Short-term Consumption of Oral Omega-3 and Dry Eye Syndrome

Short-term Consumption of Oral Omega-3 and Dry Eye Syndrome Haleh Kangari, OD, PhD, 1 Mohammad Hossein Eftekhari, MD, 2 Sara Sardari, MSc, 1 Hassan Hashemi, MD, 3 Jamshid Salamzadeh, PhD, 4 Mohammad Ghassemi-Broumand, MD, 5 Mehdi Khabazkhoob, MSc 6 Purpose: To assess the effect of oral omega-3 fatty acids on tear break-up time (TBUT), Schirmer s score, and Ocular Surface Disease Index (OSDI) through a double-blind clinical trial. Design: Randomized, double-blind clinical trial. Participants: Sixty-four patients with dry eye symptoms between the ages of 45 and 90 years were randomized into 2 groups: 33 persons in the treatment group and 31 persons in the placebo group. Methods: The treatment group received 2 capsules of omega-3 (each containing 180 mg eicosapentaenoic acid [EPA] and 120 mg docosahexaenoic acid [DHA]) daily for 30 days, and the placebo group received 2 mediumchain triglyceride oil capsules daily for 1 month. The outcomes were measured 1 month after the intervention. Main Outcome Measures: The primary outcome measure was an increase from baseline in TBUT at day 30. Secondary outcome measures were a decrease from baseline in the OSDI score and an increase in the Schirmer s score at day 30. Results: In the placebo group, before the intervention, the mean TBUT, OSDI, and Schirmer s scores were 4.5 2.1 seconds, 36.4 13.8, and 6.0 2.6 mm, respectively, and 1 month later were 4.7 2.6 seconds, 37.6 13.5, and 6.2 2.5 mm, respectively. In the treatment group, these values were 3.9 1.7 seconds, 38.7 16.5, and 5.8 2.5 mm before the intervention and 5.67 2.6 seconds, 29.3 15.9, and 6.8 2.8 mm after the intervention, respectively. Repeated-measures analysis of variance showed that improvements in TBUT, OSDI, and Schirmer s scores were significantly better in the treatment group than in the placebo group. The changes in the treatment and placebo groups were 71% and 3.3% for TBUT (P < 0.001), 26% and 4% (P¼0.004) for dry eye symptoms, and 22.3% and 5.1% for Schirmer s score (P¼0.033), respectively. Conclusions: This study demonstrated that oral consumption of omega-3 fatty acids (180 mg EPA and 120 mg DHA twice daily for 30 days) is associated with a decrease in the rate of tear evaporation, an improvement in dry eye symptoms, and an increase in tear secretion. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:2191-2196 ª 2013 by the American Academy of Ophthalmology. Dry eye syndrome (DES) is a multifactorial disease of the ocular surface. Rapid evaporation of tear film, inadequate production of tears, and inflammation of the ocular surface are among the causes of this syndrome. This condition can result in the ocular symptoms of foreign body sensation, redness, and discomfort, as well as the signs of surface damage in the cornea and conjunctiva, all leading to detrimental visual performance. The epidemiologic studies of DES worldwide have shown different prevalence rates, ranging from 14.6% to 57.5%. 1e11 In these studies, because DES is defined in different ways and various techniques are used for its assessment, the results are not fully comparable. Dry eye syndrome is one of the most common conditions causing referrals to ophthalmologists worldwide and has been found to impose a great burden to societies. 12,13 The common symptoms of DES can seriously affect patients quality of life. 14,15 Although treatments such as artificial tears, anti-inflammatory drops, autologous serum eye drop therapy, and punctal plugs tend to alleviate symptoms, there are downsides to each treatment modality; for example, artificial tears provide only short-term relief. Topical corticosteroids may induce ocular side effects. Because autologous serum is driven from the blood, the risks of anemia and blood-borne infection exist for this therapy. 16 Punctual plugs raise the risk of secondary infection by obstructing the canaliculi. 17 Because of these problems, clinicians are seeking new treatment modalities for the management of DES. Essential fatty acids in the diet have been shown to improve DES. 13 Omega-6 and omega-3 fatty acids are among the essential fatty acids that cannot be synthesized in the body and must be obtained from the diet. The ideal balance of omega-3/omega- 6 is 1:2.3, but because of industrialization and a higher intake of omega-6 in the diet, an imbalance exists in many populations. 13 As a result, many dieticians are encouraging the population to incorporate omega-3 into their diet. 18 Omega- 3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). 13 Eicosapentaenoic acid and DHA are derived from fish oil, and they have more potent immunomodulatory activity than ALA, which is derived from vegetable oils. 18 The American Dietetic Association, Dieticians of Canada, 13 and the International Society for the Study of Fatty Acids and Ó 2013 by the American Academy of Ophthalmology Published by Elsevier Inc. ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.04.006 2191

Ophthalmology Volume 120, Number 11, November 2013 Lipids 18 recommend an intake of at least 500 mg of EPA and DHA daily. Omega-3 fatty acids seem to influence DES via (1) restoring the lipid layer in the tear film by clearing meibomianitis, and (2) increasing tear secretion from the lacrimal gland. 13 In the past decade, several studies have demonstrated that increasing essential fatty acid supplements in the diet may ameliorate DES symptoms. In a clinical trial by Creuzot et al, 19 the treatment group received a daily intake of oral omega-3 (196 mg EPA, 14 mg DHA) plus omega-6 (41 mg gamma-linolenic acid, 63 mg linoleic acid) for 6 months. When the treatment group was compared with the placebo group, the symptoms showed significant improvement, whereas the results of the objective tests showed only a slight improvement. In a double-masked clinical trial, Brignole-Baudouin et al 20 showed that oral supplemental omega-3 (containing 427.5 mg EPA and 285 mg DHA) plus omega-6 (15 mg) can reduce the expression of the inflammatory marker in the conjunctival epithelium. In another pilot randomized, double-blind, clinical trial, Wojtowicz et al 21 reported that the treatment group received a daily intake of omega-3 fatty acids (450 mg EPA, 300 mg DHA, 1000 mg flaxseed oil) for 90 days. This group showed a significant improvement in dry eye symptoms. The changes in the tear volume also were significant, whereas the changes in meibum lipid composition and aqueous tear evaporation rate were not significant. Because the intake of omega-6 fatty acids is high in the diet of industrialized societies and it is believed that omega- 6 fatty acids produce some proinflammatory precursors, we decided to focus on omega-3 fatty acids, which have more anti-inflammatory precursors. We specifically chose EPA and DHA, which have more potent immunomodulatory activity than ALA. The previous investigators used a combination of omega-3 with omega-6 fatty acids 19,20 or a high dose of all 3 omega-3 fatty acids. The study duration was selected to be 1 month on the basis of the time that it takes for fatty acid oral supplements to show a beneficial effect on DES. 22 This purpose of this study was investigate the impact of omega-3 fatty acids (180 mg EPA and 120 mg DHA twice daily for 30 days) on DES (measured per Ocular Surface Disease Index [OSDI] symptom questionnaire, tear break-up time [TBUT], the Schirmer s test score) in a randomized, double-blind, clinical trial. Methods The subjects for this study were recruited from among the patients of a private ophthalmology clinic in the northern suburbs of Tehran. Patients with a positive history of DES in the records, mostly with dry eye symptoms, were contacted and invited for a follow-up visit. During the visit, their TBUT was measured using the Lowther technique by an experienced examiner (the technique is described later). The inclusion criteria for this study were (1) age 45 to 90 years, (2) TBUT <10 seconds in both eyes, and (3) no use of artificial tears for the past 3 months. The exclusion criteria were (1) active allergy or infection at the ocular surface; (2) presence of pterygium or pinguecula; (3) treatment with ocular topical steroidal or nonsteroidal antiinflammatory treatment, glaucoma medication, or anti-allergy eye drop in the past month; (4) positive history of refractive surgery or contact lens wear; (5) use of systemic medication that may interfere with tear production, such as antianxiety, antidepressive, antihypertensive, and antihistamine medications; (6) positive history of blood or coagulation disorders; (7) positive history of gastric ulcers; (8) positive history of surgery in the past 3 months; (9) undergoing head and neck radiotherapy; (10) use of omega-3 supplements in the past 3 months; and (11) positive history of allergy to fish oil or gelatinous capsules. For the patients who met these criteria, the purpose of the study was explained. If willing, they were asked to sign the informed consent form that was prepared on the basis of the Declaration of Helsinki. Sample Size Calculation The sample size was estimated on the basis of the following assumptions: alpha of 5%, beta of 20%, and a change in TBUT of at least 1 second between the groups in a 2-tailed study. The estimated sample sizes were 34 subjects in the treatment group and 34 subjects in the placebo group, which was increased to 37 per group to account for possible dropouts. A total of 74 subjects were recommended for the total sample size. Randomization The method of randomization in this study was blocked randomization. Thirteen blocks of 6 were determined. Blinding To avoid information bias, omega-3 allocation was performed in a double-blind fashion; the treatment group, the control group, and the examiners who performed the tests were all unaware of the allocation status. Patients were coded by a third person who applied the randomization protocol and provided them with the allocated type of capsules. Examinations All of the patients were examined in 2 visits, one before and one 30 3 days after the intervention. To assess patients DES-related symptoms, a validated ocular surface disease questionnaire 23 was used. One examiner orally asked each participant the questions from a Persian translated version and filled the corresponding responses in the forms. The OSDI is a 12-question survey with answers on a 5-point scale (0 ¼ none of the time and 4 ¼ all of the time), with higher scores representing greater disability. The total OSDI score is calculated on the basis of the formula 100 (sum of severity for all questions answered)/4 (total number of questions answered), where the severity was graded on a scale of 0 ¼ none of the time, 1 ¼ some of the time, 2 ¼ half of the time, 3 ¼ most of the time, and 4 ¼ all of the time. A score of 100 corresponds to complete disability, and a score of 0 corresponds to no disability. After the completion of the questionnaire, the TBUT assessment was performed using the Lowther technique in each eye. 24 A sterile fluorescein strip (Indicator, Elham Teb Co., Tehran, Iran) was moistened using nonpreserved saline. Excessive solution was shaken off. The strip gently touched the superior bulbar conjunctiva with care not to instill too much solution or cause excessive reflex tearing. After a few blinks, the patient was asked to close his/her eyes and then keep them open. The time between the eye opening and the appearance of the first dry spot was measured in seconds. The measurements were taken 3 times for each eye, and their mean was recorded. For each subject, the TBUT of 2 eyes were averaged and the average values were compared before and after the intervention. 2192

Kangari et al Omega-3 and Improvement of Dry Eye The Schirmer s 1 test was performed without anesthetic, measuring the total tear secretion (basic and reflex) in each eye. The eyes were gently dried with tissue paper over closed lids to mop up any excess secretion. The filter paper was folded 5 mm from one end and inserted at the junction of the middle and outer third of the lower lids. After 5 minutes, the filter papers were removed, and the amount of wetting was measured by a ruler. The average of the 2 measurements for each eye was calculated and compared before and after the intervention. Intervention The treatment group was assigned two 1-g capsules, each capsule containing 180 mg of EPA and 120 mg DHA (a total daily dose of 600 mg of EPA and DHA), to be taken in the morning and the evening after the meal for 1 month. These 2 omega-3 fatty acids were selected because they have more potent immunomodulatory action than ALA. On the basis of the recommendation of the International Society for the Study of Fatty Acid and Lipids (i.e., a daily intake of at least 500 mg of EPA and DHA), a total dose of 600 mg EPA and DHA was selected for this study. The duration of the treatment was selected on the basis of a previous study 22 because it takes 1 month for omega-3 fatty acids to exert changes in the signs and symptoms of DES. The control group received a dosage of two 1.0-g placebo capsules containing medium-chain triglycerides per day for 1 month. Because mediumchain triglycerides taken at a dosage of 1.7 g per day have not shown any deleterious effect, in particular on the ocular surface, it was used as the placebo in this study. The placebo capsules were prepared by the Zahravi Pharmaceutical Company (Tehran, Iran) and appeared exactly like the omega-3 capsules. Outcome Measures The primary outcome measure was an increase from baseline in TBUT at day 30; a 50% change from baseline was selected to be clinically significant. The TBUT is the time required for dry spots to appear on the surface of the eye after blinking. The longer it takes, the more stable the tear film. A positive number in change from baseline indicates an increase in TBUT (improvement). Secondary outcome measures were (1) a change from baseline in OSDI questionnaire score at day 30 (a reduction from baseline represents an improvement) and (2) a change from baseline in Schirmer s 1 test at day 30. An increase in the amount of wetting represents an improvement. Statistical Analysis To ensure group similarity at the baseline, the independent t test and chi-square analysis were performed. Within each group, the results at baseline and after the intervention were compared using a paired t test. To compare changes in the placebo and treatment groups, repeated-measures analysis of variance was used. All analyses were performed considering a 5% error. Ethical Considerations This project was approved by the ethics committee of Shahid Beheshti University of Medical Sciences and was registered at the Iranian clinical trial registration website as IRCT201012265467N1. Results A total of 73 participants were recruited into the trial, with 64 returning and completing the follow-up examination. A total of 9 subjects (5 in the treatment group, 4 in the control group) failed to complete the trial; in the treatment group, 3 subjects stopped the medication because of digestion problems, 1 subject stopped the medication because of the advice of another doctor, and the rest of the subjects were lost to follow-up. Eventually, 64 patients (33 in the treatment group and 31 in the control group) completed the study. The difference in sex distribution in the 2 groups was not significant (P¼0.417); 54.5% in the treatment group and 64.5% in the control group were female. Table 1 shows the mean age, mean baseline TBUT, OSDI score, and Schirmer s score before random allocation of omega-3 in the 2 groups; the intergroup differences regarding these variables were not statistically significant. Tear Break-up Time Test Figure 1 illustrates the mean TBUT in the treatment and placebo groups at baseline and 1 month after the intervention. The mean TBUT was 4.7 2.6 seconds in the placebo group, which was not significantly different from the baseline value (P¼0.353). However, as demonstrated in Figure 1, the mean TBUT in the treatment group increased by approximately 1.7 seconds, and this change was statistically significant (P < 0.001). Repeatedmeasures analysis of variance demonstrated a significant interaction between treatment group and change over time in the trend of mean TBUT (P¼0.003). The increase in TBUT was 71% in the treatment group versus 3.3% in the placebo group; the intergroup difference was statistically significant (P¼0.004). Ocular Surface Disease Index Figure 2 illustrates the mean OSDI scores in the placebo and treatment groups at the baseline and 1 month after intervention. At 1 month, the mean OSDI was 37.6 13.5 in the control group (P¼0.049) and had significantly decreased to 29.3 15.9 (P < 0.001) in the treatment group. Repeated-measures analysis of variance demonstrated a significant interaction between treatment groups and change over time in the trend of mean OSDI (P < 0.001). There was a 26% reduction in DES-related symptoms, whereas the control group showed a 4% increase in this regard (P < 0.001). Schirmer s Test Figure 3 illustrates the mean Schirmer s readings in the placebo and treatment groups before and after the intervention. In the placebo group, the mean Schirmer s score increased by 0.19 0.57 mm compared with baseline; this change was not statistically significant (P¼0.070). In the treatment group, a change of 0.93 1.43 mm from baseline was observed, which was statistically significant (P < 0.001). Repeated-measures analysis of variance demonstrated a significant interaction between treatment groups and change over time in the trend of Schirmer s Table 1. Baseline Characteristics of the Two Groups Placebo Mean SD Treatment Mean SD P Value Age (yrs) 61.8 8 60.6 8.7 0.590 OSDI 36.4 13.8 38.7 16.5 0.543 TBUT (s) 4.5 2.1 3.9 1.7 0.213 Schirmer s test score (mm) 6.0 2.6 5.8 2.5 0.853 OSDI ¼ Ocular Surface Disease Index; SD ¼ standard deviation; TBUT ¼ tear break-up time. 2193

Ophthalmology Volume 120, Number 11, November 2013 Figure 1. Comparison of mean and 95% confidence interval (CI) of tear break-up time in the treatment and placebo groups before (baseline) and after the intervention (outcome). score (P¼0.010). Mean improvement was 22.3% in the treatment group and 5.1% in the placebo group (P¼0.033). Discussion The results of this study demonstrated that the oral consumption of omega-3 capsules (each capsule containing 180 mg of EPA and 120 mg DHA) twice daily for 1 month improves the signs and symptoms of DES. In terms of TBUT, an improvement of 71% was observed in the treatment group versus 3.3% in the placebo group. This improvement may have occurred because of the anti-inflammatory action of these omega-3 fatty acids on the meibomian glands. These fatty acids are believed to be involved in the inflammatory Figure 2. Comparison of mean and 95% confidence interval (CI) of Ocular Surface Disease Index in the treatment and placebo groups before (baseline) and after the intervention (outcome). Figure 3. Comparison of mean and 95% confidence interval (CI) of Schirmer s readings in the treatment and placebo groups before (baseline) and after the intervention (outcome). cycle via 2 pathways: (1) by blocking the gene expression of proinflammatory cytokines, tumor necrosis factor-a, interleukin-1a, interleukin-1b, proteoglycan degrading enzymes (aggrecanases), and cyclooxygenase-2 or (2) by producing anti-inflammatory factors (e.g., prostaglandin E3 and leukotriene B5). 13 These factors may have helped to clear the meibomianitis, allowing a thinner, more uniform lipid layer to be secreted from the meibomian glands. This in turn may have retarded the evaporation of the tear film and helped to restore the tear film. A change in the TBUT score was not observed by Creuzot et al, 19 perhaps because they used a combination of omega-3 and omega-6 fatty acids in their treatment group. When omega-6 intake is high, the production of arachidonic acid and other proinflammatory cytokines could be higher and lead to less reduction in overall inflammation. In the study by Wojtowicz et al, 21 the impact of omega-3 on TBUT was not directly measured. Instead, they measured the aqueous tear evaporation by the evaporimeter and performed meibomian lipid analysis by high-performance liquid chromatography. Their findings show that the lipid compositions of their samples did not differ in the 2 groups. Because of the high lipid complexity of meibum, these investigators concentrated only on the major lipid species. The changes in the other lipid species might have led to higher TBUT in our study. With regard to DES symptoms, 1 month after the intervention in the current study, the mean OSDI score in the treatment group decreased by 9 units compared with the baseline, whereas the scores in the placebo group were indicative of a slight increase in borderline significance. The rate of improvement in the treatment group was 26%. In the study by Wojtowicz et al, 21 the rate of improvement of the symptoms measured by the OSDI questionnaire was 70% in the treatment group versus 7% in the control group. Creuzot et al 19 reported favorable outcomes in the symptoms of the treatment group. Compared with these 2 studies, the rate of improvement in the current study was less, and this could be 2194

Kangari et al Omega-3 and Improvement of Dry Eye attributed to the higher dosage and longer intervention time in their studies. Although we expected to see some improvement in our control group as a result of a placebo effect, the DES symptoms worsened in the placebo group. This indicates that failure to receive the proper treatment can outdo the placebo effect. As a result, our control group experienced worsening of symptoms. One month after the intervention, a significant increase was observed in the mean Schirmer s score, although the increase was less than what was noted in TBUT. The mean increase in the treatment group was approximately 23%, whereas the placebo group showed only a 5.1% increase. This improvement could be due to the effect of omega-3 fatty acids on the inflammatory cycle via the pathways that were discussed earlier. As a result, the amount of inflammation and apoptosis in the lacrimal gland may have been reduced and the rate of tear production increased, as described by Roncone et al. 13 Wojtowicz et al 21 observed similar results, whereas Creuzot et al 19 showed only a slight improvement in the mean Schirmer s readings. This contradiction could be due to the intake of omega-6 with omega-3 in their study, which has less reduction in the anti-inflammatory mechanism. In this study, the power analysis was performed using the mean difference in TBUT in the placebo group (0.16 0.95, with 31 subjects) and treatment group (1.71 2.66, with 33 subjects). The analysis showed a power of 88.1% for TBUT. In addition, the power analyses of the Schirmer s results and OSDI questionnaire showed a power of 77% and 99%, respectively. Study Limitations The short duration of treatment (1 month) and lack of control over the dietary intakes of the subjects were among the limitations of this study. In conclusion, although our study is one of the few to show a positive impact of omega-3 consumption on the improvement of the signs and symptoms of DES, in light of the varied causes of DES around the world and the effect of genetic, racial, and dietary differences, a multicenter clinical trial with a larger sample size and longer treatment period is suggested to observe the long-term efficacy and safety of this supplement in the improvement of DES. References 1. Chia EM, Mitchell P, Rochtchina E, et al. Prevalence and associations of dry eye syndrome in an older population: the Blue Mountains Eye Study. Clin Experiment Ophthalmol 2003;31:229 32. 2. Galor A, Feuer W, Lee DJ, et al. Prevalence and risk factors of dry eye syndrome in a United States veterans affairs population. Am J Ophthalmol 2011;152:377 384 e2. 3. Guo B, Lu P, Chen X, et al. Prevalence of dry eye disease in Mongolians at high altitude in China: the Henan eye study. Ophthalmic Epidemiol 2010;17:234 41. 4. 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Footnotes and Financial Disclosures Ophthalmology Volume 120, Number 11, November 2013 Originally received: November 27, 2012. Final revision: April 3, 2013. Accepted: April 4, 2013. Available online: May 3, 2013. Manuscript no. 2012-1779. 1 Department of Optometry, Faculty of Rehabilitation, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2 Torfe Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3 Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran. 4 Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5 Faculty of Rehabilitation, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6 Dezful University of Medical Sciences, Dezful, Iran. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. This project is funded by the Vice Chancellor for Research of Shahid Beheshti University of Medical Sciences. Correspondence: Sara Sardari, MSc, Department of Optometry, Faculty of Rehabilitation, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: sardari_op@yahoo.com. 2196