With one in five adults complaining of chronic dry eyes, and many more experiencing episodic symptoms, the demand for knowledgeable advice and effective, affordable solutions is ever-increasing. In one survey,1 19 per cent of respondents were using over the counter (OTC) products for dry eyes at least five times per week, but 69 per cent of those adults with symptoms had not taken professional advice. Worse still, 63 per cent of those using drops did not find them very effective!
A conservative estimate of the number of people experiencing dry eye problems in the UK would be around 11 million, so it is important to understand distinguishing features in modern products in order to make effective, confident recommendations. This article revises the pathophysiology of dry eye and sets out some key principles to understand and follow when choosing drops for dry eyes.
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Background
The prevalence of dry eye in western nations averages around 20 per cent in adults over 40,2 increasing with every decade to be one of the most common eye complaints in the elderly.3,4 Symptoms can range from mild irritation to debilitating pain and discomfort. Indeed, the burden and impact on quality of life of moderate dry eye has been equated to that of angina.5
It’s also easy to underestimate the visual disturbance of an abnormal tear film on the ocular surface, but patients with dry eye can be three times more likely to complain of problems with other visual tasks,6 and may have slower reactions times when driving.7 More younger people are presenting with dry eyes – perhaps because blink rates halve with concentration, particularly with computer use, and if they wear contact lenses then half of them will complain of dryness symptoms when wearing lenses,8 particularly towards the end of the day.9
Dry eye and its vicious circle
The tear film is a dynamic, transparent film that offers protection for the ocular surface by clearing away debris and pathogens, lubrication and hydration for the epithelial cells, oxygen and nutrients for the cornea (which is avascular), and a smooth optical surface for refraction of light into the eye. Microvilli on the ocular surface epithelia anchor this thin film via a mucin and protein mix (called the glycocalyx); an aqueous layer lies over this glycocalyx (containing free mucins), and an oily (lipid) layer is uppermost, at the air interface. This lipid layer slows down evaporation of the tear film, but is easily disrupted.
Understanding the pathophysiology of dry eye is fundamental to successful management. Between blinks the tear film spreads and thins; it exhibits non-Newtonian and visco-elastic behaviours, meaning that it cleverly offers minimal resistance to the blinking eyelid, but becomes more viscous and protective when the eye is open. The understanding that the tear film is a solution with a high viscosity at low shear rate (when the eye is open) and a low viscosity at high shear rate (during blinking) is important, as there are certain eye drops contain ingredients that mimic this behaviour.
Tear film instability that gives rise to excessive evaporation is by far the most common cause of modern dry eye. True deficiencies in the volume of tears produced account for less than 20 per cent of all dry eyes, and relate to conditions such as Sjögren’s syndrome, or side effects of medications such as diuretics, beta-blockers and antihistamines.
But whatever the underlying trigger, the resultant chronic effect is that the remaining tear fluid is ‘concentrated’; its osmolarity is increased, which in turn causes inflammation and detrimentally affects the microvilli and mucin-producing cells on the ocular surface. This destabilises the overlying tear film further, and so on – this is what experts describe as the ‘vicious circle of dry eye’, which amplifies and perpetuates the inflammation, allowing it to linger after the trigger is removed.
The more chronic the condition, the more likely the ocular surface is to be inflamed, and the more intervention may be required. The aim of any management is to manage the initial trigger wherever possible, and give symptomatic relief by choosing products that intervene and ‘break’ this cycle at key points (Figure 2). In fact, management of dry eye becomes more about managing the ocular surface and less about substituting tear fluid.
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What’s in a dry eye drop?
It’s important to note that it is the combination of several physical properties its subsequent behaviour in vivo (which is often different), plus patient factors such as blinking that determine whether a product effective or indeed, superior to another. The key components of interest are reviewed briefly below and summarised in Figure 3.
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Solvent
Water is the major component in most eye drops – up to 97-99 per cent.
Demulcents
Polymers acting as demulcents are included to bulk out the tear film and ‘smooth’ over the ocular surface. Many of the traditional P products and older formulations contain the primary ingredient as a polysaccharide: either carboxymethylcellulose (CMC) or hydroxypropyl methylcellulose (HPMC). Others are based on synthetic polyvinylalcohol (PVA) and polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG) which tend to have greater water-holding ability than CMC and HPMC.
More modern products might still include these ingredients but the primary component tends to be an ingredient that is a better mimic of the tear fluid under shear forces – this would be hyaluronic acid or HP-Guar (see below).
A word about viscosity
Although it may be intuitive to think that the more viscous an eye drop the more long lasting it is for the patient, robust clinical evidence to support the idea that small differences between fluid drops currently on the market is actually lacking. We see definite effects when using gels where the viscosity is much higher, but small differences between fluid products may be too small to be noticeable. One of the possible explanations for this is that blinking very quickly strives to restore the original viscosity of tear fluid, and more work needs to be carried out to establish the optimum viscosity for fluid drops.
Controlling tonicity: the electrolyte factor
Electrolytes in tear fluid such as potassium, sodium, bicarbonate and magnesium are critical to maintenance of tonicity of the solution, and the maintenance in particular of goblet cells.10 An imbalance and/or excess of such electrolytes will trigger an inflammatory response on the ocular surface.
Some eye drops strive to match this natural balance or even address the imbalance, but many eye drops may even be hypertonic, rather than the desirable hypotonic formulations. A solution must be significantly hypotonic relative to the hyperosmolarity of the fluid in a dry eye to make a difference.
Preservatives
The most commonly used preservatives are benzalkonium chloride (BAK) and one of its derivatives, polyquaternium-1 (Polyquad). Both are very effective types of detergent, but the toxic effects of BAK are well documented in the literature. As awareness of its potential to cause problems grows, particularly in glaucoma patients on multiple drops, we are seeing more preservative free formulations coming to market.
Buffering agents
Buffering agents are used to maintain tear pH (around 7.4pH units) and avoid stinging on application. The use of phosphate compounds to buffer eye drops is controversial following a recommendation from the European Medicines Agency in 2012 stating that phosphate-free treatments are recommended for the safety of ocular surface. While this particularly applies to eyes with severe existing surface damage, some pharmaceutical manufacturers sensibly choose to avoid phosphate buffers across their POM and OTC products, using alternatives such as citrate buffers.
Lipids in dry eye drops
Given that most dry eye is related to increased evaporation of the tear film, it is logical that we have seen the introduction of lipid-based products or products including a lipid component, but it should be remembered that these are relatively poor substitutes for the real thing: meibum is actually an extremely complex mix of fatty acids, their alcohol derivatives, sterols, sterol esters and triglycerides. Caring for eyelids as required via a regime of warming, massage and cleaning has to be the more effective strategy for most patients.
What would be the ideal dry eye drop?
It would:
- Be ‘kind’ to the ocular surface
- Protect the ocular surface from hyperosmolarity
- Mimic the behaviour of the tear film
- Provide long-lasting relief
- Be easy to use and apply
Advising patients on the best solution
In the past, our choice of drops for dry eye has been limited to lubricants – usually a cellulose-derivative drop preserved with benzalkonium chloride, or a lanolin ointment, both largely acting as demulcents achieving only short-term relief. Formulations have moved on dramatically over the past 20 years, largely due to the widespread availability of the more modern products classified as medical devices or cosmetics. However, it would be wrong to assume that this means the formulations are less sophisticated or effective than long-standing P products; in many cases the reverse can be true.
The best products need to achieve as much as possible: to influence both the tonicity and stability of the tear film, and protect the ocular surface from the potential desiccation in between blinks.
Here are five simple principles to follow in order to guide patients towards the most effective products, breaking the vicious circle from as many angles as possible:
1?Avoid preservatives wherever possible
The absence of the preservative, particularly if it is benzalkonium chloride, becomes more crucial than the active ingredient at this posology. The negative effects of this type of preservative on the ocular surface are widely accepted.11,12 Even other vanishing preservatives may not completely dissipate in a dry eye with low tear volume.1 If a patient is also taking other preserved topical medication for glaucoma, then it is even more important to use preservative-free formulations for dry eye.
2?Choose a sufficiently hypotonic drop
This will help to address the increased osmolarity of the tears in a dry eye 13,14 – the fundamental driver for inflammation. This may be particularly beneficial if the patient complains of stinging and burning sensations. 15
3?Look for products that contain ingredients that mimic the tear films’ viscoelastic behaviour in relation to shear forces (non-Newtonian behaviour)
The natural choice is hyaluronic acid (HA) as a viscosity agent (or its sodium salt version). It is an excellent natural lubricant in the human body, with a sponge-like structure of polysaccharide chains that act to retain water and retard evaporation when placed on an aqueous solution. Hydrated hyaluronic acid can contain up to 1,000-fold more water than its own weight, resulting in enhanced hydration of the corneal surface.
Many clinical studies demonstrate superiority over the more traditional cellulose derivatives and PVA, etc. For example, a concentration of 0.1 per cent appears to be the minimum required to delay tear break-up time.16 In hypotonic solution, HA is also known to improve vitality of corneal and conjunctival epithelial cells, 16,17 and in long-term use ocular surface damage is reduced.18 In patients using preserved eye drops to manage their glaucoma, dry eye symptoms were managed best with preservative-free 0.18 per cent sodium hyaluronate compared with 0.3 per cent HPMC/Dextran. 19
A plant-derived alternative is hydroxypropyl-guar (HP-Guar), an ingredient that behaves like a gelling agent upon contact with the tears. This confers similar properties to the tear film in its behaviour.
Both of these clever ingredients also demonstrate muco-adhesive properties, tending to coat the ocular surface well by interacting with the mucin layer.
The more traditional ingredients such as cellulose derivatives, PEG, PVA might be found in addition to hyaluronic acid or HP-Guar – here they may act as adjuncts with the aim of improving residence time.
4 Look for ingredients that protect the ocular surface
Molecules such as trehalose protect corneal epithelial cells from death by drying,20,21 and confers resistance to high osmolarity by protecting proteins and membranes from denaturation.22,23 Trehalose has also been shown to protect corneal cells prior to Lasek.24 Other osmoprotectants include solutes such as L-carnitine and erythritol, alone or in combination.
5 Finally, make sure you consider how the patient will use the product
Look for bottles that patients will find easy to squeeze, or come in unit doses – the pressure required to dispense eye drops varies enormously between products. Eye drops are seldom easy to apply – make sure your patient knows how before they leave the practice.
Conclusion
There is a plethora of products to select from, but it is possible to connect the aetiology with the science behind the formulations of modern products. In the more troublesome cases a combined approach of lid care, artificial tears and dietary advice can be advocated.
Go to opticianonline.net/dry-eye-table for a list of all available dry eye management preparations
Three clinical pearls for advising on eye drops:
- Give written instructions on use with the patient’s name on after applying a sample in the chair.
- Involve support staff in teaching how to apply the drops – the new ‘teach’ in the practice
- Instruct patients to take their dry eye drops regularly as opposed to when their eyes feel sore
References
1 The Allergan Dry Eye Survey, 2011
2 Report of the Epidemiology Subcommittee of the International Dry Eye Workshop, Ocular Surface ,2007; 5:93-107.
3 Schein OD, Munoz B, Prevalence of dry eye amongst the elderly. Am J Ophthalmol, 1997; 124(6):723-728.
4 Schein OD, Hochberg MCC et al, Dry eye and dry mouth in the elderly; a population-based assessment. JAMA Int Med, 1999; 159(12):1359-1363.
5 Schiffman RM, Walt JG et al, Utility assessment among patients with dry eye disease. Ophthalmology, 2003; 110(7):1412-1419.
6 Miljanovic B, Dana R et al, Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol, 2007; 143(3) 409-415
7 Deschamps N, Ricaud X et al, The impact of dry eye disease on visual performance while driving. Am J Ophthalmol, 2013 156(1):184-189.
8 Guillon M, Maissa C, Dry eye symptomatology of soft contact lens wearers and non-wearers. Optom Vis Sci, 2005; 82(9):829-834.
9 Nichols JJ, Sinnott LT, Tear film, contact lens and patient-related factors associated with contact lens-related dry eye. Invest Ophthalmol Vis Sci, 2006; 47:1319-28.
10 Lew H et al, Ophthalmologica, 2005; 219(3):142-146.
11 Noecker R, Effects of common ophthalmic preservatives on ocular health. Adv Therapy, 2001; 18(5):205-208.
12 Baudouin C, de Lunardo C, Short-term comparative study of topical 2 per cent carteolol with and without benzalkonium chloride in healthy volunteers, 1998;
Br J Ophthalmol 82:39–42.
13 Aragona P, Di Sg et al, Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjogren’s Syndrome patiens. Br J Ophthalmol, 2002; 86(8):879-884.
14 Troiano P, Monago G et al, Effect of hypotonic 0.4 per cent hyaluronic acid drops in dry eye patients: a cross over study. Cornea, 2008; 27(10):1126-1130.
15 Liu H, Begley C et al, A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci, 2009; 50(8):3671-3679.
16 Hamano et al, Sodium Hyaluronate eye drops enhance tear film stability. Jpn J Ophthalomol, 1996; 40:62-65.
17 Polack F, McNiece MT, The treatment of dry eyes with Na Hyaluronate (Healon). A preliminary report. Cornea, 1982; 1(2):133-136.
18 Aragon P, Papa V et al, Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol, 2002; 86:181-184.
19 Prabhasawat P et al, Effect of 0.3 per cent Hydroxypropyl Methylcellulose/Dextran Versus 0.18 per cent Sodium Hyaluronate in the Treatment of Ocular Surface Disease in Glaucoma Patients: A Randomized, Double-Blind, and Controlled Study. Journal of ocular pharmacology and therapeutics, 2015; 31(6).
20 Matsuo, Trehalose protects corneal epithelial cells from death by drying. Br J Ophthalmol, 2001; 85:610-612
21 Hill-Bator et al, Trehalose-based eye drops preserve viability and functionality of cultured human corneal epithelial cells during desiccation. Biomed Research International, 2014, June.
22 Chen et al, Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis. Exp Eye Research, 2009;
89:311-18.
23 Baudouin et al, Role of hypersomolarity in the pathogenesis and management of dry eye disease: proceedings of the Ocean group meeting, 2013.
24 Aragona et al, Protective effects of Trehalose on the corneal epithelial cells. The Scientific World Journal, 2014, June.
Professor Christine Purslow is head of medical affairs for Thea Pharmaceuticals, researcher at Cardiff University, and visiting professor at Plymouth and Aston Universities