The impact of preservatives on the ocular surface in patients with ocular hypertension or glaucoma

Preservative-related toxicity is an important factor in the lifelong management of patients with glaucoma. (Image credit: AdobeStock/RFBSIP)

The rise in ocular surface disease (OSD) among patients with glaucoma is a pressing issue that cannot be overlooked. As ophthalmologists, we must prioritize ocular health and mitigating OSD over our patients’ lifetime, not just manage their glaucoma.

Although glaucoma is not typically considered a disease of the ocular surface, literature suggests that 30% to 70% of patients with glaucoma also suffer from OSD, a stark contrast to the 5% to 30% among similarly aged adults without glaucoma.^3,4,6 This is not just a minor inconvenience. OSD is also linked to a higher rate of failure in subconjunctival glaucoma surgery.^1,2,7

A combination of risk factors—including increasing age, genetics, sex, and systemic comorbidities—may play a role in the increasing prevalence. In some patients, OSD could be a preexisting condition, exacerbated by topical treatments. Yet, there are a multitude of studies that show OSD manifesting after initiation of first-line topical glaucoma therapies in up to 59% of patients.^4,7 Use of laser trabeculoplasty as first-line treatment helps mitigate this, but most patients ultimately require topical therapy. The number of antiglaucoma medications, administrations per day, and treatment duration are also key predictors of significant OSD and severity of glaucoma.^1,2,6

Preservatives in glaucoma medications

Preservatives have long been used in ophthalmic medications to provide antimicrobial activity to maintain sterility.^4-6,8 This is a double-edged sword; while effective against pathogens, there is mounting evidence of serious, deleterious effects on the ocular surface associated with long-term use.^1-8

Benzalkonium chloride (BAK), once marketed as a disinfectant, is present in 70% of ophthalmic formulations.^6,8 Despite the extensive documentation of cytotoxic effects and association with increases in OSD, BAK is still the most widely used preservative in glaucoma treatments.^1-8

Several studies have linked higher BAK concentrations in glaucoma treatments and cumulative exposure to greater ocular surface toxicity and damage. Infiltration into the eye and accumulation in deep ocular structures such as the trabecular meshwork (TM) ultimately led totear film instability, loss of goblet cells, disruption of the corneal epithelium barrier, and damage to deeper ocular tissue.^1,2,5-7

Patients using preserved medications frequently report pain, burning, stinging, ocular dryness, and itching that are exacerbated by unstable tear film irritation, and overall worse scores on the Ocular Surface Disease Index.^1-7 These side effects are of clinical importance considering effectiveness of treatment depends on adherence. So, it is not surprising that nonadherence has been reported in up to 60% of patients with glaucoma with treatment-related side effects or among patients using preservative-containing drops.^4,7

Although most available generic glaucoma treatments contain BAK as a preservative, preservative-free formulations are becoming more widely available. These formulations have demonstrated less cytotoxicity than their BAK-preserved versions.^6,7 Clinical studies and real-world observational studies have shown decreased signs and symptoms of OSD and increased adherence to treatment without compromising IOP control.^4,6,7

With equally effective and readily available preservative-free alternatives, the question remains: why are we still prescribing treatments with molecules originally marketed as disinfectants?^6,8

As with many interventions, the challenge is insurance coverage and cost to the patient. Generic drops are inexpensive, but we need to balance this with the long-term effect on the ocular surface. The prior authorization burden to clinical practices to obtain preservative-free drops can be onerous, but the more we request them, the more payers will recognize the need to allow access to these compounds. Our overarching goal is to protect our patients’ vision by using the minimum number of medications required to reach the target IOP range.

Considering the future

Choosing preservative-free glaucoma treatments over preserved formulations is a solution within reach. These formulations can reduce OSD symptoms, promote better adherence to treatment without compromising efficacy, and decrease risk of surgery by preserving the ocular surface and TM. It is up to us to ensure that our patients are informed of their options. It is up to us to protect their vision with the utmost care and consideration for their ocular surface health.

Note: The thoughts and opinions expressed are those of the authors and do not necessarily represent the opinions of this publication.

Eydie G. Miller-Ellis, MD
E: Eydie.Miller@pennmedicine.upenn.edu
Miller-Ellis is a professor of clinical ophthalmology and the director of the glaucoma service at the Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Miller-Ellis maintains a busy clinical practice in glaucoma and has lectured nationally and internationally on glaucoma diagnosis and management. She has excelled in resident education, especially surgical training, and received the 2011 Surgical Teaching Award at the Scheie Eye Institute. Her research interests include risk factors for the development and progression of glaucoma, pharmacological and surgical treatment of glaucoma, and diagnostic techniques.

Mildred M.G. Olivier, MD
E: molivier@psm.edu
Olivier is an associate dean for Ponce’s Regional Campus in Saint Louis, Missouri, and a professor of ophthalmology at Ponce and Saint Louis University. Her academic work includes clinical instruction of medical students and residents in glaucoma at the John H. Stroger Jr. Hospital of Cook County. She is the founder and chief executive officer of the Midwest Glaucoma Center, PC. Olivier was a member-at-large of the Board of Trustees of the American Academy of Ophthalmology (AAO), past president of Women in Ophthalmology, and assistant dean for Diversity, Global Health Chair for Chicago Medical School. She served on the Diversity Issues Committee at the Association for Research in Vision and Ophthalmology and served on the Advisory Council of the National Eye Institute, and continues to be AAO delegate to the American Medical Association. 

References

1. Baudouin C, Kolko M, Melik-Parsadaniantz S, Messmer EM. Inflammation in glaucoma: from the back to the front of the eye, and beyond. Prog Retin Eye Res. 2021;83:100916. doi:10.1016/j.preteyeres.2020.100916

2. Chamard C, Larrieu S, Baudouin C, Bron A, Villain M, Daien V. Preservative-free versus preserved glaucoma eye drops and occurrence of glaucoma surgery. A retrospective study based on the French national health insurance information system, 2008-2016. Acta Ophthalmol. 2020;98(7):e876-e881. doi:10.1111/aos.14410

3. Mylla Boso AL, Gasperi E, Fernandes L, Costa VP, Alves M. Impact of ocular surface disease treatment in patients with glaucoma. Clin Ophthalmol. 2020;14:103-111. doi:10.2147/OPTH.S229815

4. Harasymowycz P, Hutnik C, Rouland JF, et al. Preserved versus preservative-free latanoprost for the treatment of glaucoma and ocular hypertension: a post hoc pooled analysis. Adv Ther. 2021;38(6):3019-3031. doi:10.1007/s12325-021-01731-9

5. Thygesen J. Glaucoma therapy: preservative-free for all? Clin Ophthalmol. 2018;12:707-717. doi:10.2147/OPTH.S150816

6. Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride exposure: problems and solutions. Eye (Lond). 2022;36(2):361-368. doi:10.1038/s41433-021-01668-x

7. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular surface disease and glaucoma medications: a clinical approach. Eye Contact Lens. 2019;45(1):11-18. doi:10.1097/ICL.0000000000000544

8. Merchel Piovesan Pereira B, Tagkopoulos I. Benzalkonium chlorides: uses, regulatory status, and microbial resistance. Appl Environ Microbiol. 2019;85(13):e00377-19. Published 2019 Jun 17. doi:10.1128/AEM.00377-19