Omega-3 fatty acids (FAs), also called n-3 fatty acids, have been used as oral supplements to aid in the treatment of various diseases, including dry eye disease (DED), for years. But, the Dry Eye Assessment and Management (DREAM) study, a large-scale, multicenter, double-masked randomized controlled trial evaluating omega-3 FA supplements for DED¹, caused much confusion and left us with more questions than it answered.

INFLAMMATION AND OMEGA-3 FAS

We now have a better understanding of how inflammation plays a role in the cycle of DED. The revised Tear Film and Ocular Surface Society’s Dry Eye Workshop (DEWS) definition of dry eye in 2017 details a loss of tear film homeostasis “in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”² Dietary intake of omega-3 FAs is thought to be anti-inflammatory,^3,4 thereby improving the signs and symptoms of DED.

Like me, you have probably added omega-3 FAs to your dry eye armamentarium because they are relatively safe, easy to obtain and use and, anecdotally, have resulted in improvements in your patients with dry eye. But, like me, you have probably also been confused by the fine details of what types of FAs are best (eicosapentaenoic acid [EPA] or docosahexaenoic acid [DHA]), what dosages are most beneficial and how they work to decrease inflammation. In fact, you may have even doubted the benefits of recommending omega-3 FAs altogether — and you are not alone. The 2018 AAO “Dry Eye Syndrome Preferred Practice Pattern” is not even definitive, stating that omega-3 FAs may be “potentially beneficial.”⁵ The truth is that the use of omega-3 FAs for dry eye, although common, is confusing.

THE BASICS OF DIETARY OMEGA-3 FAS

Omega-3 FAs are essential polyunsaturated FAs that exist as both short-chain (alpha-linolenic acid) and long-chain (EPA and DHA) subtypes. Humans do not make these FAs, so they need to be obtained from our diet.^6,7 Long-chain fatty acids are found in fish oils such as salmon, flounder, cod and tuna. Short-chain fatty acids are found in walnuts, soy beans, flaxseed and linseed oils.⁷ Inflammatory eicosanoids, such as prostaglandins, thromboxanes and leukotrienes, play a role in inflammation, and essential fatty acids are precursors for the production of eicosanoids.

Omega-3 FAs are thought to be anti-inflammatory, and omega-6 FAs are thought to be pro-inflammatory.⁸ Omega-3 FAs are anti-inflammatory by competitive enzyme inhibition with arachidonic acid as a substrate for cyclooxygenases and 5-lipoxygenase.^7,9 They block the production of pro-inflammatory eicosanoids.

DREAM CONFUSION

The confusion surrounding the use of omega-3 FA is a result of the conflicting data on its efficacy and the lack of consensus regarding the types of omega-3 FAs and their dosages.

The purpose of the DREAM study was to determine the safety and efficacy of omega-3 FAs in the treatment of DED. From October 2014 to July 2016, patients with moderate to severe DED from 27 centers were randomized to receive either omega-3 (active) or olive oil (placebo) capsules. Two-thirds of patients received omega-3 supplements, and one-third received the placebo. The active omega-3 capsules contained 400 mg of EPA and 200 mg of DHA. The placebo capsules contained 1000 mg of refined olive oil (68% oleic acid, 13% palmitic acid and 11% linoleic acid). In both trials, patients received five capsules a day. The primary outcome was the mean change in the Ocular Surface Disease Index (OSDI) score from baseline. Secondary outcomes included changes in the signs of DED, including conjunctival staining score, corneal staining score, tear break-up time and Schirmer test scores.

The results showed a statistically significant decrease in the OSDI scores from baseline to 12 months in both groups, with the greatest decrease in the first three months. Mean change in OSDI score was -13.9 + 15.6 points for the active group and -12.5 + 18.2 points in the placebo group. The mean change in the OSDI scores for the two groups was not statistically different. As for the key signs of DED, patients in both groups had statistically significant improvements from baseline to 12 months in conjunctival staining, corneal staining and tear break-up time for both groups but no statistical difference in Schirmer scores from baseline. Again, there were no statistical differences when comparing the active and placebo group for all four of these signs.¹

The study was considered “real world” as the subjects were allowed to continue their current treatments for DED, and there was a one-year follow-up period, minimizing the effects of seasonal variations. Their conclusion was that among patients who had moderate-to-severe DED randomly assigned to omega-3 FA or placebo (olive oil) supplements, symptoms and signs improved. However, the closing sentence was “We found no evidence of a beneficial effect of n-3 fatty acid supplements as compared with placebo supplements among patients with DED.”¹

A LOOK AT MORE LITERATURE

The DREAM study seemingly stoked the coals of the omega-3 controversy surrounding its efficacy. The controversy exists for many reasons. First, there is no standard regarding the formulation and dosing of the various omega-3 FA supplements, both in studies and on the market. Second, and most importantly, several studies show benefits of omega-3 FA for improving the signs and symptoms of DED, and many are inconclusive.

A recently published paper specifically assessed the efficacy of omega-3 FA supplementation for the treatment of DED by performing a meta-analysis of randomized clinical trials.⁷ The authors performed a literature search and included 17 randomized clinical trials involving 3,363 patients in an attempt to clarify the confusion. By their own admission, there are limitations to their analysis. These include the fact that the analyzed trials had differences in the patient characteristics such as age, sex, dry eye etiology and dry eye severity. Also, they could not identify a relationship between the efficacy and the dose and duration of treatment. Nonetheless, the authors’ conclusion was that omega-3 FA supplements “improve dry eye symptoms, tear film stability and tear production in patients with DED.”⁷

DREAM STUDY: GOOD, BAD AND THE UGLY

So, let’s review “the good, the bad, and the ugly” of the DREAM study, in my opinion.

The “good” is that the DREAM study design was a large, multicenter, randomized controlled trial for 12 months (with a 12-month extension) evaluating both the signs and symptoms of DED. The number of patients and the duration of the study strengthen its validity. It was also “real world” in that the patients were allowed to continue their other dry eye treatments.

The “bad” is their choice of placebo. While there are limited studies evaluating olive oil supplements for DED, several papers study the anti-inflammatory effects of olive oil in general.^10-12 The polyphenols found in olive oil in Mediterranean diets are believed to provide health benefits such as reduced risk of cardiovascular diseases and cancer because of their anti-inflammatory effects. One study showed that omega-9 oleic acid, the main compound of olive oil, is associated with an increase level of anti-inflammatory cytokine IL-10 and decreased levels of the pro-inflammatory cytokines IL-1beta and TNF-alpha.¹² The definition of a placebo is a substance or chemical that has no pharmacological effect. Given the potential anti-inflammatory effects of olive oil, the choice to use it as a placebo was an apparent mistake.

The “ugly” was the conclusion drawn by the DREAM study and the misperception it provided. The closing sentence stating “We found no evidence of a beneficial effect of n-3 fatty acid supplements as compared with placebo supplements among patients with DED”¹, taking into account the true definition of placebo, implies that omega-3 FAs have no benefit for dry eye patients. A more accurate conclusion, in my opinion, is that both omega-3 FAs and olive oil have clinical benefits in treating the signs and symptoms of dry eye and that olive oil was shown to be equally effective as omega-3 supplements.

ARE WE CLOSER TO CLARITY?

The DREAM study’s conclusion seemingly did not accurately portray the results provided. It stated that omega-3 FAs supplements were no better than placebo, yet patients showed a significant improvement in symptoms and signs of dry eye for both omega-3s and olive oil. The systematic review and meta-analysis concluded that omega-3 FA supplementation improves dry eye symptoms, tear film stability and tear production in patients with DED⁷, yet its authors acknowledged that there are limitations in the analysis based upon the lack of standardizations of the studies.

So, what exactly is clear? To me, more research is needed on the optimal dose, composition and duration of omega-3 FA supplementation as well as more studies evaluating the efficacy of olive oil for the treatment of DED. Having said that, it is clear that there is enough evidence based on anecdotal experience and controlled trials to say that omega-3 FAs have anti-inflammatory benefits and most likely help with signs and symptoms of dry eye.

As the CEDARS algorithm for treating DED demonstrates (see page 26), DED is complex and, like other diseases such as glaucoma and hypertension, requires a multi-treatment approach in many cases.¹³ There is no panacea for treating all of the signs and symptoms of DED, and omega-3 FA provide an additional safe and seemingly effective option in our algorithm. I, for one, am not ready to cut bait on fish oils. OM

REFERENCES

1. Dry Eye Assessment and Management Study Research Group, Asbell PA, Maguire, MG, Pistilli, M, et al. n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease, N Engl J Med, 2018;378:1681-1690.
2. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15:276-283.
3. Calder PC. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 2003; 38:343-352.
4. Ishihara T, Yoshida M, Arita M. Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis. Int Immunol. 2019. [Epub ahead of print]
5. Akpek EK, Amescua G, Farid M, et al. American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Dry Eye Syndrome Preferred Practice Pattern. Ophthalmology. 2019;126:P286-P334.
6. Harris W. Omega-6 and omega-3 fatty acids: partners in prevention. Curr Opin Clin Nutr Metab Care. 2010;13:125-129.
7. Guiseppe G, Pellegrini M, Sebastiani S, et al., Efficacy of omega-3 Fatty Acid Supplementation for Treatment of Dry Eye Disease: A Meta-Analysis of Randomized Clinical Trials. Cornea; 2019. [Epub ahead of print]
8. Ziemanski JF, Wolters, LR, Jones-Jordan L, Nichols JJ, Nichols KK. Relation Between Dietary Essential Fatty Acid Intake and Dry Eye Disease and Meibomian Gland Dysfunction in Postmenopausal Women. Am J Ophthamol. 2018;189:29-40.
9. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr. 2000;71:343S-348S.
10. Mao X, Xia B, Zheng M, Zhou Z. Assessment of the anti-inflammatory, analgesic and sedative effects of oleuropein from Olea europaea L. Cell Mol Biol (Noisy-le-grand). 2019;65:52-55.
11. Plastina P, Benincasa C, Perri E, et al., Identification of hydroxytyrosyl oleate, a derivative of hydroxytyrosol with anti-inflammatory properties, in olive oil by-products. Food Chem. 2019;279:105-113.
12. Medeiros-de-Moraes IM, Goncalves-de-Albuquerque CF, Kurz ARM, et al., omega-9 Oleic Acid, the Main Compound of Olive Oil, Mitigates Inflammation during Experimental Sepsis. Oxid Med Cell Longev. 2018;2018:6053492.
13. Milner MS, Beckman KA, Luchs JI, et al., Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;27 Suppl 1:3-47.

About the Author

Mark S. Milner, MD, is associate clinical professor at Yale University Medical School, Department of Ophthalmology, co-founder and co-medical director of Precision LASIK Group in Cheshire, Conn., and a founding member of the CEDARS/ASPENS (Cornea, External Diseases and Refractive Surgery/American Society of Progressive Enterprising Surgeons) Society.

Disclosures: Dr. Milner reports relationships with Aldeyra Therapeutics, Allergan, Avedro, Bausch + Lomb, BioTherapeutics, Bio-Tissue, Dompe, EyeGate Pharma, Eyevance Pharmaceuticals, Icare, Johnson & Johnson Vision, Kala Pharmaceuticals, Ocular Science, Omeros, Percept Technologies, Quidel, Shire, Sun Ophthalmics and Valeant.