Efficacy of Topical Pilocarpine in the Management of Primary Aqueous Tear Deficiency: An Initial Study

Transcription

1 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 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 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 mm ± 9.02 after 2 months (p <0.01). Symptoms improved with noted decreased OSDI score from ± to ± 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

2 Philippine Journal of OPHTHALMOLOGY 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 system 4 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 recommendations 4 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 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

3 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 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 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. 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 8 Philippine Academy of Ophthalmology

4 Philippine Journal of OPHTHALMOLOGY 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 ± 9.96 (Table 1). Table 1. Demographic characteristics of the study population (N=11). Characteristics Frequency (N=11) Percentage Age (years) Mean ± SD = ± 9.96 Sex Male Female 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). 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 ± ± After 3 days 4.09 ± ± After 7 days 4.27 ± ± After 2 weeks 3.46 ± ± 5.14 <0.01 After 1 month 5.46 ± ± After 2 months 5.55 ± ± 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). ATS ATS+ Pilo Time interval (n=11) (n=11) p value Baseline 2.91 ± ± After 3 days 2.82 ± ± After 7 days 3.09 ± ± After 2 weeks 2.91 ± ± After 1 month 3.72 ± ± After 2 months 3.64 ± ± 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 ) 59 yo, M ) 31 yo, M ) 34 yo, F ) 57 yo, F ) 37 yo, F ) 55 yo, F ) 55 yo, F ) 55 yo, F ) 51 yo, F ) 56 yo, F Baseline After 2 months p value OSDI Mean ± SD ± ± Range January - June

5 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) Mean ± SD Range p value Baseline 2.36 ± After 3 days 2.46 ± After 7 days 2.46 ± After 2 weeks 2.46 ± After 1 month 2.46 ± After 2 months 2.46 ± DISCUSSION 0.81 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 hypofunctioning 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 Emina 11 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 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 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. 10 Philippine Academy of Ophthalmology

6 Philippine Journal of OPHTHALMOLOGY 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. 121: Reddy P, Grad O, Rajagopalan K. The economic burden of dry eye: A conceptual framework and preliminary assessment. Cornea External Dis 2004;23: Kymionis G, Bouzoukis D, Diakonis V, et al. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol 2008;2: References 1. American Academy of Ophthalmology; Preferred Practice Pattern, Dry Eye Syndrome; November Moss SE, Klein R, Klein BEK. Prevalence of and risk factors for dry eye syndrome Arch Ophthalmol 2000; 118: Lin PY, Tsai SY, Cheng CY, et. al. Prevalence of dry eye among elderly Chinese population in Taiwan (The Shihpai Eye Study). Ophthalmology 2003; 110: The definition and classification of Dry Eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye Workshop. Ocul Surf 2007; 5: Drug Highight: Pilocarpine, Indian Journal of Pallative Care (serial online) 2006 (cited 11 April 2011); 12: Goodman and Gilman. The Pharmacological Basis of Therapeutics, 11th ed; McGraw-Hill Companies, Inc.; Chapter 7: Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren s syndrome: a randomized, placebocontrolled, fixed dose, multicenter trial. P92-01 Study Group. Arch Intern Med 1999; 159: Papas AS, Sherrer YS, Charney M, et al. Successful treatment of dry mouth and dry eye symptoms in Sjogren s syndrome patients with oral pilocarpine: a randomized, placebocontrolled, dose-adjustment study. J Clin Rheuma 2004;10: Tsifetaki N, Kitsos G, Paschides CA, et al. Oral pilocarpine for the treatment of ocular symptoms in patients with Sjogren s syndrome: a randomized 12 week-controlled study. Ann Rheumatic Dis 2003; 62: Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118: Emina MO. Aging and topical pilocarpine concentrations: effects on pupil size and tear flow rate. J Optometry 2010; 3: American Academy of Ophthalmology Basic and Clinical Science Course.Neuroophthalmology Section 5, : Albietz JM. Prevalence of dry eye subtypes in clinical optometry practice. Optom Vis Sci 2000; 77: Pflugfelder SC, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorder. New York: Informa Healthcare; American Academy of Ophthalmology Basic and Clinical Science Course. External Disease and Cornea. Section 8, : Ramos- Casals M, Tzioufas A, Stone J, et al. Treatment of primary Sjögren Syndrome: A systematic review. JAMA 2010; 304: Winter JH, Berghold A, Schmut O, et al. Evaluation of the clinical course of dry eye syndrome. Arch Ophthalmol 2003; January - June