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Review

Artificial Tears: A Systematic Review

       

Authors Semp DA , Beeson D , Sheppard AL, Dutta D, Wolffsohn JS 

Received 1 August 2022

Accepted for publication 17 December 2022

Published 10 January 2023 Volume 2023:15 Pages 9—27

DOI https://doi.org/10.2147/OPTO.S350185

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Mr Simon Berry

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David A Semp, Danielle Beeson, Amy L Sheppard, Debarun Dutta, James S Wolffsohn

School of Optometry, College of Health and Life Sciences, Aston University, Birmingham, UK

Correspondence: James S Wolffsohn, Tel +44 121 2044140, Email [email protected]

Abstract: Artificial tears are the mainstay of dry eye disease management, but also have a role in corneal abrasion and wound healing, pain and inflammation management, conjunctivitis, keratitis, contact lens rewetting and removal, and foreign body removal. A systematic review of randomized controlled trials (PROSPERO registration CRD42022369619) comparing the efficacy of artificial tears in patients with dry eye to inform prescribing choices using Web of Science, PubMed and Medline databases identified 64 relevant articles. There is good evidence that artificial tears improve symptoms of dry eye disease within a month of regular use, applied about four times a day, but signs generally take several months to improve. Not all patients with dry eye disease benefit from artificial tears, so if there is no benefit over a month, alternative management should be considered. Combination formulations are more effective than single active ingredient artificial tears. Artificial tears containing polyethylene glycol are more effective than those containing carboxymethylcellulose/carmellose sodium and hydroxypropyl methylcellulose. Those classified as having evaporative dry eye disease, benefit from artificial tears with liposomes, especially of higher concentration. The data available is limited by the definition of dry eye disease applied in published studies being variable, as well as the disease severity examined and compliance with artificial tears being rarely quantified.

Keywords: artificial tears, dry eye, comfort, contact lenses

Artificial tear drops are most commonly associated with the management of dry eye disease (DED). Artificial tears are typically included in first-line management options for dry eye, as they are easy to use, accessible in a wide range of formulations, and have a low risk-profile.1 Most artificial tear preparations have been found to be effective in reducing the symptoms and signs of DED, however the Tear Film and Ocular Surface Society (TFOS) dry eye workshop in 2017 (DEWS II) concluded there had been relatively few high quality randomized controlled trials comparing different formulations with each other.1,2 Furthermore, few clinical trials have compared the efficacy of different artificial tear products, and attempted to correlate this with patient characteristics, in order to aid management decisions for an individual.3,4 The issue with this is that both practitioners and patients are faced with a bewildering array of different products with varying ingredients, and little or no clear way of knowing which is the most effective. Practitioners will often be asked “which is the best drop for dry eye”, but with no scientific evidence to base their answer on. In addition, other aspects that influence practitioner and patient choices are:

  • formulation
    • percentage concentration5
    • molecular weight5
    • preservative used6
  • storage bottle design.7–10

Patients may therefore face a trial-and-error approach to product selection, incurring mounting costs and frustration in the process. This will be felt even more keenly by patients who are highly price sensitive, since over-the-counter products are no longer easily available via National Health Service (NHS) subsidised prescriptions11 in the UK. A recent study12 on the reported experience of dry eye management across four continents identified that on average, DED still caused a moderate impact on an individual’s quality of life (median impact 3/10); less than half of the individuals in any country had undergone a consultation with an eye or health-care practitioner about their dry eye; about half had tried dry eye treatment, with artificial tears being the most common treatment, followed by warm compresses, and both therapies were rated as reasonably effective (median 5–7/10).

Formulation

The majority of artificial tear products are aqueous-based and contain viscosity-enhancing agents, such as carbomer 940, carboxymethyl cellulose (CMC), dextran, hyaluronic acid, sodium hyaluronate (which has a smaller molecular size), hydroxypropyl guar (HP-guar), hydroxypropyl methylcellulose (HPMC hypromellose), polyvinyl alcohol, polyvinylpyrrolidone and polyethylene glycol, which aid lubrication and increase on-eye retention time.1 Other ingredients may include osmotic agents, osmoprotectants, antioxidants, preservatives and inactives such as pH buffers, excipients and electrolytes.1 Aqueous-based artificial tears target principally the muco-aqueous phase of the tear film, but have been shown to improve dry eye symptoms related to all subtypes of DED.2

In recent years, there has been an increase in the popularity and availability of lipid-based drops, which target the superficial tear lipid layer13,14 as the emphasis on meibomian gland dysfunction and its role in evaporative dry eye continues to increase.1 It has been demonstrated in randomised controlled trials that lipid-based drops are more effective at managing DED classified as evaporative.3,4 These can take the form of nano-emulsion drops or liposomal sprays, which are applied to the closed eye and may be easier for those who struggle to instil drops, for example those with reduced manual dexterity or hand tremor. A completely water-free drop comprised of 100% lipid (perfluorohexyloctane) is available now, with the added benefit of being preservative-free.15

Preservatives

Multidose eye drops, including artificial and medicated topical ocular drops, commonly contain preservatives to maintain sterility and prolong shelf life, however, these are also known to produce toxicity. Benzalkonium chloride, commonly found in multidose drops, can produce toxic, proinflammatory and detergent effects, which may actually lead to or exacerbate DED.16 For this reason, there has been a move towards preservative-free and unit dose formulations, due to the risk of toxic and allergic reactions, especially when frequent instillation is required. Newer preparations may contain less damaging preservatives such as polyquaternium, or “vanishing” preservatives such as sodium perborate and purite, or feature specially designed bottles, which prevent the entry of microorganisms.17 Preservative-free formulations are recommended for all types of dry eye, however this is even more important for severe dry eye or sensitive individuals, and more details can be found in the TFOS DEWS II iatrogenic report.6

Ideal Properties

It is important that artificial tear drops behave in a similar way to natural tears. One aspect of this is the physical property of rheology, which refers to the way fluids and soft solids flow. The viscosity of human tears is high between blinks, but reduces during each blink cycle in order to protect the ocular surface from damage due to fluid turbulence.1 Hence, they do not display Newtonian behaviours and are referred to as having non-Newtonian properties. Hyaluronic acid has been the subject of a significant amount of research and has been shown to exhibit these non-Newtonian shear-thinning properties,18 making it more like the tear film and hence suitable for use in artificial tears.19 Hyaluronic acid, a common constituent of artificial tears, is a naturally occurring glycosaminoglycan, which is found in and around body cells and tissues, for example in synovial fluid, and vitreous and aqueous humour.20 Its use in ophthalmology was pioneered by Andre Balazs in the late 1960s,21 with Polack and McNiece22 being the first to report its use in dry eye. Hyaluronic acid is water soluble and is capable of binding large quantities of water, compared to its own weight, but its physical properties vary depending upon its molecular weight.23 There is evidence to suggest that high molecular weight hyaluronic acid (HMWHA) is clinically superior in the treatment of DED compared to its low molecular weight counterpart.24 Furthermore, HMWHA has been found to be protective against corneal cell apoptosis due to benzalkonium chloride toxicity, ultraviolet light radiation and chemical burns,25–27 as well as being anti-inflammatory and having a role in reducing pain sensation.24,28

Artificial Tears for Dry Eye Disease

There have been several systematic reviews2,29–31 conducted over the past decade, concluding that artificial tears are a safe and effective way of treating DED. A meta-analysis concluded that the effectiveness of sodium hyaluronate did not differ based on its preparation30 and another32 suggested that CMC appeared to be better than hyaluronic acid in treating DED, but the results were not statistically significant. Two recent reviews5,33 both identified that while hyaluronic acid was effective in reducing the symptoms of DED, the ideal drop frequency and formulation (both concentration and molecular weight) for different ages and severities were yet to be investigated.

To date, there has been no review of studies which compared different artificial tears to identify whether certain formulations are more effective. Hence, with the objective to better understand the evidence for the effect of different artificial tears in managing dry eye, a search was made of the Web of Sciences databases (Clarivate Analytics, Philadelphia, USA) which includes the Science Citation Index Expanded covering over 9200 of the world’s most impactful journals from 1900 to the present day along with PubMed (including MEDLINE) from its inception. The systematic review was prospectively registered on PROSPERO (CRD42022369619) and was conducted in the format prescribed by PRISMA (2020).34 A search for “artificial tear*” AND “randomi?ed” identified 481 unique results which were screened independently by two researchers (DB and DS) and verified by a third (JSW). Studies were eligible to be accepted if they were in full paper form (not abstracts or book chapters), compared two or more artificial tears against each other (not just with a placebo) and involved randomisation to avoid bias. This resulted in 64 papers being accepted (Figure 1) and the full text scrutinized for the key factors, which were tabulated in a spreadsheet and are summarised in Table 1. The study design, artificial tears compared, number and age profile of participants completing the trial, duration of use and dosing, tests conducted which showed a significant difference/did not differentiate between the products or change from baseline and general comments (dyes used for ocular surface staining, adverse events when reported and subanalyses) were extracted. Missing information is highlighted in the table and risk of bias analysis performed with the Cochrane Tool reported.35 No data synthesis was attempted due to heterogeneity particularly in drop duration.

Table 1 Randomised Clinical Trials That Have Used Artificial Tears for the Treatment of Dry Eye Disease

Figure 1 PRISMA 2020 flow diagram of the systematic review search results.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.127

All studies are prospective (as expected) and involve parallel groups (unless stated otherwise) of dry eye patients (diagnosed using National Eye Institute, arbitrary or recently TFOS DEWS II criteria). However, less than half (20 out of 42) are registered with a clinical trials database and even those that are have high risk of bias characteristics,35 hence the certainty of the result is generally low. The lack of a definitive severity classification has been identified as a factor in differentiating the effectiveness of the available artificial tears,31 but previous attempts at a severity matrix table in TFOS DEWS I36 led to patients being graded at different levels of severity by different tests and was abandoned in TFOS DEWS II;37 severity to a dry eye patient is based on symptoms whereas it is more likely to be based on signs on the ocular surface to a cataract surgeon for example. While the intention of many of the analysed studies is to demonstrate non-inferiority compared to an established treatment, some are underpowered (see TFOS sample size recommendations)37 and/or both eyes included without accounting for the correlation between the two eyes38 of an individual.39–43 In most studies, fluorescein sodium is used for assessing corneal staining (although an appropriate blue light with a peak around 395nm [not cobalt blue whose peak is ~450nm] and yellow filter with a cut off around 500nm is often not stated).44 Most studies use lissamine green for conjunctival staining (unless otherwise stated in Table 1) which is the recommended practice,37 but few state the brand which can dramatically affect the staining observed.45 Some studies46,47 report differences even when they do not meet the standard criteria of p < 0.05 and therefore any “difference” should be considered as noise in the data. While many trials comparing artificial tears are manufacturer initiated or sponsored, unless the research was conducted by the company or not conducted by a reputable research organisation, this should not lead to concerns regarding bias.

From the studies summarised to date (with the caveat that the effects might be affected by dry eye severity and full artificial tear formulation as well as the patient demographic) it would appear from direct comparisons between artificial tears that:

  • Combination formulations are more effective than single active ingredient artificial tears.
    • The combination of CMC with hyaluronic acid is more effective than either in isolation.48,49
    • Hyaluronic acid50 and sodium hyaluronate51 benefit from the addition of trehalose.
    • CMC is enhanced by the addition of glycerine.52
    • CoQ10 enhances the effectiveness of hyaluronic acid.53
    • Newer versions of Systane (Complete and Balance) outperform earlier versions with less complexity (Ultra).54,55
  • Some studies suggest sodium hyaluronate could be more effective than CMC40 and carbomers,56 while others find no difference,57,58 the optimal percentage is not clear.59,60
  • PEG containing artificial tears are more effective than those containing CMC61–65 and HPMC.66,67
  • Cationic formulations are more effective than sodium hyaluronate (for objective signs)68 and polyvinyl alcohol.69
  • Hyaluronic acid containing artificial tears might be better than those with HPMC,70 but worse than those with CMC.39
  • Carbomer containing artificial tears might be more effective than those based on PVA71 or CMC72 or cellulose/mineral oils,73 but less56,74 or as effective43 as sodium hyaluronate.
  • Most studies recommend 4x/day use, but reported/measured use is generally less than that advised.42
  • Long-term compliance is needed to improve ocular surface signs rather than just symptoms4 and symptoms benefit from 4x/day compared to “as needed” dosing.75
  • Higher liposomal concentration increases effectiveness.76,77
  • Lower osmolarity drops increase the effectiveness of an artificial tear drop.46
  • Higher concentration (viscosity) CMC is more effective in reducing corneal and conjunctival staining, but caused more reports of visual disturbance.78
  • While drops targeting individual layers of the tear film seem equally effective,41,79 studies have shown that the most effective drop for an individual can be predicted from their baseline classification; drops containing phospholipids are more effective in those with evaporative dry eye3,4 and osmoprotectants benefit those with high tear film osmolarity.3
  • Artificial tears may not be effective for as much as one-third of patients, but this can be predicted by one month of compliant use.4

These findings can inform clinical dry eye practice; in summary: non-preserved or soft preserved artificial tears being appropriate to prescribe to patients, regardless of the severity of their DED; patients with evaporative dry eye should be prescribed artificial tears containing a high concentration of liposomes; one month’s compliant use 4x/day is recommended to determine whether an artificial tear can manage the patients’ symptoms in the longer-term; signs of ocular surface disease typically take up to 4 months to start improving so patience is needed; artificial tears with multiple active ingredients (especially with PEG) seem to outperform more basic previous generation drops; ability to use different types of artificial tear bottles/sprays varies9 and should be part of the prescribing consideration. While the efficacy of artificial tears is well established for managing DED, its use in ocular surface disease without symptoms to improve post-surgical symptomology and to reduce refractive ‘surprises’ from poor ocular biometry80 is less well established. The data available as reviewed in this study is limited by the definition of dry eye disease applied in published studies being variable as well as the disease severity examined and compliance with artificial tears being rarely quantified.

Other Therapeutic Functions of Artificial Tears

As well as being a management option for dry eye disease and the ocular surface, artificial tears can also be utilised for a wide range of therapeutic functions such as in the treatment of anterior eye trauma, infection, inflammation and disease as well as contact lens management.

Corneal Abrasion and Wound Healing

Corneal abrasions can be caused by foreign bodies, trauma, and trichiasis, and may result in pain, redness, lacrimation, and photophobia. Artificial tears improve epithelial healing.81 Ideally, preservative free drops are used as they tend to be associated with better ocular surface health and tolerability.82 The most common treatment for perioperative corneal abrasions is artificial tears followed by a combination of artificial tears and antibiotic ointment.83 Most artificial tears contain hydrogels; these are known to activate the epidermal growth factor (EGF) receptor which promotes the healing of corneal epithelial wounds.84

Pain and Inflammation Management

Artificial tears are commonly used in the management of ocular pain and inflammation. In the treatment of episcleritis, the combination of artificial tears and cold compresses provide symptomatic relief.85 No significant differences have been observed in the signs or symptoms of idiopathic episcleritis when either artificial tears or topical ketorolac (NSAID) is used.86 Following photorefractive keratectomy (PRK) surgery, the application of preservative-free artificial tears reduces postoperative ocular discomfort and increases visual recovery.87 Cooled artificial tears have been shown to reduce corneal and conjunctival sensation, with 4°C being the most comfortable temperature.88 In contrast to this, Bitton et al found no improvement in perceived patient comfort when refrigerated Systane Ultra artificial tears were used for mild to moderate dry eye sufferers.89 It is also worth noting that pain complaints can be associated with contrasting subjective responses,90 and in some patients artificial tears are not effective in relieving uncomfortable symptoms.91

Conjunctivitis

Allergic conjunctivitis causes ocular itching, watery discharge, lid oedema and conjunctival chemosis. Bilkhu et al exposed 18 participants (who had a known allergy to grass pollen) to grass pollen, and found that artificial tears and cold compresses improved the signs of allergic conjunctivitis and provided symptomatic relief.92 However, if symptoms are persistent, short-term use of topical antihistamines and mast cell stabiliser drops is recommended.93

Viral (non-herpetic) conjunctivitis causes redness, discomfort, and watering. Follicles on the palpebral conjunctiva and punctate epithelial lesions on the cornea may also be observed. It has been shown that 0.5% topical ketorolac,94 0.45% ketorolac tromethamine,95 and 1% prednisolone acetate96 are no better in relieving signs or symptoms of viral conjunctivitis compared to artificial tears.

Bacterial conjunctivitis causes redness, discomfort, and produces a sticky discharge with crusting of the eyelids. Bacterial conjunctivitis usually self-resolves, but the application of artificial tears and eye bathing aids ocular comfort and hygiene. If bacterial conjunctivitis persists after 3–4 days, the application of topical antibiotics is usually recommended.97

Keratitis

Keratitis is an inflammation of the cornea and has several different aetiologies including viral (Herpes Simplex), bacterial (marginal keratitis), fungal, contact-lens associated and unprotected exposure to ultraviolet radiation (photokeratitis). In dry eye and photokeratitis,98 the application of artificial tears has been recommended. In herpetic keratitis, marginal keratitis, fungal keratitis, and contact-lens associated keratitis, artificial tears are advised (for lubrication and symptomatic relief) alongside additional treatment such as topical antivirals, topical and/or oral antibiotics, and antifungals.

Contact Lens Rewetting and Removal

Contact lens wearers commonly use preservative free artificial tears for ocular lubrication, comfort and contact lens rehydration.99–101 Towards the end of wear, contact lenses become drier and fit tighter. The application of artificial tears reduces friction against the cornea and can facilitate safe lens removal.

Foreign Body Removal

Corneal foreign bodies can cause irritation, lacrimation, blurred vision, and redness. Loose foreign bodies can be irrigated away with normal saline or artificial tears. Upon successful removal of a foreign body, prophylactic antibiotics,102 analgesia and artificial tears are advised.103

Summary

Artificial tears are the mainstay of DED management, but also have a role in corneal abrasion and wound healing, pain and inflammation management, conjunctivitis, keratitis, contact lens rewetting and removal, and foreign body removal. A review of randomized controlled trials comparing artificial tears identified 64 papers. There is good evidence that artificial tears improve symptoms of DED within a month of regular use, applied ~4x a day, but signs generally take several months. Not all patients with DED benefit from artificial tears, so if there is no benefit over a month, alternative management should be considered. Combination formulations are more effective than single active ingredient artificial tears. PEG containing artificial tears are more effective than those containing CMC and HPMC. Those classified as having evaporative DED, benefit from artificial tears with liposomes, especially of higher concentration.

Disclosure

JSW is on the executive of the Tear Film and Ocular Surface Society and the Aston University Optometry Research Group have received research funding from Alcon, the Eye Doctor, Scope Ophthalmic and Thea Pharmaceuticals. No funding was received to conduct this review. The authors report no other conflicts of interest in this work.

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