1. Table 2. Summary of study design, participants, interventions, and follow‐up period.
|
Study ID Study design |
Condition(s) included | Total number of randomized participants | Intervention(s) studied | Follow‐up period | ||||
|
Aragona 2005 Randomized, parallel‐group, controlled trial |
Moderate to severe dry eye disease associated with primary Sjögren’s syndrome | 40 | Omega‐6 supplementation: oral sachets containing linoleic acid 112 mg and γ‐linolenic acid 15 mg, twice daily (daily dose of linoleic acid 224 mg and γ‐linolenic acid 30 mg) |
Placebo oral sachets, twice daily Each placebo sachet contained placebo with only non‐active excipients (matched to the omega‐6 arm), as follows ‐ Fructose 2383.3 mg ‐ Monohydrate citric acid 50 mg ‐ Aspartame 12.5 mg ‐ Silicon dioxide 6 mg ‐ Bigrade aroma 45 mg ‐ Citrus aroma 131 mg |
1 month | |||
|
Asbell 2018 Randomized, controlled trial |
Moderate to severe dry eye disease | 535 | Omega‐3 supplementationa: 5 soft gelatin oral capsules per day containing triglyceride omega‐3 PUFAs (400 mg EPA and 200 mg DHA) (daily dose of 2000 mg EPA and 1000 mg DHA) |
Placebo (5 oral 1000 mg olive oil capsules), comprising 68% oleic acid, 13% palmitic acid, and 11% linoleic acida (daily dose of 5000 mg olive oil) |
12 months | |||
|
Barabino 2003 Randomized, parallel‐group, controlled trial |
Dry eye disease | 26 | Omega‐6 supplementationb: oral tablets containing linoleic acid 28.5 mg and γ‐linolenic acid 15 mg, twice daily (daily dose of linoleic acid 57 mg and γ‐linolenic acid 30 mg) |
Placebo ("specially made tablets containing a low quantity of sugar at the same dose as the study group") oral tablets twice dailyb | 45 days | |||
|
Bhargava 2013 Randomized, parallel‐group, controlled trial |
Dry eye syndrome | 518 | Omega‐3 supplementation: oral 500 mg soft gel capsule containing EPA 325 mg and DHA 175 mg, twice daily (daily dose of EPA 650 mg and DHA 350 mg) |
Placebo oral capsules (500 mg), containing corn oil, twice daily | 3 months | |||
|
Bhargava 2015a Randomized, parallel‐group, controlled trial |
Dry eye associated with computer vision syndrome | 478 | Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA) |
Placebo capsules containing olive oil (dose not reported), twice daily | 3 months | |||
|
Bhargava 2015b Randomized, parallel‐group, controlled trial |
Dry eye associated with contact lens wear | 496 females | Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA) |
Placebo oral capsules containing corn oil (dose not reported), twice daily | 6 months | |||
|
Bhargava 2016a Randomized, parallel‐group, controlled trial |
Dry eye in rosacea patients | 130 | Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA) |
Placebo oral capsules containing olive oil (dose not reported), 2 capsules/time, twice daily | 6 months | |||
|
Bhargava 2016b Randomized, parallel‐group, controlled trial |
Dry eye in visual display terminal users | 522 | Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 4 capsules/time, twice daily (daily dose of 1440 mg EPA and 960 mg DHA) |
Placebo oral capsules containing olive oil (dose not reported), 4 capsules/time, twice daily | 45 days | |||
|
Brignole‐Baudouin 2011 Randomized, parallel‐group, controlled trial |
Mild to moderate dry eye syndrome | 138 | Combined omega‐3 and omega‐6 supplementation: oral soft gel capsule containing fish oil (omega‐3 average of 285 mg, including EPA 142.5 mg and DHA 95 mg, and omega‐6 average of 5 mg), 3 capsules daily (daily dose of omega‐3: 855 mg including EPA 427.5 mg and DHA 285 mg, and omega‐6: 15 mg) |
Placebo oral soft gel capsule containing medium‐chain triglycerides (daily dose: 575 mg) |
3 months | |||
|
Creuzot 2006 Randomized, parallel‐group, controlled trial |
Mild to moderate dry eye syndrome | 71 | Combined omega‐3 and omega‐6 supplementation: oral capsule containing omega‐3 PUFAs (DHA 196 mg and EPA 14 mg), omega‐6 PUFA (γ‐linolenic acid 41 mg or linoleic acid 63 mg), various vitamins (C, E, B6, B9, B12), and a trace element (zinc) (Nutrilarm, Laboratoires Thea), twice daily (daily dose of EPA 28 mg and DHA 392 mg as omega‐3 PUFAs, and γ‐linolenic acid 82 mg or linoleic acid 126 mg as omega‐6 PUFAs) |
Placebo oral capsule containing oleic acid (dose not reported) twice daily (2 capsules per day) | 6 months | |||
|
Creuzot‐Garcher 2011 Randomized, parallel‐group, controlled trial |
Moderate dry eye | 181 | Combined omega‐3 and omega‐6 supplementation: oral capsule containing omega‐3 PUFAs (DHA 196 mg and EPA 14 mg), omega‐6 PUFA (γ‐linolenic acid 41 mg or linolenic acid 63 mg), various vitamins (C, E, B6, B9, B12), and a trace element (zinc) (Nutrilarm, Laboratoires Thea), twice daily (daily dose of EPA 28 mg and DHA 392 mg as omega‐3 PUFAs, and γ‐linolenic acid 82 mg or linolenic acid 126 mg as omega‐6 PUFAs) |
Placebo oral capsule (composition not reported) twice daily (2 capsules per day) | 6 months | |||
|
Deinema 2017 Randomized, parallel‐group, controlled trial |
Mild to moderate dry eye disease | 60 | Omega‐3 supplementation: fish oil capsules (triglyceride omega‐3 PUFAs) (daily dose of 1000 mg EPA and 500 mg DHA) |
Omega‐3 supplementation: krill oil capsules (phospholipid omega‐3 PUFAs) (daily dose of 945 mg EPA and 510 mg DHA) |
Placebo oral capsules (daily dose of 1500 mg) |
90 days | ||
|
Epitropoulos 2016 Randomized, parallel‐group, controlled trial |
Dry eye disease associated with meibomian gland dysfunction | 122 | Omega‐3 supplementation: oral capsules containing re‐esterified omega‐3 PUFAs: 420 mg EPA and 140 mg DHA (daily dose of 1680 mg EPA and 560 mg DHA) |
Control oral capsules containing 3136 mg linoleic acid (safflower oil, omega‐6 fatty acid) |
12 weeks | |||
|
Gilbard 2008 Randomized, parallel‐group, controlled trial |
Sjögren’s syndrome | 61 | Omega‐3 supplementation: TheraTears Nutrition (no other details reported, although this product contains EPA, DHA, and ALA) |
Placebo oral capsules containing wheat germ oil (dose not reported) | Not reported | |||
|
Goyal 2017 Randomized, controlled trial |
Dry eye associated with LASIK | 60 | Omega‐3 supplementation: oral capsule containing 180 mg EPA and 120 mg DHA, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA) |
Placebo oral capsule containing vitamin E (daily dose of 400 mg) |
13 weeks | |||
|
Kangari 2013 Randomized, parallel‐group, controlled trial |
Dry eye syndrome | 73 | Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, twice daily (daily dose of EPA 360 mg and DHA 240 mg) |
Placebo oral capsule (1 g) containing medium‐chain triglycerides, twice daily | 1 month | |||
|
Kawakita 2013 Randomized, controlled trial |
Dry eye | 27 | Omega‐3 supplementation: oral soft gel capsule containing EPA 83 mg and DHA 36 mg 3 times daily, 5 capsules/time, 3 times daily (15 capsules/d) (daily dose of EPA 1245 mg and DHA 540 mg) |
Placebo oral capsules containing mainly medium‐chain triglycerides (dose not reported) | 3 months | |||
|
Kawashima 2016 Randomized, controlled trial |
Dry eyec | 40c | Omega‐3 supplementation: oral capsules containing 40.5 mg EPA and 27 mg DHA, 2 capsules/time, once daily (daily dose of 81 mg EPA and 54 mg DHA) |
"Vehicle" (no further details provided), 2 capsules/time, once daily | 8 weeks | |||
|
Kokke 2008 Randomized, parallel‐group, controlled trial |
Dry eye associated with soft contact lens wear | 76 females | Omega‐6 supplementation: oral capsule containing evening primrose oil (linoleic acid about 57 mg and γ‐linolenic acid 50 mg, Equazen UK Ltd.), 6 capsules daily (daily dose of linoleic acid about 342 mg and γ‐linolenic acid 300 mg |
Placebo capsule containing olive oil (78.0% oleic acid, 11.2% palmitic acid, and 5.6% mainly linoleic acid), 6 capsules daily | 6 months | |||
|
Korb 2015 Randomized, controlled trial |
Lipid deficient/evaporative dry eye | 26 | Omega‐3 supplementationd: oral 1000 mg capsule of "omega‐3 fatty acids" (unspecified) |
No oral capsules; warm wet microfiber compress to both eyelids for 8 minutes once daily | 3 months | |||
|
Macsai 2008 Randomized, controlled trial |
Simple obstructive meibomian gland dysfunction and blepharitis | 38 | Omega‐3 supplementatione: flaxseed oil oral 1000 mg capsules 2 capsules/time, 3 times daily (daily dose of 6 g flaxseed oil, comprising approximately 55% ALA, 15% linoleic acid, and 19% oleic acid. Total daily dose of omega‐3 fatty acids: 3.3 g) |
Olive oil oral capsules (dose not reported), 6 capsules dailye | 1 year | |||
|
Manthorpe 1984 Randomized, cross‐over, controlled trial |
Keratoconjunctivitis sicca associated with primary Sjögren’s syndrome | 36 | Omega‐6 supplementation: oral capsule (500 mg) containing cis‐linoleic acid 365 mg and γ‐linolenic acid 45 mg, Efamol twice daily (3 capsules at a time) plus a tablet containing vitamin C 125 mg, pyridoxine 25 mg, niacin 25 mg, and ZnSo4 5 mg (Efavit) twice daily (3 tablets at a time) (daily dose of linoleic acid 2190 mg and γ‐linolenic acid 270 mg) |
"Placebo" oral 500 mg capsule (composition not reported), dosed twice daily (3 capsules at a time) | 3 weeks in each cross‐over phase | |||
|
Mohammadpour 2017 Randomized, controlled trial |
Post cataract surgery dry eye | 48 | Omega‐3 supplementationf: oral 1000 mg (Advanced Canada containing 180 mg EPA and 120 mg DHA), every 8 hours (daily dose of 510 mg EPA and 360 mg DHA) |
"Standard therapy" alone, comprising artificial tears every 4 hours and betamethasone 0.1% eye drops every 8 hours | 1 month | |||
| NCT01107964 | Dry eye syndrome | 27 | Omega‐3 supplementation of 4 g/d (1 g capsule, 4 times daily) containing omega‐3 acid ethyl esters (exact dose not specified) | Placebo oral capsule (1 g) containing corn oil, 4 times daily (dose not specified) | 45 days | |||
|
Oleñik 2013 Randomized, parallel‐group, controlled trial |
Symptomatic meibomian gland dysfunction, no tear instability | 64 | Omega‐3 supplementationg: oral capsule containing EPA 42.5 mg, DHA 350 mg, and DPA 30 mg (Brudysec 1.5 g, Brudy Lab SL), 1 capsule/time, 3 times daily (daily dose of EPA 127.5 mg, DHA 1050 mg, DPA 90 mg) |
Placebo oral 500 mg capsule containing sunflower oil, 1 capsule/time, 3 times daily | 3 months | |||
|
Oral sea buckthorn oil study 2010 Randomized, parallel‐group, controlled trial |
Dry eye symptoms | 100 | Combined omega‐3 and omega‐6 supplementation: oral capsule (1000 mg) containing sea buckthorn oil (Aromtech Ltd.), 1 capsule/time, twice daily |
Placebo oral capsule containing palm and coconut oil triacylglycerols of medium‐chain fatty acids, 1 capsule/time, twice daily | 3 months | |||
|
Oxholm 1986 Randomized, cross‐over, controlled trial |
Keratoconjunctivitis sicca associated with primary Sjögren’s syndrome | 28 | Omega‐6 supplementation: oral capsule (500 mg) containing evening primrose oil (primarily comprising linoleic acid 365 mg and γ‐linolenic acid 45 mg, Efamol), 6 capsules daily (daily dose of 3 g of Efamol containing linoleic acid 2190 mg and γ‐linolenic acid 270 mg) |
"Placebo" oral capsule (500 mg, composition not reported), 6 capsules daily | 8 weeks in each cross‐over phase | |||
|
Papas 2007 Randomized, parallel‐group, controlled trial |
Dry eye associated with Sjögren’s syndrome | 41 | Omega‐3 supplementation: omega‐3 supplement containing a flaxseed and fish oil blend (TheraTears Nutrition, Advanced Vision Research); daily dose not reported |
Germ seed oil oral capsule (composition and dose not reported) | 3 months | |||
|
Pinazo‐Durán 2013 Randomized controlled trial |
Mild to moderate dry eye | 30 | Omega‐3 supplementationg: oral 1.5 g capsule containing EPA 42.5 mg, DHA 350 mg, DPA 30 mg (Brudysec 1.5 g, Brudy Laboratories), 2 capsules daily (daily dose of EPA 85 mg, DHA 700 mg, DPA 60 mg) |
No treatment | 3 months | |||
|
Pinheiro 2007 Randomized, parallel‐group, controlled trial |
Keratoconjunctivitis sicca associated with rheumatoid arthritis or systemic lupus erythematosus | 38 | Omega‐3 supplementation: flaxseed oil capsules, 1 capsule plus 1 placebo capsule (daily dose of flaxseed oil 1 g) |
Omega‐3 supplementation: flaxseed oil, 2 capsules (daily dose of flaxseed oil 2 g) |
Placebo oral capsule containing 950 mg synthetic mineral oil and 50 mg evening primrose oil, 2 capsules daily | 6 months | ||
|
Reeder 2006 Randomized, parallel‐group, controlled trial |
Dry eye | 20 | Omega‐3 supplementation: omega‐3 supplement containing flaxseed oil and fish oil (TheraTears Nutrition); daily dose not reported |
Oral capsule containing flaxseed oil (1000 mg) | 2 months | |||
|
Sheppard 2013 Randomized, parallel‐group, controlled trial |
Moderate to severe keratoconjunctivitis sicca in postmenopausal women | 38 females | Combined omega‐3 and omega‐6 supplementationh: oral capsules containing omega‐6 PUFAs (γ‐linolenic acid 177.5 mg, linoleic acid 177.5 mg, and arachidonic acid < 0.75 mg) and omega‐3 PUFAs (EPA 31.5 mg, DPA 24.75 mg, DPA 9.75 mg), 2 capsules/time, twice daily (daily dose of omega‐3s: ALA 196 mg, EPA 126 mg, DHA 99 mg, and DPA 39 mg; and omega‐6s: linoleic acid 710 mg, γ‐linolenic acid 240 mg, and arachidonic acid < 3 mg) |
Placebo oral capsule, with a main ingredient of sunflower oil, 2 capsules/time, twice dailyh | 6 months | |||
|
Theander 2002 Randomized, parallel‐group, controlled trial |
Dry eye associated with primary Sjögren’s syndrome | 90 | Omega‐6 supplementation: oral γ‐linolenic acid 800 mg daily (Scotia Pharmaceutical Ltd.) |
Omega‐6 supplementation: oral γ‐linolenic acid 1600 mg daily (Scotia Pharmaceutical Ltd.) |
Placebo, containing mostly corn oil (dose not reported) | 6 months | ||
|
Wojtowicz 2011 Randomized, parallel‐group, controlled trial |
Dry eye, some with concomitant meibomitis or meibomian gland dysfunction | 36 | Omega‐3 supplementation: oral capsules containing fish oil 1600 mg (containing EPA 450 mg and DHA 300 mg) and flaxseed oil (1000 mg) daily (TheraTears Nutrition, Advanced Vision Research) |
Placebo oral capsules containing wheat germ oil (dose not reported) | 3 months | |||
aParticipants who were regularly using treatments for dry eye disease (including omega‐3 fatty acid supplements: eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA] at a dose of < 1200 mg daily), systemic medications that are known to cause ocular dryness, systemic glucocorticoids, or other immunosuppressive agents were allowed to continue those treatments if they committed to using them for the 12‐month duration of the trial.
bThe omega‐6 oral supplement was administered in association with preservative‐free substitute tears, four times daily.
cNote: only 12 of the 40 enrolled participants had "confirmed dry eye disease," with the remainder classed as having probable dry eye (n = 22) or non‐dry eye (n = 5).
dThe omega‐3 oral supplement was administered in association with lid hygiene (Systane Lid Wipes) once daily and 1 drop of lipid emulsion eye drops (Systane Balance).
eParticipants were also counseled to continue their daily eyelash hygiene, which involved daily eyelash shampoo with a dilute non‐irritating baby shampoo on a washcloth in the shower, followed by a thorough rinse with the eyes closed.
fThe omega‐3 oral supplement was administered in association with "standard therapy for dry eye," as prescribed in the control arm, comprising Artelac artificial tears every 4 hours and betamethasone 0.1% eye drops every 8 hours.
gThe omega‐3 oral supplement also contained vitamin A 133.3 ug, vitamin C 26.7 mg, vitamin E 4 mg, tyrosine 10.8 mg, cysteine 5.83 mg, glutathione 2 mg, zinc 1.6 mg, copper 0.16 mg, manganese 0.33 mg, selenium 9.17 ug.
hThe combined omega‐6 and omega‐3 oral supplement also contained a daily dose of vitamin A 2180 IU, vitamin B6 12.8 mg, vitamin C 262.0 mg and vitamin E 13.7 mg, and magnesium (sulfate) 40.8 mg. Participants were provided with Refresh artificial tears (Allergan, Inc., Irvine, CA, USA) to use as needed for the duration of the study.
ALA: alpha‐linolenic acid; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; LASIK: laser in situ keratomileusis.