Oral omega-3 supplementation for dry eye

Practitioner Summary box

What are omega-3s?

Omega-3s are essential fatty acids that are needed by the body for healthy metabolism. As we cannot produce them on our own, they must be consumed as part of our diet. Omega-3 fatty acids exist in a long chain (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and short-chain (alpha-linolenic acid [ALA]) forms. Long chain omega-3s are derived mainly from fish oil while short chain omega-3s are present in vegetable oils, like flaxseed and canola oil.

Clinical summary: Omega-3s are essential fatty acids that come in a long-chain form found in fish oil (EPA & DHA) and short-chain form founds in vegetable oils like flaxseed oil (ALA).

How do omega-3s relate to omega-6s?

Omega-6s are generally derived from vegetable oils, such as corn and safflower oils, in the form of linolenic acid (LA), that is then converted to gamma-linoleic acid (GLA) and arachidonic acid (AA) once ingested. Omega-3s and omega-6s compete for metabolic enzymes within the body to produce to eicosanoids that modulate systemic inflammation. Eicosanoids produced from Omega-3s are anti-inflammatory while eicosanoids produced by omega-6s can be either anti-inflammatory or pro-inflammatory[1]. Therefore, a higher ratio of omega-6 to omega-3 results in a more inflammatory status in the body.
A typical Western diet does not provide enough omega-3 supplementation and contains a higher ratio of omega-6 to omega-3 than is desirable. In a typical western diet the ration of omega-6 to omega-3 is 15:1 while the ideal ration should be 4:1[2].
the American Dietetic Association and Dietitians of Canada recommends an intake of 500mg of omega-3s per day[3]. The recommendation from health bodies in Australia and New Zealand is similar with 610 mg per day recommended for men and 430 mg per day for women to reduce the risk of chronic disease[4].

Clinical summary: A higher ratio of omega-6 to omega-3 increases the inflammatory status of the body. We do not consume enough omega-3s in a typical Western diet and should aim to consume at 500mg a day.

What do omega-3s do for dry eye?

Omega-3 supplements have been studied extensively in the literature and many studies have shown that they offer a clinical benefit to dry eye patients[5, 6]. Omega-3 supplementation improves meibomian gland quality, osomolarity, meibomian gland expressibility, and tear break up time[7].

The proposed mechanism is that omega-3s act on the meibum in meibomian glands to break it down from a more solid form that is found in MGD, into a more natural liquid form[8, 9]. Omega-3s also have anti-inflammatory properties[10]. A 2018 study showed that a 12-week course of oral omega-3s has similar anti-inflammatory effects to a two-week course of topical corticosteroid (FML 0.1%)[10].

Clinical summary: Omega-3 supplementation helps to break down meibum and improve expressibility of meibomian glands. They also help with their anti-inflammatory properties

How long should patients be on them?

Patients need to be on them for at least 12 weeks as shorter periods are not sufficient to produce clinically significant benefits[7, 10, 11]. It seems that there is a continuous benefit from ongoing supplementation with omega-3s with one study showing an ongoing improvement when taking omega-3s for up to 6 months[12].

Clinical summary: For chronic dry eye patients, I normally recommend ongoing supplementation with omega-3s, and at least for 3 months. They are a natural supplement and easy to keep taking, so I recommend taking them as an ongoing treatment option.

Triglycerides Vs Ethyl Esters

During the manufacturing process, alcohol is added to omega-3s to remove mercury. This converts them from their natural triglyceride form into ethyl esters. Some studies have shown that ethyl esters are not absorbed as easily into the body as triglycerides, with re-esterified tryglycerides showing an even higher rate of absorption than natural tryglycerides[13]. Some studies have shown no difference[14] between the two forms of omega-3, but there is a view that ethyl esters are absorbed better when taken with fatty meals[15], which may explain why they perform as well as triglycerides in some studies. In dry eye studies where tear film osmolarity was shown to improve with omega-3 supplementation, the supplements used were in re-esterified triglyceride form[7, 11].

Clinical summary: I recommend omega-3s in re-esterified triglyceride form (see below for brands that meet these criteria in your region).

How much omega-3s are recommended?

In studies that found a positive effect of omega-3 supplementation on tear film osmolarity, the dosage was at least 1000mg of EPA and 500mg of DHA[7, 11]. This is a significant dosage and I recommend using concentrated versions of fish oil capsules to reduce the number of capsules per day.

Clinical summary: I aim for a ratio of 2:1 EPA to DHA, and more precisely 1000mg EPA to 500mg DHA.

Which brands are recommended?

I would recommend using brands that have a high concentration of omega-3 in a triglyceride form.  Based on my own research, the following brands meet these criteria:

Australia

• Dry Eye Forte (MD Eyecare) – also contains Vitamin D, Vitamin E, GLA.
• Caruso’s triple strength fish oil – this brand was used in two Australian studies7,10.

Canada

• PRN (Physician Recommended Nutriceuticals) DE3 Dry Eye Omega Benefits® – this brand was used in once study11.

New Zealand

• Dry Eye Forte
• Nutra-Life One-a-Day Fish Oil

United Kingdom

• PRN DE3 Dry Eye Omega Benefits®

USA

• PRN DE3 Dry Eye Omega Benefits®

Please note that the above list is not exclusive. These are brands that I am aware of but it is very easy to check if a brand meets my criteria by contacting the manufacturer.

TheraTears Nutrition

Many optometrists use this product as a form of omega-3 supplementation for their patients so I will briefly discuss it here. One randomized, double-masked, placebo-controlled clinical trial showed that TheraTears Nutrition had no effect in meibum composition or on tear film evaporation rate16.

However, it is important to note that quantity of omega-3 was almost half that which has been shown to be effective in other studies. They used 450mg of EPA and 350mg of DHA, which is a capsule of TheraTears Nutrition. Based on this I was willing to give this product a chance as long as 2 capsules were recommended and as long as it was in triglyceride form. I did contact Akron, the manufacturers of TheraTears Nutrition, and they confirmed that it is in triglyceride form.

A study later came that did in fact use 2 capsules of TheraTears nutrition (fish oil and flaxseed oil) and compared it to a fish oil product (Caruso’s – see above). In this study, TheraTears was found to reduce IL-6 (inflammatory markers) levels in the tear film. It had no effect on symptoms or on IL-17A levels. The fish oil however was successful at reducing both IL-6 and IL-17A, and improving symptoms and its anti-inflammatory effect was comparable to a two-week course of topical corticosteroid.

If you routinely prescribe this product, I would recommend prescribing at least 2 capsules a day instead of one based on the results of the above study. However, you may want to consider trying a different product that has been shown to be more effective.

Do omega-3s increase bleeding?

There is some concern by some medical practitioners that omega-3 supplementation can increase bleeding. This is based on studies carried out in the 1970’s that showed Greenland Inuits had markedly higher levels of EPA, and that their bleeding times were significantly more prolonged, than mainland Danes17. The authors concluded that omega=3 supplementation was to blame. Although it is established that omega-3s can effect platelet function18, no studies have proven any link between prolonged bleeding and omega-3 consumption19. In fact, in some clinical settings, omega-3s were found to reduce the risk of bleeding19.

Clinical summary: There is no evidence to suggest that omega-3 supplementation increases the risk of bleeding.

Further reading

The two recent literature reviews by Downie et al5 and Giannaccare et al6 provide a good summary on the topic.

Financial disclosure: I have no financial interest in any products discussed in this article.

References

1. Calder PC. n− 3 Polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 2003;38(4):343-352.
2. Simopoulos A. The importance of the ratio of omega-6/omega-3 essential fatty acids. Alternative Medicine Review. 2003;8(1):83-84.
3. Kris-Etherton PM, Innis S, Assocition DAAD. Position of the American Dietetic Association and Dietitians of Canada: dietary fatty acids. Journal of the American Dietetic Association. 2007;107(9):1599-1611.
4. Commonwealth Department of Health and Ageing Australia, Ministry of Health New Zealand, National Health and Medical Research Council. Nutrient Reference Values for Australia and New Zealand including Recommended Dietary Intakes. In. Canberra 2006.
5. Downie LE, Ng SM, Lindsley KB, Akpek EK. Omega‐3 and omega‐6 polyunsaturated fatty acids for dry eye disease. Cochrane Database of Systematic Reviews. 2019(12).
6. Giannaccare 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;38(5):565-573.
7. Deinema LA, Vingrys AJ, Wong CY, Jackson DC, Chinnery HR, Downie LE. A randomized, double-masked, placebo-controlled clinical trial of two forms of omega-3 supplements for treating dry eye disease. Ophthalmology. 2017;124(1):43-52.
8. Mascai M. The role of omega 3 supplementation in blepharitis and meibomian gland dysfunction. Trans Am Ophthalmol Soc. 2008;106:336-356.
9. Oleñik A, Jiménez-Alfaro I, Alejandre-Alba N, Mahillo-Fernández I. A randomized, double-masked study to evaluate the effect of omega-3 fatty acids supplementation in meibomian gland dysfunction. Clinical interventions in aging. 2013;8:1133.
10. Downie LE, Gad A, Wong CY, et al. Modulating contact lens discomfort with anti-inflammatory approaches: a randomized controlled trial. Investigative ophthalmology & visual science. 2018;59(8):3755-3766.
11. Epitropoulos AT, Donnenfeld ED, Shah ZA, et al. Effect of oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea. 2016;35(9):1185.
12. Creuzot C, Passemard M, Viau S, et al. Amélioration de la symptomatologie chez des patients atteints de sécheresse oculaire et traités oralement par des acides gras polyinsaturés. Journal français d’ophtalmologie. 2006;29(8):868-873.
13. Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB. Bioavailability of marine n-3 fatty acid formulations. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2010;83(3):137-141.
14. Luley C, Wieland H, Grünwald J. Bioavailability of omega-3 fatty acids: ethylester preparations are as suitable as triglyceride preparations. Aktuelle Ernährungsmedizin. 1990;15(3):123-125.
15. Nordøy A, Barstad L, Connor WE, Hatcher L. Absorption of the n− 3 eicosapentaenoic and docosahexaenoic acids as ethyl esters and triglycerides by humans. The American journal of clinical nutrition. 1991;53(5):1185-1190.
16. Wojtowicz JC, Butovich I, Uchiyama E, Aronowicz J, Agee S, McCulley JP. Pilot, prospective, randomized, double-masked, placebo-controlled clinical trial of an omega-3 supplement for dry eye. Cornea. 2011;30(3):308-314.
17. Dyerberg J, Bang H. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. The Lancet. 1979;314(8140):433-435.
18. Knapp HR. Dietary fatty acids in human thrombosis and hemostasis. The American journal of clinical nutrition. 1997;65(5):1687S-1698S.
19. Wachira JK, Larson MK, Harris WS. n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. British Journal of Nutrition. 2014;111(9):1652-1662.