31 (24.8) 25 (20.7) 20 (15.8) .20 

Flu syndrome 11 (8.8) 16 (13.2) 18 (14.2) .38 

Nausea 11 (8.8) 15 (12.4) 15 (11.8) .62 

Rhinitis 7 (5.6) 9 (7.4) 13 (10.2) .38 

Dizziness 11 (8.8) 6 (5.0) 13 (‘0.2) .29 

Urinary 

frequency† 

2 (1.6) 13 (10.7) 12 (9.5) .01 


†Events with a probable relationship to pilocarpine use. Other events with 

a probable relationship to drug use but with 10% incidence are flushing 

(placebo group, 1.6%; 2.5-mg pilocarpine group, 1.7%; and 5-mg 

pilocarpine group, 9.5%) and increased salivation (0%, 0%, and 2.4%, 

respectively). 

locarpine group compared with the placebo group. The 

adverse experiences meeting 1 or more of these criteria 

(Table 4) were sweating (placebo group, 7.2%; 2.5-mg 

pilocarpine group, 10.7%; and 5-mg pilocarpine group, 

43.3%), urinary frequency (1.6%, 10.7%, and 9.5%, respectively), 

flushing (1.6%, 1.7%, and 9.5%, respectively), 

and increased salivation (0%, 0%, and 2.4%, respectively). 

These events were typically of mild or 

moderate intensity and occurred in roughly dosedependent 

fashion. The events reported with severe intensity 

were sweating (4 patients) and urinary frequency 

(1 patient), all of which were in the 5-mg 

pilocarpine group. A review of adverse experiences in patients 

who entered the study with a history of respiratory 

abnormalities, including asthma (placebo group, 

n = 31; 2.5-mg pilocarpine group, n = 27; and 5-mg pilocarpine 

group, n = 27), showed a comparable incidence 

of adverse events as that reported in the total population. 

In the 5-mg pilocarpine group, the most commonly 

reported events (10%) vs placebo, respectively, 

were sweating (55.6% vs 12.9%), headache (14.8% 

vs 22.6%), nausea (22.2% vs 12.9%), flu syndrome (14.8% 

vs 6.5%), diarrhea (11.1% vs 3.2%), dizziness (11.1% vs 

6.5%), and dyspepsia (0% vs 12.9%). One case of bronchitis 

was reported during this study in a patient receiving 

5-mg pilocarpine tablets 4 times daily. 

Two percent (5/248) of the patients taking pilocarpine 

tablets withdrew from the study because of 1 or more 

drug-related adverse experiences, ie, 1 patient receiving 

2.5-mg pilocarpine tablets (urinary frequency) and 4 

patients receiving 5-mg pilocarpine tablets (sweating, 4 

patients; flushing, 1 patient; and hypersalivation, 1 patient). 

Of the total population, a comparable proportion 

of patients from each treatment group (5.6%-7.4%) withdrew 

because of adverse experiences, whether or not related 

to use of the study drug (Table 3). Of the remaining 

reasons for withdrawal, none differed among treatment 

groups by more than 1 patient. One patient, in the 2.5-mg 

pilocarpine group, died during the study because of complications 

of a probable pulmonary embolus and Clos- 



179 


tridium difficile enterocolitis. The investigator and treating 

physician did not consider these events to have any 

relationship to use of the study drug. 

Two VAS questions were asked to assess the potential 

adverse effects of pilocarpine tablets on vision after 

administration of the study drug: difficulty with night driving 

and difficulty reading (visual acuity). No exacerbation 

of these symptoms was noted during the study after 

use of 2.5- or 5-mg pilocarpine tablets (P = .64 and P = .63, 

respectively). 

COMMENT 

Saliva is a chemically complex fluid containing several 

organic and inorganic components, all of which play an 

essential role in maintaining oral health. 18 Saliva is not 

only required to preserve the dentition and mucosal surfaces 

but also to facilitate digestion, phonation, mastication, 

deglutition, and gustation. Therefore, the oral consequences 

of salivary gland hypofunction extend beyond 

those of a dry mouth. Common oral symptoms in SS can 

also include dysphonia, dysphagia, stomatopyrosis (burning 

mouth), dysgeusia (altered taste), oral ulcers, and sleep 

disruption caused by nocturnal fluid ingestion. 5,19 Attempts 

to treat these symptoms with replacement therapy 

using artificial salivas and oral lubricants have been largely 

unsuccessful, and patient satisfaction and compliance have 

been low. 20 

For the treatment of symptoms associated with dry 

eyes in primary and secondary SS, there is a plethora of 

artificial tear and lubricant preparations available. However, 

the frequency with which they must be applied suggests 

the need for novel therapeutic interventions. Ultimately, 

tear preservation by punctal occlusion or cautery 

is the last resort to solve this problem. To date, no artificial 

tear or saliva preparation has successfully duplicated 

the physiochemical properties of the body’s own 

fluids well enough to provide a comparable degree of 

benefit. 

The medicinal properties of pilocarpine, including 

its ability to stimulate salivation, have been recognized 

for many centuries by the Tupi Indian tribe of northern 

Brazil, who named this indigenous shrub “jaborandi,” or 

the “slobber-mouth plant.” In 1888, a British physician 

21 described a 65-year-old woman with xerostomia 

and xerophthalmia who probably had SS and who responded 

symptomatically to treatment with tincture of 

jaborandi, administered orally and subcutaneously. The 

benefit of pilocarpine tablets for treatment of symptoms 

of dry mouth from various causes, including SS, has been 

previously suggested in smaller studies and case reports. 

22-26 Data from the present multicenter trial indicate 

that the use of 5-mg pilocarpine tablets administered 

4 times daily (20 mg/d) provides significant 

symptomatic relief of dry mouth caused by SS and significantly 

increases saliva production in measurable quantities. 

Regular use of pilocarpine tablets at this dosage significantly 

improves other specific symptoms of salivary 

gland hypofunction in patients with SS, such as oral discomfort, 

nocturnal fluid ingestion, and the need for saliva 

substitutes. Some benefit for dysphonia may also occur, 

as evidenced by the trend toward statistically

significant improvement in the 5-mg pilocarpine group 

for this symptom. 

Although the data show that pilocarpine-induced 

stimulation of salivary flow occurred within 30 minutes 

of ingestion of the first dose and was maintained through 

week 12, the onset of subjective benefit for various symptoms 

took 6 to 12 weeks. Because dry mouth develops 

rather insidiously in most patients with SS, 27 it is not unreasonable 

to expect that improvement or reversal of 

symptoms after treatment would be delayed. This observation 

suggests that a patient’s symptoms on a given day 

may reflect not only the quantity of saliva but also the 

cumulative effect of chronic tissue dehydration. For this 

reason, it seems that a prolonged treatment course with 

pilocarpine tablets (eg, 6-12 weeks) should be recommended 

to patients to allow sufficient time for symptomatic 

benefits to occur. In this study, the most dramatic 

response occurred in patients who took 5-mg 

pilocarpine tablets 4 times daily. Although salivary flow 

rates were measured during only the first 90 minutes of 

the dosing interval, results of previous studies 16 in healthy 

participants indicate that the pilocarpine effect on flow 

rates lasts 3 to 5 hours. Optimal therapeutic benefit can 

therefore be best achieved through a 4-times-daily dosing 

regimen. 

Results of this study also indicate symptomatic relief 

of dry eyes after use of 5-mg pilocarpine tablets 4 times 

daily. Significantly more patients reported improvement 

in their global assessment of dry eyes, blurred vision, 

ability to focus the eyes during reading, and ocular 

problems in the higher-dose (5-mg) treatment group compared 

with the placebo group. However, some ocular 

symptoms did not significantly change. This could be due 

to a differential degree of cholinergic stimulation by pilocarpine 

on the eyes compared with the mouth or could 

reflect the need for higher doses or a longer treatment 

period to achieve maximal benefit. As noted in a second 

study 28 of pilocarpine tablet use for patients with SS, which 

used doses up to 30 mg/d, statistically significant response 

for relief of ocular symptoms was observed in 8 

of 9 measures in the pilocarpine group compared with 

the placebo group. 

As one could predict from pilocarpine’s pharmacological 

effect, this investigation also suggests that pilocarpine 

tablets, at doses of 20 mg/d, can stimulate exocrine 

gland secretion in other organ systems besides the 

eyes and mouth. At study end point, statistically significant 

improvement was also observed in other sicca symptoms 

associated with SS, including nasal dryness, dry skin, 

vaginitis sicca, and the ability to expectorate. These data 

therefore suggest that treatment with pilocarpine tablets 

not only offers relief of symptoms of dry mouth and 

dry eyes but of whole-body dryness as well. 

In this multicenter trial, the incidence of adverse effects 

related to the use of pilocarpine tablets reflected the 

cholinergic activity of this drug. 6,29 The most common 

drug-related adverse experiences included sweating, urinary 

frequency, and flushing. Despite a relatively high 

incidence of sweating, this and other adverse effects were 

perceived as minor by most patients, and the withdrawal 

rate due to drug-related adverse experiences was 

low (2%). No significant differences between treatment 



180 


groups were observed for alterations in blood pressure 

or heart rate, and no drug-related serious events were reported, 

including hematopoietic, renal, or hepatotoxic 

effects. No significant drug interactions were noted. This 

study did not demonstrate any pulmonary safety issues 

in this patient population. However, the package insert 

16 for Salagen tablets (oral pilocarpine) does note that 

pilocarpine should be administered with caution and under 

close supervision to patients with controlled asthma, 

chronic bronchitis, or chronic obstructive pulmonary disease 

requiring medical therapy. 

From a physiologic standpoint, treatment of patients 

with SS with a systemic cholinergic agonist such 

as pilocarpine to stimulate the body’s own multiorgan secretions 

not only is the most efficacious and costeffective 

strategy to alleviate multiple symptoms but also 

offers the best potential treatment for prevention of longterm 

complications caused by severe dryness. Although 

the efficacy of long-term oral pilocarpine therapy for dental 

caries prophylaxis or prevention of oral infections in 

humans is not known, data from animal models suggest 

such a possible benefit. In a study 30 of partially desalivated 

rats fed a cariogenic diet, treatment with pilocarpine 

reduced the incidence of sulcal cavities compared 

with nontreated controls. These findings did not significantly 

correlate with a lower incidence of infection by 

cariogenic bacteria (eg, Streptococcus sobrinus). However, 

in another study, 31 the incidence of oral infection 

by S sobrinus in surgically desalivated rats was significantly 

reduced after pilocarpine treatment compared with 

untreated controls. Furthermore, stimulation of salivary 

flow by pilocarpine treatment can reportedly reverse 

sucrose-induced fissure caries in albino rats. 32 Consequently, 

further studies to determine this treatment’s 

ability to prevent complications (eg, dental caries) from 

dry mouth and other sicca symptoms from SS seem reasonable. 

In conclusion, the administration of 5-mg pilocarpine 

tablets 4 times daily (20 mg/d in divided doses) produced 

significant benefits for the symptomatic treatment 

of dryness associated with SS that clearly outweighed 

adverse effects and risks in this 12-week study. Patients 

experienced improvement in symptoms of dry mouth and 

dry eyes, and improvement in dryness of the nose, skin, 

and vagina and the ability to expectorate. Treatment success 

with pilocarpine will most likely depend on existence 

of residual exocrine gland function. In SS, this may 

vary in different organs and cannot always be predicted 

based on the duration of symptoms. As data from the present 

study suggest, use of pilocarpine tablets offers a wide 

range of potential therapeutic effects for patients with SS. 

Therefore, at the present time, almost any patient with 

SS with some degree of exocrine gland function could 

potentially benefit from this treatment depending on therapeutic 

goals. As with other patient groups with rheumatic 

conditions, early diagnosis and treatment offer the 

best hope for a good outcome. 

Accepted for publication May 19, 1998. 

From the Division of Rheumatology, University of Pennsylvania 

Health System, Philadelphia (Dr Vivino); Department 

of Periodontics, Baylor College of Dentistry, Dallas,

Tex (Dr Al-Hashimi); Department of Dental Oncology and 

Maxillofacial Prosthodontics, J. Graham Brown Cancer Center, 

Louisville, Ky (Dr Khan); Department of Oral Medicine, 

Harper Hospital, Detroit, Mich (Dr LeVeque); Department 

of Dentistry, Bowman Gray School of Medicine, 

Winston-Salem, NC (Dr Salisbury); California Neuropsychopharmacology 

Clinical Research Institute, San Diego (Dr 

Tran-Johnson); and MGI Pharma Inc, Minnetonka, Minn 

(Drs Muscoplat, Trivedi, and Goldlust and Ms Gallagher). 

This study was supported by grants from MGI Pharma 

Inc. 

Members of the P92-01 Study Group are Michael Ellman, 

MD, The University of Chicago, Chicago, Ill; Robert 

I. Fox, MD, Scripps Clinic & Research Foundation, La Jolla, 

Calif; Daniel Furst, MD, Virginia Mason Research Center, 

Seattle, Wash; W. Leroy Griffing, MD, Mayo Clinic, 

Scottsdale, Ariz; Cyril Meyerowitz, DDS, University of Rochester, 

Rochester, NY; Nelson L. Rhodus, DMD, University 

of Minnesota, Minneapolis; Stephen Sonis, DMD, Brigham 

and Women’s Hospital, Boston, Mass; Leo M. Sreebny, DDS, 

State University of New York at Stony Brook, Stony Brook; 

Norman Talal, MD, University of Texas Health Science Center, 

San Antonio; Frederick Wolfe, MD, Arthritis Research 

and Clinical Centers, Wichita, Kan; and Richard Yee, University 

of Texas Science Center, Houston. 

Reprints: Frederick B. Vivino, MD, Division of Rheumatology, 

Thomas Jefferson University, 1015 Walnut St, 

Suite 613, Philadelphia, PA 19107. 

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