Preserved glaucoma eye drops, especially those containing benzalkonium chloride (BAK), are associated with greater ocular surface toxicity, including meibomian gland dysfunction, which can increase the risk of chalazia and styes compared to preservative-free formulations.
Preservative-free drops generally show better ocular surface tolerance and less glandular damage, though the risk is not entirely eliminated and may depend on the active ingredient.[1-2]
BAK-preserved drops have been shown to cause cytotoxicity to conjunctival goblet cells, induce pro-inflammatory cytokine release, and promote meibomian gland atrophy and dysfunction, all of which contribute to tear film instability and increased risk of eyelid lesions such as chalazia and styes.[1-3] Preservative-free and alternatively preserved drops (e.g., Polyquad®) are less likely to cause these changes, with studies demonstrating lower rates of ocular surface inflammation and better meibomian gland health.[1-3]
Comparative studies and meta-analyses indicate that while both preserved and preservative-free drops are similarly effective at lowering intraocular pressure, preservative-free formulations are associated with improved tear break-up time, less hyperemia, and fewer symptoms of dry eye and ocular surface disease.[4-8] However, inconsistencies in study design and reporting mean that the precise risk reduction for chalazia/styes is not fully quantified, though the trend favors preservative-free options.
Switching to preservative-free glaucoma drops may reduce the risk of meibomian gland dysfunction and subsequent chalazia/styes. The choice of active agent also matters, as some (notably prostaglandin analogues) may have direct effects on eyelid and gland health independent of preservatives.[2][8]
General Chalazia and Styes Advice
If you have glaucoma and use eye drops long-term, you may notice more frequent chalazia (bumps on the eyelid) or styes (painful, red lumps). This is because some glaucoma drops, especially those with preservatives or certain active ingredients, can affect the glands in your eyelids and make these problems more likely.[1][2][3]
What can you do to help manage and prevent these bumps?
Warm compresses: Place a clean, warm washcloth over your closed eyelids for 5-10 minutes, 2-4 times a day. This helps open up the blocked glands and can make the bump go away faster.[4][5]
Eyelid hygiene: Gently clean your eyelids daily with a mild cleanser or baby shampoo diluted with water. This keeps the glands clear and reduces the risk of new bumps.[5]
Avoid touching or squeezing: Do not try to pop or squeeze the bump, as this can make things worse or cause infection.
Medication: Most bumps get better with warm compresses and cleaning. Antibiotic ointments or drops are usually not needed unless there is an infection, and studies show they do not help most chalazia or styes resolve faster.[6][7]
Advanced treatments: If bumps keep coming back or do not go away after a few weeks, your eye doctor may suggest other treatments. These include steroid injections, minor surgery, or newer therapies like light-based treatments (intense pulsed light, IPL), which have shown good results for stubborn cases.[8][9][10][11]
Tips for people using glaucoma drops:
As mentioned above, ask your doctor if you can use drops without preservatives, as these may be gentler on your eyelids.[3]
Make sure you are using your drops correctly—avoid touching the tip to your eye or eyelid, and wipe away any excess liquid.
Let your eye doctor know if you keep getting bumps, as they may want to check your eyelids and adjust your treatment.
When to call your doctor:
If the bump is very painful, getting bigger, or not improving after 2-4 weeks of home care.
If you notice swelling, redness spreading, or changes in your vision.
With good eyelid care and regular check-ins, most people can manage these bumps and keep their eyes healthy while treating glaucoma.
References 1
1.
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.
Nagstrup AH.
Acta Ophthalmologica. 2023;101 Suppl 278:3-21. doi:10.1111/aos.15808.
Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence-based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first-choice treatment option, the most common approach for managing glaucoma is IOP-lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta-analyses investigate potential differences in efficacy and safety between BAK-preserved and BAK-free anti-glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK-preserved eye drops. However, the meta-analyses addressing hyperemia, number of ocular adverse events, and tear break-up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta-analysis finds that there are no differences in the IOP-lowering effect between BAK-preserved and BAK-free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK-preserved and BAK-free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP-lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK-preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative-free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK-preserved travoprost is found to be cytotoxic in a time-dependent manner, while Polyquad®-preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK-preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad-preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)-6 and IL-8, unlike BAK-preserved latanoprost. A review highlights the active and inactive components of IOP-lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro-inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.
2.
Topical Glaucoma Medications - Possible Implications on the Meibomian Glands.
Fineide F, Magnø M, Dahlø K, et al.
Acta Ophthalmologica. 2024;102(7):735-748. doi:10.1111/aos.16728.
New Research
One of the most common causes of blindness on a global scale is glaucoma. There is a strong association between glaucoma and increased intraocular pressure (IOP). Because of this, adequate IOP-lowering is the most important treatment strategy, mostly through topical eyedrops. Well-functioning meibomian glands are paramount for maintaining a stable tear film, and their dysfunction is the most common cause of dry eye disease. There is a growing concern that both topical glaucoma medications themselves and their added preservatives damage the meibomian glands, and consequently, the ocular surface. Preserved topical glaucoma medications appear to cause dysfunction and atrophy of the meibomian glands. Upon comparison, preserved formulations caused more symptoms of dry eye, tear film instability, inflammatory changes and meibomian gland dropout than the preservative-free counterpart. However, although seemingly less detrimental, unpreserved alternatives may diminish glandular efficacy, and, depending on the active ingredient, lead to glandular death. This negatively impacts quality of life, adherence to treatment regimens and prognosis. In this review, we explore the available evidence regarding the effects of IOP-lowering eye drops on the meibomian glands.
3.
Profiling Ocular Surface Responses to Preserved and Non-Preserved Topical Glaucoma Medications: A 2-Year Randomized Evaluation Study.
Mohammed I, Kulkarni B, Faraj LA, et al.
Clinical & Experimental Ophthalmology. 2020;48(7):973-982. doi:10.1111/ceo.13814.
Background: Use of topical glaucoma medications has been reported to cause ocular surface (OS) discomfort and inflammation. This study explores the profile of inflammatory cytokines and OS symptoms induced in response to preserved and non-preserved drops.
Methods: Prospective, randomized evaluation on 36 treatment-naïve patients over 24 months of three differently preserved glaucoma drop preparations: Preservative-free (PF), polyquad (PQ) and benzalkonium chloride (BAK). Study participants were evaluated at baseline and then at 1, 3, 6, 12 and 24 months while on medication. At each visit, participants completed the OS disease index (OSDI) questionnaire, had basal tear sampling and impression cytology (IC) of the conjunctival epithelium. Quantitative polymerase chain reaction was performed to measure the gene expression of inflammatory cytokines [interleukin (IL)-6, IL-8, IL-10, IL-12A, IL-12B, IL-17A, IL-1β and tumour necrosis factor-α] in the IC samples. Corresponding protein expression of cytokines in tear samples was assessed by the Becton-Dickinson cytometric bead arrays.
Results: Compared to PF and PQ groups, mRNA and protein expression of IL-6, IL-8 and IL-1β increased in samples from the BAK group in a time-dependent fashion, whereas all other cytokines showed a non-significant increase. In the BAK group, there was a strong correlation between OSDI and the levels of IC/IL-1β (r = .832, R = .692 and P = .040); IC/IL-10 (r = .925, R = .856 and P = .008) and tear/IL-1β (r = .899, R = .808 and P = .014).
Conclusions: BAK-preserved topical drops stimulate a sterile inflammatory response on the OS within 3 months which is maintained thereafter, whereas PF-drops and PQ-preserved drops showed no significant OS inflammation.
4.
Comparative Efficacy and Safety of Preserved Versus Preservative-Free Beta-Blockers in Patients With Glaucoma or Ocular Hypertension: A Systematic Review.
Skov AG, Rives AS, Freiberg J, et al.
Acta Ophthalmologica. 2022;100(3):253-261. doi:10.1111/aos.14926.
Preservative-free topical medications have been introduced for glaucoma care to reduce ocular adverse events associated with preservatives. This is a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing the efficacy and safety of beta-blockers, or combination using beta-blockers, with and without preservatives. PubMed, EMBASE and Web of Science were examined. Risk of bias was assessed using the Cochrane Handbook for Systematic Reviews. The primary outcome was change in intraocular pressure (IOP) from baseline to final follow-up. Secondary outcomes included ocular and systemic side effects, and other clinical and quality of life outcomes. Of 242 records identified, seven RCTs (1125 patients) were included. The follow-up period ranged from one to 12 months. Timolol was used in five studies, and two studies used a combination (timolol with bimatoprost or dorzolamide). The difference in mean change (MD) in IOP between the preservative-free and the preserved drugs was statistically significant but not clinically relevant: (MD 0.29 mmHg, 95% confidence interval 0.07-0.51 mmHg, p = 0.010; moderate-certainty evidence). Regarding adverse events: Level of evidence for all ocular surface outcome was low or very low and reported in few studies. No significant difference was observed on ocular surface symptoms. Tear break-up time (TBUT) was better with preservative-free drops (p < 0.001). Schirmer's test was better in the preservative-free group (p < 0.001). Level of evidence for all ocular surface outcomes was low or very low. There was no difference in other secondary outcomes. We found no clinically relevant difference in mean change in IOP between the preserved and the preservative-free treatments. Data on adverse events used different methods and were incompletely reported. Although some measures of ocular surface health favoured preservative-free medications, more evidence is needed. The increasing use of preservative-free drops may be associated with better ocular surface and tolerability, but strong evidence from RCTs would be welcome.
5.
Comparison of Ocular Surface Assessment and Adherence Between Preserved and Preservative-Free Latanoprost in Glaucoma: A Parallel-Grouped Randomized Trial.
Kim DW, Shin J, Lee CK, et al.
Scientific Reports. 2021;11(1):14971. doi:10.1038/s41598-021-94574-x.
Given that nonadherence is related to subject characteristics and drug tolerance and preserved eye drops tend to be more intolerable than preservative-free ones, we conducted a phase 4, parallel-grouped, investigator-blind, active-control, randomized, multicenter study. A total of 51 patients with intraocular pressure (IOP) ≥ 15 mmHg diagnosed with open-angle glaucoma or ocular hypertension were randomly assigned to the preserved latanoprost group (n = 26) and the preservative-free latanoprost group (n = 25). The efficacy variables were corneal/conjunctival staining grade, Ocular Surface Disease Index (OSDI), adherence at 12 weeks after the first administration; corneal/conjunctival staining grade at 4 weeks; and IOP, tear break-up time (TBUT), and hyperemia score at 4 and 12 weeks. The safety variables included visual acuity and drug tolerance questionnaire results. There was no statistically significant difference in corneal/conjunctival staining grade, OSDI, or TBUT between the groups at 4 and 12 weeks. However, the adherence rate was higher and the hyperemia score was lower in the preservative-free group than in the preserved group. The severity and duration of stinging/burning sensation were lower in the preservative-free group than in the preserved group. Overall, preservative-free latanoprost showed better ocular tolerance assessed by hyperemia scores and stinging/burning symptoms following higher adherence than preserved latanoprost.
6.
Preservative-Free Prostaglandin Analogs and Prostaglandin/Timolol Fixed Combinations in the Treatment of Glaucoma: Efficacy, Safety and Potential Advantages.
Holló G, Katsanos A, Boboridis KG, Irkec M, Konstas AGP.
Drugs. 2018;78(1):39-64. doi:10.1007/s40265-017-0843-9.
Leading Journal
Glaucoma therapy-related ocular surface disease (OSD) is a serious pathology with a broad spectrum of insidious clinical presentations and complex pathogenesis that undermines long-term glaucoma care. Preservatives, especially benzalkonium chloride (BAK), contained in topical intraocular pressure-lowering medications frequently cause or aggravate OSD in glaucoma. Management of these patients is challenging, and to date often empirical due to the scarcity of controlled long-term clinical trials. Most of the available data are extracted from case series and retrospective analysis. Preservative-free prostaglandins and prostaglandin/timolol fixed combinations are novel options developed to remove the harmful impact of preservatives, especially BAK, upon ocular tissues. Based on what is currently known on the value of preservative-free antiglaucoma therapies it is tempting to speculate how these new therapies may affect the future medical management of all glaucoma patients. This article provides a comprehensive and critical review of the current literature on preservative-free prostaglandins and preservative-free prostaglandin/timolol fixed combinations.
7.
Efficacy and Safety Evaluation of Benzalkonium Chloride Preserved Eye-Drops Compared With Alternatively Preserved and Preservative-Free Eye-Drops in the Treatment of Glaucoma: A Systematic Review and Meta-Analysis.
Hedengran A, Steensberg AT, Virgili G, Azuara-Blanco A, Kolko M.
The British Journal of Ophthalmology. 2020;104(11):1512-1518. doi:10.1136/bjophthalmol-2019-315623.
Background/aims: This systematic review compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye-drops with alternatively preserved (AP) and preservative-free (PF) eye-drops.
Methods: PubMed, EMBASE and MEDLINE were searched for randomised controlled trials in June and October 2019. Study selection, data extraction and risk of bias assessment were made by two independent reviewers using the Cochrane Handbook. Studies on prostaglandin analogue or beta-blocker eye-drops and patients with glaucoma or ocular hypertension were included. Primary outcome was change in intraocular pressure (IOP). Secondary outcomes were safety measures as assessed in original study.
Results: Of 433 articles screened, 16 studies were included. IOP meta-analysis was conducted on 13 studies (4201 patients) ranging from 15 days to 6 months. No significant differences between BAK versus PF and AP were identified (95% CI -0.00 to 0.30 mm Hg, p=0.05). Meta-analyses revealed no differences between BAK versus AP and PF with regards to conjunctival hyperaemia (risk ratio (RR) 1.05, 95% CI 0.91 to 1.22, 3800 patients, 9 studies), ocular hyperaemia (RR 1.31, 95% CI 0.96 to 1.78, 2268 patients, 5 studies), total ocular adverse events (RR 1.03, 95% CI 0.88 to 1.20, 1906 patients, 5 studies) or tear break-up time (mean difference 0.89, 95% CI -0.03 to 1.81, 130 patients, 3 studies). Diverse reporting on safety measures made comparison challenging. Risk of bias was assessed as high or unclear in many relevant domains, suggesting potential selective reporting or under-reporting.
Conclusion: No clinically significant differences on efficacy or safety could be determined between BAK versus AP and PF. However, there were substantial uncertainties on safety.CRD42019139692.
8.
Association Between the Use of Prostaglandin Analogues and Ocular Surface Disease: A Systematic Review.
Monge-Carmona R, Caro-Magdaleno M, Sánchez-González MC.
Eye (London, England). 2025;39(1):28-39. doi:10.1038/s41433-024-03372-y.
References 2
- Topical Antiglaucoma Treatment With Prostaglandin Analogues May Precipitate Meibomian Gland Disease. Cunniffe MG, Medel-Jiménez R, González-Candial M. Ophthalmic Plastic and Reconstructive Surgery. 2011 Sep-Oct;27(5):e128-9. doi:10.1097/IOP.0b013e318201d32f.
- Comparison of the Long-Term Effects of Various Topical Antiglaucoma Medications on Meibomian Glands. Arita R, Itoh K, Maeda S, et al. Cornea. 2012;31(11):1229-34. doi:10.1097/ICO.0b013e31823f8e7d.
- Managing Adverse Effects of Glaucoma Medications. Inoue K. Clinical Ophthalmology (Auckland, N.Z.). 2014;8:903-13. doi:10.2147/OPTH.S44708.
- Conservative Therapy for Chalazia: Is It Really Effective?. Wu AY, Gervasio KA, Gergoudis KN, et al. Acta Ophthalmologica. 2018;96(4):e503-e509. doi:10.1111/aos.13675.
- Chalazion Treatment: A Concise Review of Clinical Trials. Tashbayev B, Chen X, Utheim TP. Current Eye Research. 2024;49(2):109-118. doi:10.1080/02713683.2023.2279014.
- Efficacy of Care and Antibiotic Use for Chalazia and Hordeola. Alsoudi AF, Ton L, Ashraf DC, et al. Eye & Contact Lens. 2022;48(4):162-168. doi:10.1097/ICL.0000000000000859.
- The Impact of Topical Treatment for Chalazia on the Odds of Procedural Management. Alsaloum M, Alsaloum P, Rotruck JC. Journal of AAPOS : The Official Publication of the American Association for Pediatric Ophthalmology and Strabismus. 2023;27(4):213-216. doi:10.1016/j.jaapos.2023.04.010.
- Efficacy of Combined Doxycycline and Intense Pulsed Light Therapy for the Management of Intractable Recurrent Chalazion. Yoon HJ, Moon JY, Yoon KC. Frontiers in Medicine. 2024;11:1454049. doi:10.3389/fmed.2024.1454049.
- Novel Treatment of Chalazion Using Light-Guided-Tip Intense Pulsed Light. Zhu Y, Zhao H, Huang X, et al. Scientific Reports. 2023;13(1):12393. doi:10.1038/s41598-023-39332-x.
- Intralesional Triamcinolone Acetonide Injection for Primary and Recurrent Chalazia: Is It Really Effective?. Ben Simon GJ, Huang L, Nakra T, et al. Ophthalmology. 2005;112(5):913-7. doi:10.1016/j.ophtha.2004.11.037.
- Extralesional Triamcinolone Acetonide Injection in the Treatment of Small Chalazion. Gan L, Liu Y, Zhou X, et al. Indian Journal of Ophthalmology. 2023;71(8):2959-2961. doi:10.4103/IJO.IJO_3186_22.
