Opening our eyes to the impact of preservatives

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Glaucoma is a leading cause of irreversible blindness worldwide. The pathogenesis of glaucoma is not entirely understood; however, major risk factors are well established and include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only known modifiable risk factor is IOP. Evidence-based treatments to lower IOP include topical ophthalmic medications, laser procedures, sustained release implants, and/or surgical interventions. The most common approach for managing glaucoma, especially for the primary care optometrist, is IOP-lowering medication.¹ Often patients with glaucoma are on multiple topical therapeutic agents to achieve optimal IOP measurements. While effective at lowering IOP, topical medications have historically contained preservatives. Preservatives are detergents used to prolong the shelf life of medications and maintain sterility; however, their presence can also have some adverse effects on the eye and cause challenges for the ocular surface.²

The world’s population is aging, resulting in an increase in the geriatric demographic, leading to a rise in certain diseases, including glaucoma. It is estimated that approximately 3 million Americans are currently being treated for glaucoma and this number is expected to double by 2050.³ The Glaucoma Research Foundation reports a dramatic increase in glaucoma diagnosis in patients over 60 years⁴; coupled with an estimated life expectancy in the US of 77.5 years,⁵ this means that most patients with glaucoma are relying on topical antiglaucoma medications for years, if not decades. The risk of developing ocular surface complications increases with the duration of topical therapy use and the number of preserved topical therapies a patient uses. As optometrists, we should be mindful of these ocular surface issues and prescribe with patient compliance, comfort, and quality of life in mind.

Preservatives and glaucoma treatment

Most topical ophthalmic medications are formulated with preservatives, including benzalkonium chloride (BAK), stabilized oxychloro complex (Purite), polyquaternium-1 (Polyquad), and SofZia.⁶ The most commonly used preservative in topical ophthalmic medications is BAK, present in approximately 70% of therapies currently produced.⁷ BAK can break the intracellular junctions in the corneal epithelium, improving drug penetration; however, this benefit comes at the expense of healthy epithelial cells.⁸ The toxic effects of BAK have been consistently demonstrated in laboratory, experimental, and clinical studies.⁹ Based on these experimental and clinical reports, it would be beneficial to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those experiencing preexisting or concomitant ocular surface diseases, and those experiencing adverse effects related to the ocular surface.⁹ Although stabilized oxychloro complex, polyquaternium-1, and SofZia have all demonstrated less corneal and adnexal toxicity than BAK, with chronic usage, these issues can still arise.⁶

Ocular surface disease (OSD), a common finding in patients with glaucoma, is a complex condition that can cause a range of symptoms (eg, dryness, irritation, fluctuating vision, and pain) and can significantly impact the quality of life of affected individuals. OSD that is caused or exacerbated by a prescribed treatment is known as iatrogenic OSD and is prevalent in patients with glaucoma on long-term topical ocular antihypertensive drugs containing preservatives.⁷ Iatrogenic OSD has been linked to damage to the ocular surface barrier, corneal epithelial cells, nerves, conjunctival goblet cells, and the trabecular meshwork.⁷ Long-term use of preserved topical drugs has been shown to cause OSD in up to 49% to 59% of the patients with glaucoma who rely on them for disease management. Ocular surface changes may include ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, and corneal surface impairment. Severe cicatricial conjunctivitis secondary to topical glaucoma therapy has been reported in close to 20% of eyes.⁶

The toxic effects of these preservatives have implications not only for tolerability, but also for medication compliance, which is known to be poor in long-term glaucoma management.¹⁰ As an example, we briefly present a case of an 84-year-old female patient who was on maximum topical therapy for severe glaucoma. She had a history of very poor treatment compliance and constant complaints of red, watery, irritated eyes. In her mind, glaucoma was not a priority when it was OSD that was making her miserable in her daily life. Slit lamp evaluation revealed epiphora, punctal stenosis, and meibomian gland atrophy complicated by permanent makeup (tattooed eyeliner), follicular conjunctivitis, and confluent superficial punctate keratitis in both eyes. Adding drops had only increased her ocular surface symptoms which, in turn, decreased her treatment compliance. All of these factors combined significantly impacted her quality of life. Ideally, previous providers might have considered preservative-free options to prevent the severity of her resulting OSD.

Treating without preservatives

At present, there are relatively new topical therapeutic formulations on the market that do not contain preservatives. There are several glaucoma medications that come in preservative-free formulations: timolol, tafluprost, latanoprost, and a dorzolamide/timolol fixed combination.¹¹ Given that around 50% of patients with glaucoma either have a higher risk of or a concurrent diagnosis of OSD, there is substantial justification for considering preservative-free options. Taking into consideration that patients are on these topical therapies long-term, and that the number of glaucoma diagnoses is projected to significantly increase,³ in the absence of any cost premium or positive indication for preservative-added medication, preservative-free glaucoma medication for all patients is well worth considering.¹¹

Glaucoma is a chronic, potentially blinding condition in which topical therapy continues to be part of the treatment mainstay. The decisions optometrists make today will make a difference to patients in the long-term, potentially impacting compliance, and ultimately influencing the course of the disease. Patients should be educated on all available treatment options, including the potential adverse effects of those treatments. It is up to glaucoma treatment providers to be mindful of the ocular surface and what can invoke long-term damage and impact vision, comfort, and quality of life if left unchecked. Preservative-free treatments can reduce adverse effects and improve compliance, which are both critical for successful long-term management of glaucoma.¹² As optometrists, the primary care providers of the eye, we are in an ideal position to improve the long-term quality of life for our patients with glaucoma by prescribing treatments that consider the health of the ocular surface.

References:

1. Nagstrup AH. The use of benzalkonium chloride in topical glaucoma treatment: an investigation of the efficacy and safety of benzalkonium chloride-preserved intraocular pressure-lowering eye drops and their effect on conjunctival goblet cells. Acta Ophthalmol. 2023;101(suppl 278):3-21.doi:10.1111/aos.15808

2. Sarkar R. Effects of preservatives used in ocular medications on the eye: a comparative review. Ophthalmol J. 2021;6:44-52.doi:10.5603/OJ.2021.0009

3. Anspaugh M. How to get the most out of topical glaucoma therapies. Optometry Times. February 13, 2024. Accessed December 10, 2024. https://www.optometrytimes.com/view/how-to-get-the-most-out-of-topical-glaucoma-therapies

4. Glaucoma Research Foundation. Glaucoma Facts and Stats. Updated November 8, 2024. Accessed December 10, 2024. https://glaucoma.org/articles/glaucoma-facts-and-stats

5. Centers for Disease Control and Prevention. Life Expectancy. Updated October 25, 2024. Accessed December 10, 2024. https://www.cdc.gov/nchs/fastats/life-expectancy.htm

6. Andole S, Senthil S. Ocular surface disease and anti-glaucoma medications: various features, diagnosis, and management guidelines. Semin Ophthalmol. 2023;38(2):158-166. doi:10.1080/08820538.2022.2094714

7. Kahook MY, Rapuano CJ, Messmer EM, Radcliffe NM, Galor A, Baudouin C. Preservatives and ocular surface disease: a review. Ocul Surf. 2024;34:213-224. doi:10.1016/j.jtos.2024.08.001

8. Kabashima K, Murakami A, Ebihara N. Effects of benzalkonium chloride and preservative-free composition on the corneal epithelium cells. J Ocul Pharmacol Ther. 2020;36(9):672-678. doi:10.1089/jop.2019.0165

9. Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F.. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-334. doi:10.1016/j.preteyeres.2010.03.001

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

11. Glaucoma Foundation. Preservative-free glaucoma eye drops. June 15, 2023. Accessed December 10, 2024. https://glaucomafoundation.org/preservative-free-glaucoma-eye-drops/

12. Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol. 2008;86(7):716-726. doi:10.1111/j.1755-3768.2008.01250.x