Download Efficacy of Topical Pilocarpine in the Management of Primary

Original Article
Efficacy of Topical Pilocarpine in the
Management of Primary Aqueous
Tear Deficiency: An Initial Study
Ma. Theresa B. Urriquia, MD and Jose David F. Marin, Jr., MD
Department of Ophthalmology
Manila Central University
Filemon D. Tanchoco Medical Foundation Caloocan City, Philippines
Correspondence: Ma. Theresa B. Urriquia, MD
Department of Ophthalmology
Manila Central University
Filemon D. Tanchoco Medical Foundation
Caloocan City, Philippines
Email: [email protected]
Disclosure: None of the authors received any financial support during the course of this study. The authors have no proprietary interests in
the products used in this study.
ABSTRACT
Objective: To determine the efficacy of topical pilocarpine (0.05%) in the management of patients with primary
aqueous tear deficiency (ATD).
Methods: This was a single center, randomized, double-blind, placebo-controlled clinical trial of 11 dry eye
patients (22 eyes) with ATD who were screened from July 2012 to March 2013. They were evaluated using the
Ocular Surface Disease Index (OSDI) for symptoms of ATD with abnormal Schirmer’s I and tear-break-up time
(TBUT) results. The eyes of each subject were randomized to either the interventional (pilocarpine 0.05%) or the
control (aqueous tear substitute) groups given for 2 months. Results were evaluated by statistical testing at different
time intervals.
Result: Topical pilocarpine 0.05% significantly increased the tear production from a Schirmer’s I baseline of 4.09
mm ± 1.30 to 12.46 mm ± 9.02 after 2 months (p <0.01). Symptoms improved with noted decreased OSDI score
from 33.72 ± 24.88 to 13.84 ± 8.98 (p = 0.01). There was no increase in pupil size.
Conclusion: After 2-month treatment with topical pilocarpine 0.05%, there was a significant increase in mean tear
flow in patients with primary aqueous tear deficiency with improvement in OSDI scores. There was no significant
side effects noted.
Keywords: Pilocarpine, Dry Eye, Aqueous tear deficiency, Ocular Surface Disease Index
Philipp J Ophthalmol 2014;39:6.11
Philippine Academy of Ophthalmology
Philippine Journal of
Dry eye syndrome (DES) refers to a group of
conditions characterized by varying symptoms of
ocular discomfort associated with diminished aqueous
tear production and/or excessive tear film evaporation.
It is quite common, affecting approximately 5-30%
of the population and one of the leading causes of
ophthalmology consultation. Epidemiologic studies
in the United States have found that dry eye affected
as many as 17% of women and 11.1% of men.2 The
prevalence in Asia is reportedly higher, up to 33.7%,3
and this is certain to increase as the population ages.
DES was classified according to etiology
into 2 main categories by the International Dry
Eye Workshop (DEWS)4: aqueous tear deficiency
(ATD) characterized by decreased tear production
and evaporative tear dysfunction or excessive tear
evaporation. These 2 conditions often coexist. ATD
can be separated into Sjogren’s syndrome (SS) dry
eye, a systemic autoimmune disorder affecting the
lacrimal and salivary glands, and non-SS dry eye that
comprises other causes of tear deficiency. Primary
dry eye is a condition wherein the dry eye is not
attributable by any other causes, such as anatomical
abnormalities, systemic diseases, nor drug-induced.
Evaporative dry eye is caused by deficiency and or
alteration in lipid secretion by the meibomian glands
resulting in increased evaporation of tears from the
ocular surface.
Dry eye is often a frustrating clinical problem to
identify because of its varying clinical presentation
and often times conflicting results as to its appropriate
treatment. Some patients would complain of severe
ocular irritation and yet have minimal objective signs,
whereas others presented with severe DES and
sight threatening corneal complications only to have
minimal complaints. In terms of treatment, a large
part of the inconsistencies was due to the failure of
investigators to classify dry eye and its severity, making
recommendations confusing.
A specific system4 of classifying dry eye based
on severity has been developed according to a
combination of signs and symptoms, with more
emphasis on symptoms. Due to the nature of the
syndrome, however, certain characteristics overlapped
at different levels of severity. Although specific
treatment recommend­ations4 were given for each level,
the sequence and combinations of therapies should be
determined not only on the basis of the patient’s needs
and acceptance but also on the type of dry eye being
treated. This was further complicated by the customary
OPHTHALMOLOGY
practice of using artificial tear substitute regardless of
the type of DES.
The pathology in aqueous tear deficiencies
(ATD) is the hypofunctioning of the lacrimal gland.
In most cases, the symptoms are associated with a
decrease in lacrimal gland secretion causing reduced
tear volume that triggers an inflammatory response
resulting to ocular manifestations. Since almost 90%
of the total volume of the tear film is made up of the
middle aqueous layer and at least 65% comes from the
lacrimal gland, a decrease in the secretion will result to
tear deficiency. Moreover, this layer contains critical
antimicrobial component that protects the eye from
pathologic and opportunistic microbes that may enter
it through defects of the corneal epithelium as a result
of dryness of the eye. It is, therefore, rational to target
the increase in lacrimal gland secretion as the primary
and main treatment of primary ATD while assuring
prophylactic treatment against ocular infection that
can be potentially blinding.
Pilocarpine and cevimeline, both cholinergic
agonists, have been approved by the US FDA to treat
dry mouth and dry eyes in patients with Sjogren’s
syndrome.5,6 These medications bind to muscarinic
receptors found in the exocrine glands of salivary,
sweat, lacrimal, gastric, and pancreatic glands;
intestinal and respiratory mucous cells and smooth
muscle, thereby stimulating secretion.6
In a study by Vivino using oral pilocarpine, it
showed significant improvement in symptoms of dry
mouth, dry eyes, and other xeroses in patients with
Sjogren’s syndrome.7 Similar results were observed by
Papas using a higher dose that was shown to be more
beneficial.8 Oral pilocarpine was also reported to help
in dry eye induced by radiation therapy.9
Studies on oral pilocarpine have shown significant
improvement in global assessment of dry eyes. Due
to its systemic side effects, however, its use has not
been widely accepted by patients.
The effects of topical pilocarpine in increasing
tear production have not been widely investigated,
though it has been employed for decades in the
treatment of glaucoma at concentrations up to 4%
and in presbyopia at 0.125% with no major systemic
side effects. Topical pilocarpine 0.05%, if proven
to stimulate tear secretion, is a promising treatment
option and can be use as a mainstay for ATD because
it directly addresses the cause of the problem.
January - June 2013
Another benefit of topical pilocarpine is cost
effect­iveness and availability. Comparing other agents
that stimulate lacrimal gland secretion, such as cevimeline (not locally available) and cyclosporine, topical pilocarpine is cheaper, alleviating the financial burden
imposed by chronic use of eye drops.
Thus, a systematic approach to study the efficacy
of topical pilocarpine in increasing the tear secretion
by direct stimulation, using a small concentration to
eliminate systemic and local side effects, was undertaken.
This study focused on the use of topical pilocarpine
0.05% as a treatment option for primary aqueous
tear deficiency (ATD). Specifically, it determined and
measured the increase in tear flow rate in those treated
with topical pilocarpine 0.05% using Schirmer’s I test,
measured the improvement in dry eye symptoms
using the Ocular Surface Disease Index (OSDI)10, and
determined the effects on tear film stability. This study
also identified the side effects of topical pilocarpine
0.05% and measured its effects on pupil size.
METHODOLOGY
Patients seeking consult at the outpatient
department were screened for dry eye from July
2012 to March 2013. The diagnosis of ATD involved
patients with typical symptoms of dry eye using a
list of symptoms and their relative frequencies as
described in the OSDI. The translated Filipino version
was pre-tested and validated with a Cronbach alpha of
0.82.4 An OSDI score of at least 25 was considered
indicative of a probable tear film abnormality. Other
clinical signs included absent, decreased, or low tear
marginal strip or tear meniscus; absent, decreased,
or low lacrimal lake; presence of conjunctival folds;
presence of mucus threads; presence of conjunctival
or corneal surface irregularities; increased blinking
or eye closure preference; focal or generalized ocular
redness; stickiness of lids to eyes in the morning
without significant eye discharge.
They further underwent fluorescein dye,
Schirmer’s I, and tear break-up time (TBUT) tests.
The inclusion criteria were as follows:
1) Adult male or female at least 18 years of age;
2) Schirmer’s I test ≤5 mm;
3) Best-corrected monocular visual acuity of at least
20/70, with a binocular visual acuity of at least
20/40;
4) Availability of patient for follow ups.
Philippine Academy of Ophthalmology
The exclusion criteria were:
1) Patients receiving concurrent treatment, either
systemic or topical medications, that could affect
tear production. Excluded were present, regular or
chronic use of ß blockers (i.e. betaxolol, timolol,
metoprolol, propranolol, atenolol, etc.), cholinergics
(i.e. atro­pine), antihistamines (i.e. chlorpheniramine
or pheniramine maleate, cetirizine, loratadine),
antidepressants, antipsychotics, and Parkinson’s
medications.
2) Anatomical abnormalities of the periocular, lids,
and adnexal tissues;
3) Those with history of eye injury, infection, trauma
or surgery within the previous 6 months;
4) Contact lens wearer;
5) Those with malnutrition;
6) Diagnosed with diabetes mellitus;
7) Pregnant or lactating women;
8) High myopia.
The study was approved by the institutional
review board of the hospital. Informed consent was
obtained by the investigator from all the subjects
after explanation of the nature, benefits, and possible
consequences of the study.
Subjects who qualified were randomly distributed
by simple systematic randomization. They were asked
to pick a piece of paper from a box with either an
A-B or B-A written on it. Those who picked “A-B
treatment” had their right eye treated with artificial
tear substitute (ATS) [Cellufresh MD, Allergan,
USA] and the left eye with topical pilocarpine 0.05%
[prepared aseptically from Pilocarpine 2% eye drops,
Alcon, USA] diluted in the same ATS. Those who
picked the “B-A treatment” were treated with the
reverse scheme. All eye drops were placed in identical
bottles and instilled 3 times a day.
To minimize systemic absorption of pilocarpine,
patients were instructed to perform lacrimal sac
occlusion by applying pressure at the medial canthus
for at least 3 minutes or to close the eyes for at
least 3 minutes after instillation. They were not told
which eye was receiving the experimental drug. The
eye symptoms, Schirmer’s I values, TBUT, and pupil
size (mm) determined at the same lighting condition
were evaluated before treatment by the investigator.
Parameters were evaluated after 3 days, one week, two
weeks, one month, and 2 months from the start of
treatment by an independent trained examiner unaware
of the treatment scheme the patients belonged. Any
side effects experienced by the patients, particularly
Philippine Journal of
brow ache, blurring of vision especially at night,
conjunctival hyperemia, and burning discomfort were
noted during follow-up evaluation.
Results of the tests were encoded and tallied in
SPSS version 10 for windows. Descriptive statistics
were generated for all variables. For nominal data,
such as demographics, frequencies and percentages
were computed. For numerical data, such as Schirmer’s
score, TBUT, OSDI, and pupillary size, mean ± SD
were generated. Analyses of the different variables
were done using the following test statistics: t-test
comparing the results between eyes treated with ATS
and ATS+ pilocarpine; paired t-test for Schirmer’s
score, TBUT, OSDI, and pupillary size between
baseline and single follow up of a given group;
repeated measures ANOVA comparing the results
of Schirmer’s score, TBUT, OSDI, and pupillary size
between baseline and subsequent follow ups of a
particular group.
RESULTS
A total of 508 patients were screened for the
study and 11 patients (22 eyes) who met the inclusion/
exclusion criteria were enrolled. The mean age for the
study population was 48.82 ± 9.96 (Table 1).
Table 1. Demographic characteristics of the study population
(N=11).
Characteristics
Age (years)
31 – 40
41 – 50
51 – 60
Mean ± SD = 48.82 ± 9.96
Sex
Male
Female
Frequency
(N=11)
Percentage
3
1
7
27.3
9.1
63.6
2
9
18.2
81.8
The mean Schirmer’s scores at baseline did
not vary between the two groups (Table 2). After
the 3rd day of pilocarpine, mean Schirmer’s scores
significantly increased 2-3 fold and onwards until
after 2 months of therapy (p <0.01). The final mean
Schirmer’s scores were 5.55 ± 3.90 mm in the ATS
and 12.46± 9.02 mm in the ATS + pilocarpine treated
groups (p = 0.01). Within 2 months of treatment,
there was an increase in tear volume in the ATS +
pilocarpine group as determined by Schirmer’s test
(Table 2).
OPHTHALMOLOGY
Table 2: Comparison of mean Schirmer’s test (mm) at different
intervals between ATS and ATS + Pilocarine groups (N=22 eyes).
Time interval
ATS (n=11)
ATS +
Pilocarpine
(n=11)
p value
Baseline
3.00±1.67
4.09±1.30
0.10
After 3 days
4.09±1.92
6.64±3.38
0.04
After 7 days
4.27±3.95 11.00±8.86 0.01
After 2 weeks
3.46±2.73 8.64±5.14 <0.01
After 1 month
5.46±3.88 11.46±8.76 0.02
After 2 months
5.55±3.90 12.46±9.02 0.01
ATS: artificial tear substitute
There was no difference in the TBUT scores
between the 2 groups from baseline until after 2
months of treatment (Table 3). The final mean TBUT
was 3.64± 0.92 in the ATS and 3.91±1.14 in the ATS
+ pilocarpine groups (p = 0.54).
Table 3: Comparison of TBUT (seconds) at different intervals
between ATS and ATS+ Pilocarpine groups (N=22 eyes).
Time interval
ATS
(n=11)
ATS+ Pilo
(n=11)
p value
Baseline
2.91±1.14
2.82±1.16
0.86
After 3 days
2.82±1.08
3.36±1.36
0.31
After 7 days
3.09±1.04
3.64±1.96
0.42
After 2 weeks
2.91±1.30
3.64±1.80
0.30
After 1 month
3.72±1.10
3.46±1.29
0.60
After 2 months
3.64±0.92
3.91±1.14
0.54
The OSDI scores showed significant decrease
in ocular symptoms after completion of 2 months
treatment (Table 4). There was a significant difference
in the OSDI from initial (33.72 ± 24.88) and after 2
months (13.84 ± 8.98) [p = 0.01].
Table 4. Comparison of OSDI at baseline and after 2 months.
Patient
Baseline OSDI OSDI after 2 months Difference
1) 50 yo, F
13.88
2.77
11.11
2) 59 yo, M
9
9
0
3) 31 yo, M
52.27
27.08
25.19
4) 34 yo, F
18.75
25
-6.25
5) 57 yo, F
14.58
6.25
8.33
6) 37 yo, F
63.63
15.9
47.73
7) 55 yo, F
62.5
27.27
35.23
8) 55 yo, F
18.75
5
13.75
9) 55 yo, F
77.5
10
67.5
10) 51 yo, F
22.5
15
7.5
11) 56 yo, F
17.5
15
2.5
OSDI
Mean ± SD
Range
Baseline
After 2 months
33.72 ± 24.88
9.0 – 77.5
13.84 ± 8.98
2.77 – 27.27
p value
0.01
January - June 2013
There was no difference in the pupillary size
from baseline (2.36 ± 0.51) and after 2 months (2.46
± 0.52) [Table 5].
Table 5: Comparison of pupil size between baseline and follow ups.
Pupillary Size
(mm)
Baseline
After 3 days
After 7 days
After 2 weeks
After 1 month
After 2 months
Mean ± SD
Range
p value
2.36±0.51
2.46±0.52
2.46±0.52
2.46±0.52
2.46±0.52
2.46±0.52
2–3
2–3
2–3
2–3
2–3
2–3
0.81
DISCUSSION
Dry eye syndrome has been recognized as one
of the public health problems for decades imposing
economic burden and affecting the individual’s
quality of life. The increasing knowledge on the
etiopathogenesis of the different types of dry eyes,
as well as the factors responsible for the condition,
provides a rationale for multiple and appropriate
treatment options. Vast researches have been
conducted to address the problem, yet other concerns
were still not met. The problem is confounded with
the use of a single class of medication regardless
of the type of dry eye. Realizing the existence and
differences between the 2 major classifications of dry
eye, specific treatment approaches should be followed
to achieve higher treatment success and patient
satisfaction.
The pathology in primary ATD is hypo-­
functioning of the lacrimal gland. Pilocarpine, a
cholinergic agonist, binds to muscarinic receptors
of exocrine glands stimulating secretion. The effect
of topical pilocapine in increasing tear flow rate had
been studied by Emina11 using concentrations of 2%
and 4%. Both showed increased tear flow rate but
caused significant pupillary constriction, blurring
of vision, conjunctival hyperemia, and stinging
sensation after instillation. Topical pilocapine 0.05%
was used in this study to reduce these side effects.
It is similar in concentration to Restasis 0.05%
(cyclosporine A, Allergan, USA) but much less
expensive. This concentration was chosen based on
studies in neuroophthalmology that pilocarpine 0.1%
insignificantly caused pupillary constriction among
normal eyes.12
A total of 508 patients were screened but only 11
10
Philippine Academy of Ophthalmology
patients (22 eyes) had primary aqueous tear deficient
dry eye, a prevalence of approximately 2% similar to
other studies.13 As expected, there was a predominance
of females, with mean age of 49 years and age ranging
from 31 to 59. Studies have shown that females with
ATD usually belonged to the age of approximately 40
years, considered a perimenopausal age ranging from
37-59 years. In our study, the youngest subject was a
31 year old male, considered young for this condition.
He was chronically exposed to wind for more than 5
years, riding his bike each day for 1 hour without eye
protection in going to and from work.
After instillation of topical pilocarpine 0.05%, our
data showed that there was a steady stepwise increase
in mean tear flow rate as compared to baseline (4.09
± 1.30) and after 2 months (12.46 ± 9.02) (p <0.01).
A longer period of observation is needed to ascertain
its long term effect.
TBUT values from baseline and at different
intervals showed no improvement (p >0.05), indicating
that pilocarpine had no effect on tear film stability.
There was symptomatic improvement in the
OSDI scores of 80% of the patients. One patient had
no change and another had worse ocular symptoms
after treatment. Lack of improvement could possibly
be explained by the nature of the work of the
patients since they were continuously exposed to air
conditioning for 8 hours and had irregular working
hours during night shifts.
There was no change in the pupillary size of
all patients after 2-month use of topical pilocarpine
0.05%.
The strengths of this study were its design as
a prospective, controlled, double-blind and the first
research conducted employing the use of topical
pilocarpine 0.05% eye drops for stimulating tear
production. However, the sample size was relatively
small due to the strict criteria employed in limiting
the study to pure ATD and the low prevalence of
ATD subtype.11 Additional prospective controlled
trials utilizing a larger population is recommended for
further confirmation of our results, including a longer
follow-up period to verify if the increase in tear flow
rate is maintained over time. Future researches in
testing the different lower concentrations of topical
pilocarpine devoid of its undesirable side effects may
also be conducted.
Philippine Journal of
This study, therefore, showed that topical pilocarpine 0.05% was efficacious in increasing the tear
flow rate with improved OSDI scores and has the
potential to be considered as a treatment modality
in managing patients with primary aqueous tear
deficiency.
OPHTHALMOLOGY
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19.Kymionis G, Bouzoukis D, Diakonis V, et al. Treatment of
chronic dry eye: focus on cyclosporine. Clin Ophthalmol
2008;2:829- 836.
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