At the completion of this article, the reader should…
• Understand how preservatives in glaucoma medications affect the ocular surface and patient outcomes.
• Review clinical evidence supporting preservative-free artificial tears in glaucoma patients.
• Discuss practical strategies for recommending preservative-free tears to improve comfort and adherence.
Dr Jeremiah Lim
BOptom, MPhil, PhD (Melb)
Senior Lecturer, Department of Optometry and Vision Sciences, School of Health and Clinical Sciences, University of Western Australia, Perth, WA
Lisa Jansen
BOptom(Hons), CertOcTher,
Grad Cert Ter Teaching, FHEA
Deputy head, Department of Optometry and Vision Sciences, School of Health and Clinical Sciences, University of Western Australia, Perth, WA
Dr Jeremiah Lim and Lisa Jansen explore how preserved glaucoma medications affect the ocular surface, highlight the advantages of preservative-free IOP-lowering treatments, and emphasise the role of preservative-free lubricants for patient comfort and adherence.
Optometrists, in their role as primary eye health practitioners, play an important role in diagnosing, monitoring and treating the ocular surface complications that frequently accompany chronic glaucoma therapy.
Dry eye disease affects a substantial proportion of glaucoma patients, with about 50% of glaucoma patients experiencing comorbid ocular surface disease.1
In this article, we explore the use of preservative-free artificial tears in managing dry eye among glaucoma patients, and examine the evidence for the prescription of preservative-free intraocular pressure (IOP)-lowering drops.
A particular focus is placed on the rationale for selecting preservative-free lubricants to minimise the cumulative preservative burden in this high-risk population.
Introduction
Glaucoma affects approximately 1.5% – 3.4% of the non-indigenous Australian population,2 often necessitating lifelong topical therapy to control intraocular pressure. The chronic nature of topical glaucoma treatment can create a clinical conundrum for eyecare providers: while topical therapy can keep IOP in check, it can also contribute to ocular surface disease.
Indeed, dry eye disease is remarkably common in glaucoma patients, with studies demonstrating that roughly half of glaucoma patients on topical therapy report dry eye symptoms,1 representing more than double the likelihood of age-matched controls in an Australian study.3
This high prevalence reflects both the direct effects of antiglaucoma medications and the cumulative burden of preservatives, particularly benzalkonium chloride (BAK), which is present in approximately 70% of ophthalmic formulations.4
For patients requiring long-term IOP therapy, the additive effect of preservatives across multiple daily drops becomes clinically relevant, particularly when adjunctive lubricants are introduced.
In an analysis of the consequences of this burden, one study of a Miami veteran population reported that glaucoma patients with dry eye symptoms were approximately 30% less likely to be adherent to treatment, compared to those without symptoms.5
Impact of preservatives on the ocular surface
Historically, preservatives were considered necessary to prevent contamination in multidose bottles and to enhance corneal penetration of active ingredients.
The most commonly used preservative in glaucoma medications is BAK, a quaternary ammonium compound that maintains sterility in multidose formulations.4
BAK functions as a preservative through its cationic detergent properties, disrupting microbial cell membranes. However, this same mechanism causes cytotoxic damage to ocular surface cells, primarily through oxidative stress.4
The compound also disrupts tear film lipid layers, causes conjunctival goblet cell death, and triggers release of pro-inflammatory cytokines including IL-6, IL-8, and IL-1ß.6
Chronic exposure to BAK-preserved glaucoma medications produces cumulative ocular surface damage.
Preclinical studies demonstrate that BAK-preserved latanoprost and travoprost are cytotoxic to conjunctival goblet cells in a time-dependent manner, while preservative-free or alternatively preserved formulations do not affect goblet cell survival.6
Despite disruption to the ocular surface, studies suggest that BAK does not enhance glaucoma therapeutic efficacy, with recent evidence demonstrating that preservative-free formulations can achieve equivalent IOP reduction.6,7
The Impact of glaucoma drugs and role of preservative-free eye drops
Although the evidence supporting preservative-free glaucoma medications is compelling, it does not exist without controversy. A meta-analysis conducted by Hedengran et al., 2020, pooled data from 13 studies involving4, 201 patients, and found no significant difference in IOP reduction between BAK-preserved and preservative-free formulations.7
Although the efficacy is equivalent, Hedengran et al., 20207 found no significant differences in conjunctival hyperaemia, total ocular adverse events or tear break-up time between BAK, non-BAK and preservative free formulations. This finding suggests that the active ingredients in glaucoma medications themselves may also contribute to the development of these adverse ocular effects, rather than the preservative alone.
However, this represents a narrow view of ocular surface disease. Studies demonstrate that preservative-free formulations improved patient-reported outcomes for dryness symptoms, Schirmer test values and impression cytology outcomes compared to preserved alternatives.6,8
The recently published TFOS DEWS III Workshop9 defines dry eyes as a multifaceted disease comprising of various aetiologies. They propose a risk matrix (Figure 1), where preserved topical medications are regarded as a ‘consistent’ yet modifiable contributor to dry eye disease, reinforcing the role of the clinician in tailoring therapy for patients at risk of dry eye.
Beyond ocular surface parameters, preservative-free medications demonstrate improved tolerability and patient satisfaction, which may enhance adherence.5
The cumulative evidence suggests that preservative-free glaucoma therapy represents a safer long-term treatment strategy, particularly for patients requiring multiple medications or those with pre-existing ocular surface disease.10,11
Preservative-free artificial tears as adjunctive therapy
Given the high prevalence of ocular surface disease in glaucoma patients, artificial tears serve as an important adjunctive therapy.
It is estimated that more than 50% of glaucoma patients were prescribed adjunctive artificial tears by their eyecare practitioner, on average within 10 months of commencing topical therapy.12
In a Brazilian-based study evaluating comprehensive ocular surface disease treatment (preservative-free sodium hyaluronate lubricants, eyelid hygiene, and anti-inflammatory therapy) in glaucoma patients, the authors found not only improved OSDI score but also improvements in various ocular surface parameters. Interestingly, there was a trend towards an additional mean IOP reduction of 1.59 mmHg in the treatment group, which could reflect better compliance.13
Lipid-based vs aqueous artificial tears
The selection between lipid-based and aqueous artificial tears depends on the underlying dry eye pathophysiology.14
Sodium hyaluronate-containing eyedrops have been shown to produce beneficial effects on objective and subjective markers of dry eyes, and work well in patients with aqueous deficient dry eye.14,15
Evaporative dry eye, often associated with meibomian gland dysfunction, is common in glaucoma patients on topical preserved therapy. These patients may benefit preferentially from lipid-containing formulations.
A six-month randomised controlled trial comparing lipid-based drops with non-lipid aqueous drops found significantly greater improvement in patients with suboptimal baseline lipid layer thickness.16
This suggests that lipid-based formulations address a specific deficiency that aqueous drops cannot fully correct.
For glaucoma patients, the choice should be guided by clinical assessment of tear film composition and meibomian gland function. Those with predominantly aqueous deficiency may respond adequately to non-lipid formulations, while patients with evaporative dry eye or meibomian gland dysfunction benefit from lipid supplementation.14,16
Anti-inflammatory strategies: ciclosporin and corticosteroids
Occasionally, patients who have been transitioned to preservative-free glaucoma drops and supplemented with preservative-free tear lubricants continue to experience persistent ocular surface inflammation.
When inflammation remains refractory despite these measures, topical ciclosporin represents an important therapeutic option. Topical ciclosporin 0.05% has been investigated as a potential adjunct for ocular surface disease in glaucoma patients, with two studies demonstrating efficacy in improving OSDI scores, tear film parameters, reducing ocular surface staining, and decreasing inflammatory markers after a four- to six-month period of use.17,18
The introduction of newer TGA-approved versions of ciclosporin, both available in 0.09% and preservative-free, offers a promising avenue for treatment of underlying ocular surface inflammation without risking an increase in IOP, though further research is required.
Topical corticosteroids represent another anti-inflammatory option, particularly for acute exacerbations.
Evidence suggests that short-term corticosteroid use may improve dry eye symptoms and corneal fluorescein staining,13 though the risk of elevated intraocular pressure necessitates careful monitoring in glaucoma patients.
Clinical recommendations
Screening for ocular surface disease
All glaucoma patients on topical therapy should undergo routine screening for ocular surface disease. This should include symptom assessment using validated questionnaires (OSDI or similar), tear film break-up time measurement, ocular surface staining evaluation, and assessment of meibomian gland function.
The high prevalence of ocular surface disease in this population justifies systematic screening rather than waiting for patient complaints.
Choosing preservative-free glaucoma medications
When initiating or modifying glaucoma therapy, preservative-free formulations should be strongly considered, particularly for patients requiring multiple medications, those with pre-existing ocular surface disease, or those planning future glaucoma surgery.
The equivalent efficacy and superior safety profile of preservative-free options make them an appropriate first-line choice. Alternatively, non-BAK formulations may also be considered, though options remain limited.
Selecting appropriate tear supplementation
The choice of artificial tear formulation should be guided by dry eye subtype. For patients with predominantly aqueous deficiency, preservative-free aqueous-based tears containing sodium hyaluronate or carboxymethylcellulose are appropriate.
For those with lipid layer deficiencies or significant meibomian gland dysfunction, lipid-based formulations provide superior benefit.
Across both subtypes, preservative-free preparations should be prioritised to minimise the effects of cumulative preservative exposure in patients receiving glaucoma therapy.
Dosing strategies and timing
Artificial tears should be used at least four times daily for optimal benefit, with some patients requiring more frequent application. Correct drop instillation technique should be demonstrated, and patients should be encouraged to report symptoms early rather than tolerating discomfort.
Aligning instillation times with daily routines (e.g., meals) can simplify the complexity of drop regimes. While specific evidence on optimal timing relative to glaucoma medication administration is limited, general principles suggest allowing five to 10 minutes between different eye drop instillations to prevent dilution of the glaucoma therapeutic agent.
For patients with severe symptoms, consider more viscous formulations (gels) at bedtime to provide prolonged ocular surface protection. The use of ointments should be reserved for nighttime application due to visual blurring.
Escalation to anti-inflammatory therapy
For patients with persistent moderate-to-severe symptoms despite preservative-free glaucoma medications and artificial tears, topical ciclosporin eye drops should be considered. Patients should be counselled that improvement may take 12 weeks and that initial burning or stinging is common but typically diminishes with continued use.
Short-term topical corticosteroids may be used for acute exacerbations, but require close IOP monitoring in glaucoma patients.
Patient education and adherence
Patient education is critical for optimising outcomes, particularly when addressing the interplay between chronic therapy and ocular surface disease.
Patients should understand that ocular surface disease is a common consequence of glaucoma therapy, not a reason to discontinue IOP-lowering medications. Clear explanations about why symptoms occur, how they can be managed, and the importance of continuing glaucoma therapy support a collaborative patient centred care approach.
Clinicians should also emphasise that choosing preservative-free lubricants is part of a broader strategy to protect the ocular surface and support ongoing adherence to glaucoma therapy.
Simplifying the medication regimen when possible, using combination formulations, once-daily medications when clinically appropriate and addressing ocular surface symptoms proactively may improve overall adherence to glaucoma therapy.
Written instructions outlining the timing of drops and dosage can be helpful as a reminder for patient adherence.
Conclusion
The evidence supporting preservative-free artificial tears in glaucoma patients is substantial. Just as preservative-free IOP-lowering medications achieve equivalent efficacy with superior safety, preservative-free artificial tears provide effective symptom relief and objective improvement in ocular surface parameters without the additional preservative burden.
The choice between lipid-based and aqueous formulations should be guided by dry eye subtype, with lipid-containing tears offering specific advantages for lipid layer deficiencies and meibomian gland dysfunction.
For patients with inadequate response to tear supplementation alone, topical ciclosporin represents an evidence-based escalation strategy. A systematic approach to screening, prevention, and treatment of ocular surface disease in glaucoma patients can improve quality of life, potentially enhance adherence, and optimise long-term outcomes.
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