Treatment of ocular surface inflammation secondary to preserved and unpreserved eyedrops: a narrative review

Introduction

Background

Topical eyedrops are the mainstay treatment for a wide range of ophthalmic conditions, including glaucoma, ocular surface disease, infection, and postoperative care. Patients may use multiple different eyedrops over years or decades, many of which may need to be administered multiple times a day. While these drops may be beneficial and necessary for treating these various conditions, there is increasing evidence that topical eyedrops themselves can induce ocular surface inflammation (1,2). This iatrogenic response may present in various ways, with tear film instability, conjunctival hyperemia, epithelial staining, punctate keratitis, persistent epithelial defects, stromal inflammation, and even corneal melt.

Ocular surface inflammation secondary to eyedrop use can result from exposure to preservatives, direct toxicity from the medication itself, hypersensitivity reactions, or a combination of mechanisms. Preservatives are commonly used to maintain sterility and prolong shelf life, but have been implicated in ocular surface damage through disruption of epithelial integrity, tear film instability, and inflammatory pathway activation. However, preservative-free formulations may also contribute to ocular surface inflammation due to the pharmacologic properties of the active medication itself.

Ocular surface disease secondary to eyedrop use can impair quality of life, reducing adherence to therapy and ultimately complicating treatment outcomes (3,4). As such, it is essential for clinicians to be able to promptly diagnose and understand various treatment options for ocular surface inflammation induced by topical medications.

Rationale and knowledge gap

Although prior reviews have examined medication-induced ocular surface disease, many focus on specific drug classes or on specific contributors such as ophthalmic preservatives (1,3,5). As a result, important differences in pathogenic mechanisms and management strategies across medication classes may be underappreciated.

Objective

The purpose of this review is to synthesize the available evidence on treatments for ocular surface inflammation secondary to both preserved and preservative-free topical ophthalmic medications, with specific attention to tailored therapeutic strategies for various medication classes. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-1-0012/rc).

Methods

A literature search was conducted from January 20, 2026 through February 20, 2026 using PubMed and Google Scholar. The search strategy incorporated combinations of the following keywords and Medical Subject Headings (MeSH) terms: ocular surface inflammation, eyedrop toxicity, topical ophthalmic medications, glaucoma medications, preservatives, preservative-free, ocular surface disease, antibiotic eyedrops, antiviral eyedrops, topical NSAIDs, antiallergic eyedrops, topical corticosteroids, ocular decongestants, corneal toxicity, drug-induced keratitis, and ocular surface management. Boolean operators (AND, OR) were used to refine search combinations, and reference lists of relevant articles were manually reviewed to identify additional pertinent studies. The search included articles published up to February 2026, without restriction on initial publication date, to capture all studies relevant to medication-induced ocular surface disease.

Inclusion criteria consisted of English-language peer-reviewed articles, including randomized controlled trials, observational studies, systematic reviews, and clinically relevant case series that addressed the management of ocular surface inflammation associated with topical ophthalmic medications or preservatives. Exclusion criteria included non-English publications without accessible English abstracts, studies not involving ocular surface effects of topical medications, and articles lacking clinically relevant data. Isolated case reports were included selectively when they illustrated rare but clinically significant adverse effects.

Selection process

Two authors independently screened titles and abstracts for relevance, followed by full-text review of eligible articles. Screening was conducted independently to minimize selection bias. Discrepancies regarding study inclusion were resolved through discussion and consensus among the authors. Given the narrative nature of this review, formal quality scoring or meta-analysis was not performed. However, priority was given to higher-quality evidence and frequently cited foundational studies within each topic area (Table 1).

Results

The literature review demonstrated that ocular surface inflammation has been associated with a broad range of topical ophthalmic medications across multiple therapeutic classes, including glaucoma medications, antibiotics, antivirals, nonsteroidal anti-inflammatory drugs, anesthetics, antiallergic agents, corticosteroids, ocular decongestants, ocular cleaning agents, and ophthalmic preservatives themselves. A summary of the major medication classes, proposed mechanisms, clinical features, and treatment strategies is provided in Table 2.

Importantly, many topical ophthalmic medications are available in both preservative-containing and preservative-free formulations, and ocular surface inflammation may result from either the preservative, the active pharmaceutical compound itself, or both. Because preservatives can be found in most topical medications and are broadly implicated as contributors to medication-induced ocular surface disease, the following sections first discuss the independent effects of preservatives and strategies for preservative-associated ocular surface management. Subsequent sections then review specific ophthalmic medication classes and focus on the contribution of the active drug compounds to ocular surface inflammation, while acknowledging that preservatives within these formulations may continue to play additive or synergistic effects in ocular surface toxicity.

General treatment principles

The management of ocular surface inflammation secondary to topical eyedrop use should begin with a careful history and clinical examination, as well as an understanding of the offending agent’s mechanisms of toxicity. The first and most critical step in treatment is to discontinue or modify the causative medication as soon as clinically possible, as persistent exposure to the drug may lead to persistence or worsening of symptoms. Switching to preservative-free formulations or reducing the number of topical medications through combined drops can decrease exposure and improve ocular surface health (6,7). When discontinuation of the offending agent is not possible, strategies such as dose reduction or other adjuvant therapies should be considered.

Preservative-free lubricants can be added to support epithelial healing and stabilize the tear film (8). In cases of chronic inflammation, topical immunomodulators such as cyclosporine A have been shown to reduce surface inflammatory markers in various ocular surface inflammatory conditions (9), though specific high-level evidence in drug-induced ocular surface inflammation is limited. Short courses of topical corticosteroids can also be beneficial for acute anti-inflammatory treatment when used judiciously (10). In severe or refractory cases, biologic tear substitutes such as autologous serum eye drops may be employed to provide growth factors and anti-inflammatory mediators that promote epithelial regeneration (11). In circumstances of profound epithelial breakdown or stromal involvement, protective measures such as bandage contact lenses or amniotic membrane therapy can also be critical to restoring surface integrity (12,13).

Preservative-containing drops

Preservatives are commonly added to ophthalmic medications to maintain sterility and extend shelf life by preventing microbial contamination. Although these agents improve medication stability and safety, increasing evidence suggests that chronic exposure to certain preservatives can adversely affect the ocular surface, particularly in patients requiring long-term topical therapy or multiple medications. A list of common preservatives used in topical ophthalmic medications is listed in Table 3.

Benzalkonium chloride (BAK) is one of the most commonly used preservatives in topical ophthalmic medications, reportedly in approximately 70% of ophthalmic formulations across several classes of eyedrops (14). A list of common eyedrops containing BAK is listed in Table 4. Despite its widespread use, BAK has been implicated in the development of ocular surface inflammation through multiple mechanisms. BAK is a quaternary ammonium preservative, and its detergent-like properties with both hydrophilic and hydrophobic properties are thought to contribute directly to epithelial toxicity, conjunctival goblet cell loss, tear film instability, and increased oxidative stress and inflammatory markers in ocular tissues (5,14-16). BAK-containing drops have been reported to cause dry eye sensation, burning, tearing, decreased tear break-up time, and other ocular symptoms (7,17).

In response to the undesirable ocular effects of BAK, several newer ophthalmic preservatives have been developed, including Polyquad^® (polyquaternium-1), Purite^®, SofZia^®, and sodium perborate. Compared to BAK, these preservatives have been reported to have improved tolerability and and fewer side effects, though they have less robust research supporting their use. It is important to note that these alternative preservatives still can cause ocular surface inflammation despite being less cytotoxic than BAK. Other less common preservatives also include chlorobutanol, which was more common prior to BAK, as well as sodium perborate, which is primarily used in certain brands of artificial tears.

Polyquad^® is a larger quaternary ammonium compound that is commonly used in contact lens solutions, artificial tears, and some glaucoma medications. It appears to penetrate epithelial cells less readily than BAK due to its large size and hydrophilic properties, and as such has been proposed to lead to less cytotoxicity compared to BAK (18). This has been supported by various in vitro studies, animal studies, and clinical studies, which have demonstrated greater viability of corneal cells and lower rates of ocular surface disease (18,19).

Purite^® is a stabilized oxochloro complex that dissociates into water and chloride ions upon instillation in the eye. These components, which are naturally found in the tear film, are thought to be gentler on the epithelium and the ocular surface. Compared to BAK, Purite has demonstrated improved tolerability in clinical studies (14).

SofZia^® is an ionic buffered preservative system designed to minimize epithelial injury while maintaining antimicrobial activity. It is comprised of borate, sorbitol, propylene glycol, and zinc. Upon contact with cations on the ocular surface, the components degrade quickly, thereby reducing cytotoxicity (5). Studies comparing SofZia^®-preserved travoprost with BAK-preserved latanoprost have shown improved ocular surface findings with SofZia^® formulations while maintaining intraocular pressure (IOP) control (20).

Management of preservative-associated ocular surface inflammation begins with timely identification. Patients on chronic topical therapy should be assessed routinely for symptoms of irritation or signs of surface changes. Diagnosis is largely clinical and may involve slit-lamp examination demonstrating punctate epithelial keratopathy, conjunctival injection, reduced tear break-up time, ocular surface staining with fluorescein or lissamine green, and evaluation of meibomian gland dysfunction or conjunctival cicatricial changes in more advanced disease. When medication-induced inflammation is suspected and multiple preserved agents are in use, clinicians should consider transitioning medications. Preservative-free formulations and medications using alternative preservatives (such as Purite^®, SofZia^®, and Polyquad^® as discussed above), have demonstrated improved ocular surface tolerability in some studies, though more research is needed to investigate these alternatives (20,21). Patients who are switched from preservative-containing to preservative-free formulations experience reduced irritation and signs of surface inflammation (22,23). Preservative-free formulations offer several advantages, including reduced epithelial toxicity, improved tear film stability, lower rates of conjunctival inflammation, and improved patient comfort and adherence, particularly in patients requiring long-term multidrop therapy (14). In many cases, modification of the medication regimen leads to improvement in ocular surface health and clinical measures (24).

Supportive therapy with preservative-free lubricants can also aid epithelial recovery during and after the transition away from BAK-containing drops. Adjunctive short-term anti-inflammatory treatment can also be considered in patients with more significant surface disease (6,9). Close follow-up is essential to monitor for resolution of surface inflammation and to adjust treatment as needed.

Topical glaucoma medications

Topical glaucoma therapy represents one of the most common and most well-studied sources of medication-induced ocular surface inflammation. Unlike many other conditions requiring short-term topical treatment, glaucoma necessitates chronic, often lifelong therapy, frequently involving multiple agents administered several times a day. As a result, glaucoma patients experience prolonged exposure to pharmacologic compounds that can subsequently damage the ocular surface. Medication-induced ocular surface inflammation in this patient population is particularly important, as it may reduce treatment adherence, lead to disease progression, and worsen quality of life (25,26).

Glaucoma patients are particularly vulnerable to medication-related ocular surface disease for several reasons. Long-term topical therapy is associated with cumulative epithelial stress and inflammation that may progress over time (27). Additionally, topical glaucoma drops have been associated with reduced corneal sensitivity and altered tear reflexes (28), which can delay symptom recognition and allow inflammatory damage to advance before intervention. The frequent use of combination regimens further amplifies surface exposure, and limited opportunities for treatment interruption make recovery from inflammatory insults more difficult. The following are five commonly used clinical classes of topical glaucoma medications and their associated ocular surface side effects.

Prostaglandin analogs, including latanoprost, travoprost, bimatoprost, and tafluprost, are widely prescribed as first-line agents due to their robust ability to lower intraocular pressure. However, studies have consistently demonstrated an association between prostaglandin use and conjunctival hyperemia, punctate epithelial erosions, tear film instability, meibomian gland dysfunction, and increased conjunctival inflammatory cell infiltration (29-31). These effects are thought to arise from prostaglandin-mediated vasodilation and upregulation of inflammatory cytokines on the ocular surface (32).

Beta-blockers such as timolol and betaxolol have also been implicated in ocular surface dysfunction (33,34). These agents reduce aqueous production but may adversely affect tear film physiology by decreasing basal lacrimal secretion and destabilizing the ocular surface (35-37). Studies have reported increased corneal staining and worsening dry eye symptoms in patients using topical beta-blockers (33,34).

Alpha-2 adrenergic agonists, particularly brimonidine, are strongly associated with immune-mediated ocular surface inflammation. Studies have shown that patients can present with follicular conjunctivitis, conjunctival hyperemia, eyelid edema, and ocular discomfort following brimonidine use (38-40). These reactions can often develop weeks to months after initiation.

Topical carbonic anhydrase inhibitors, including dorzolamide and brinzolamide, have been associated with corneal epithelial toxicity. Use of carbonic anhydrase inhibitors has been linked to superficial punctate keratitis, epithelial edema, burning, tearing, and itching (41,42). These effects are thought to result from disruption of epithelial carbonic anhydrase activity, which plays a role in corneal hydration and epithelial integrity.

Rho kinase inhibitors, such as netarsudil, are increasingly recognized for their ocular surface side-effect profile. Studies have reported high rates of conjunctival hyperemia, ocular irritation and inflammation, and corneal verticillata (43-45). These effects are believed to stem from vascular smooth muscle modulation at the ocular surface (43). While many of these changes are reversible, treatment intolerance is not uncommon.

Treatment of these issues begins with recognition that ocular surface inflammation may be medication-related rather than a manifestation of dry eye disease. Once identified, the primary goal is reduction of ocular surface exposure to the offending agent while maintaining adequate intraocular pressure control. Initial management commonly involves modification of topical therapy. Several drops are available as preservative-free formulations and can help reduce symptoms (7,17,46-48). However, preservative-free formulations may still cause ocular surface irritation due to the active pharmaceutical compound itself, particularly with chronic exposure or frequent dosing. When feasible, reducing the number of medications or dosing frequency can improve surface inflammation (49). Combination drops may also help by limiting preservative exposure.

Switching within the same medication class may be effective for patients with mild toxicity, particularly among prostaglandin analogs, where individual tolerance varies (29). In contrast, agents associated with immune-mediated reactions (such as alpha-2 adrenergic agonists) generally require complete discontinuation, as continued exposure may perpetuate inflammation (50). Resolution of follicular conjunctivitis and hyperemia typically follows withdrawal of the causative medication.

When medication-induced ocular surface inflammation limits tolerance and adherence, escalation to non-pharmacologic intraocular pressure-lowering strategies should be considered. Laser trabeculoplasty has been shown in studies to reduce medication burden while maintaining effective pressure control (51). Minimally invasive glaucoma surgeries offer additional opportunities to decrease reliance on topical therapy, particularly in patients undergoing cataract surgery at the same time (52,53). Traditional filtering surgeries or tube shunts may also be considered to reduce the drop burden and improve the ocular surface (54). In these cases, aggressive preoperative management of ocular surface inflammation is essential, as chronic conjunctival inflammation has been associated with poorer surgical outcomes (55,56).

Importantly, treatment of medication-induced ocular surface inflammation in glaucoma patients is not a one-time intervention but an ongoing process that requires longitudinal assessment. As disease severity evolves and treatment regimens change, the ocular surface must be consistently reevaluated to prevent recurrence of inflammation. Early incorporation of laser or surgical options should be considered in patients with significant surface disease that limits drop adherence and results in disease progression.

Topical antibiotics

Topical antibiotic eye drops are a mainstay of therapy for ophthalmic infections and perioperative prophylaxis. Although these medications are generally effective and well tolerated in most patients, studies have shown that certain topical antibiotic formulations can contribute to ocular surface irritation (57), particularly when used repeatedly and for prolonged courses, which is often the case for the ophthalmic use of antibiotics. This toxicity is multifactorial and may result from direct epithelial toxicity, inhibition of corneal epithelial healing, hypersensitivity reactions, and in some cases, drug precipitation on the ocular surface (58-60).

One study found that antibiotic drops, particularly aminoglycosides, are among the most frequently implicated topical medications in toxic ocular surface reactions (2). Another study found that fortified aminoglycoside-cephalosporin combinations were associated with a higher incidence of ocular discomfort than fluoroquinolone monotherapy (57). Notably, ciprofloxacin has been noted to cause white precipitate formation on the corneal surface, which can slow epithelial healing and increase surface irritation (57,61).

Management of antibiotic-associated surface inflammation is particularly challenging given the difficulty in differentiating medication-induced toxicity from infection-related inflammation. Clinical features suggestive of antibiotic-related surface inflammation include persistent conjunctival hyperemia, worsening punctate epithelial staining, or ocular discomfort that improves rapidly following modification or discontinuation of therapy. Discontinuation of the offending agent often leads to resolution of inflammatory signs, but only when clinically safe to do so. Results of bacterial cultures and microbial susceptibility can help guide antibiotic selection and the switch to an alternative antibiotic with a more favorable surface tolerability profile. Reducing dosing frequency when clinically safe or selecting preservative-free formulations may also be strategies to decrease further surface injury. Adjunctive therapy with preservative-free lubricants can support epithelial recovery and reduce discomfort during the healing period.

Topical antivirals

Topical antiviral medications used for herpetic epithelial keratitis are a recognized cause of ocular surface inflammation. Early-generation nucleoside analogs, including trifluridine, inhibit viral DNA synthesis in a non-selective manner, affecting both infected and uninfected epithelial cells (62). As a result, these agents are associated with punctate epithelial keratopathy, delayed epithelial healing, and conjunctival inflammation (62). Trifluridine is still used in the United States and is notable for its frequent dosing requirements, which increase cumulative ocular surface exposure and risk of medication-induced inflammation.

More selective antiviral agents demonstrate improved ocular surface tolerability. Topical acyclovir preferentially inhibits viral DNA polymerase within infected cells and is associated with lower rates of epithelial toxicity compared with earlier agents (63). However, topical formulations may still cause surface irritation (64). Studies have shown comparable efficacy between oral and topical acyclovir for epithelial Herpes simplex virus (HSV) keratitis, suggesting that systemic therapy may be a reasonable alternative in patients who develop topical drug–induced ocular surface inflammation (65). In fact, many specialists use oral medication as first-line therapy. Ganciclovir represents another alternative in topical antiviral therapy, with enhanced selectivity for virus-infected cells and minimal accumulation in healthy epithelium. It is generally well tolerated and has been shown to be as effective as acyclovir for epithelial HSV keratitis, with fewer ocular surface adverse effects (66,67). Consequently, ganciclovir is often preferred in patients with preexisting ocular surface disease or those who exhibit intolerance to less selective topical antivirals.

Avoiding prolonged use of more cytotoxic topical antivirals such as trifluridine is a key strategy to prevent ocular surface inflammation. In all cases of antiviral use, discontinuation of the offending agent at the earliest safe opportunity and the use of adjunctive supportive therapies such as preservative-free lubricants can mitigate medication-induced toxicity. In cases where antiviral toxicity contributes significantly to ocular surface compromise, anti-inflammatory therapies such as topical corticosteroids may be used cautiously once active infection has been ruled out or controlled.

Topical nonsteroidal anti-inflammatory drugs (NSAIDs)

Topical NSAIDs are widely used in ophthalmology in postoperative settings and for ocular inflammation by inhibiting cyclooxygenase enzymes and reducing prostaglandin synthesis. The most common adverse effects of topical NSAIDs include transient burning, stinging on instillation, and mild conjunctival hyperemia (68). NSAID-associated corneal toxicity may involve inhibition of normal epithelial healing pathways due to increased susceptibility to enzymatic degradation of stromal collagen and alterations in matrix metalloproteinase expression (69). These effects may be accentuated when NSAIDs are combined with other topical medications like corticosteroids, which can further delay epithelial healing. Superficial punctate keratitis and persistent epithelial defects have also been reported in studies, showing that NSAID use may cause ocular surface inflammation and delayed re-epithelialization in some patients (70,71). These effects are typically uncommon when NSAIDs are used for short durations but underscore the potential for medication-induced ocular surface disease.

In addition to superficial epithelial changes, more severe corneal complications have been documented. Several case reports have described corneal melt in patients receiving topical NSAIDs, particularly bromfenac, ketorolac, and nepafenac (72-76). These events are rare but have been reported in the setting of specific circumstances such as prolonged use, concurrent topical corticosteroid use, underlying ocular surface compromise, diabetes, or autoimmune connective tissue disease (77). Some cases have even reported corneal perforation requiring surgical intervention (78,79).

Treatment strategies for NSAID-associated surface toxicity begin with prompt discontinuation of the offending agent as soon as toxicity is suspected. For mild irritation and punctate keratitis, cessation of NSAIDs and the use of preservative-free lubricants may be enough to resolve symptoms. In cases with persistent epithelial defects, superficial ulceration, or stromal involvement, more aggressive interventions are warranted. Short courses of topical corticosteroids may be considered once epithelial health begins to improve. Autologous serum can be used to support epithelial regeneration by providing growth factors and anti-inflammatory mediators. In severe cases of corneal melt, bandage contact lenses, amniotic membrane application, or even surgical grafting may be necessary forms of treatment.

Topical anesthetics

Although topical anesthetics are intended for short-term procedural use and are generally safe, chronic or abusive use can lead to severe ocular surface toxicity. Topical anesthetic use is often a cycle: many patients begin using topical anesthetic drops during the course of an underlying ocular disease, and toxicity of the anesthetic drop can result in increased pain that further perpetuates abuse and damage. Patients abusing topical anesthetics can present with epithelial defects, ring infiltrates, endothelial damage and intraocular inflammation with possible hypopyon (80,81). These patients can have clinical courses complicated by superimposed infections with poor visual outcomes, with some even requiring corneal transplants or, in severe cases, enucleation (82).

One of the most important factors for the successful management of topical anesthetic abuse is prompt diagnosis. Often, these patients may initially be misdiagnosed and treated as acanthamoeba keratitis given its similar presentation, and diagnosis can thus be delayed (83). A high degree of suspicion is needed for diagnosing patients who are not responding to treatment as expected. It is also important to keep in mind that several studies have reported that patients denied anesthetic abuse multiple times prior to ultimately admitting abuse, further making initial diagnosis challenging (84).

Management requires immediate cessation of the offending agent, aggressive ocular surface protection, and anti-inflammatory therapy once infection is excluded. Often, many patients with anesthetic abuse have been found to have an underlying psychiatric condition (83,84) and may benefit from co-management with a psychiatrist. Management strategies should also incorporate alternative methods of pain control in patients with underlying painful ocular conditions that initiated the cycle of abuse. In these cases, oral analgesics or, in selected cases, peribulbar, sub-Tenon, or retrobulbar injections peribulbar, sub-Tenon, or retrobulbar injections can be considered in recalcitrant cases.

Topical antiallergic medications

Topical antiallergic medications, including antihistamines and mast cell stabilizers, are widely used for the management of allergic conjunctivitis and related ocular surface conditions. These agents are generally well tolerated and effective in reducing symptoms such as itching and hyperemia. Antihistamines function by inhibiting histamine receptors and stabilizing mast cells to reduce inflammatory mediator release. While these mechanisms are beneficial in controlling allergic inflammation, clinical trials have reported that mild to moderate ocular irritation, dry eye symptoms, discharge, and conjunctival hyperemia are among the most common adverse effects associated with these medications (85). These side effects can be particularly challenging to distinguish from the underlying allergic conjunctivitis that it aims to treat, as allergic conjunctivitis may also present with similar symptoms.

On the other hand, preservative-free formulations of antiallergic medications have demonstrated improved tolerability, suggesting that underlying surface effects may be driven by preservatives. Studies comparing preserved and preservative-free antihistamine formulations have demonstrated improved ocular tolerance and lower cytotoxicity (86,87). These formulations are particularly advantageous in patients with coexisting dry eye disease or chronic ocular surface inflammation.

An important limitation highlighted in recent literature is that many clinical trials of antiallergic eyedrops do not adequately assess ocular surface parameters such as tear break-up time, tear volume, or epithelial biomarkers (85). This makes it difficult to fully characterize long-term ocular surface effects of antiallergy drops, and underscores the need for more research regarding ocular surface outcomes for antiallergic therapies.

Management of antiallergic drop-induced ocular surface inflammation involves identifying the contribution of both the active agent and the preservative, and separating this from the underlying allergic conjunctivitis. High suspicion should be had for patients who have some clinical improvement in signs and symptoms, but continue to have unexplained symptoms. In such cases, transitioning to preservative-free formulations is often a good first step. Reducing dosing frequency when clinically feasible and incorporating preservative-free lubricants can further support tear film stability.

Topical corticosteroids

Topical corticosteroids are frequently employed in the management of ocular inflammation. However, their formulations often contain preservatives that may independently contribute to or exacerbate ocular surface toxicity, paradoxically worsening symptoms such as foreign body sensation and ocular discomfort (88-90).

The challenge is particularly relevant in patients requiring prolonged or repeated steroid courses, such as those with chronic inflammatory conditions, postoperative inflammation, or immune-mediated ocular surface disease. In these cases, cumulative exposure to preservatives may contribute to persistent or worsening surface inflammation, complicating the clinical picture and potentially reducing therapeutic efficacy. Importantly, it may be difficult to distinguish between steroid-related adverse effects, preservative toxicity, and underlying disease progression.

Strategies to mitigate preservative-associated toxicity in steroid therapy focus on minimizing or eliminating preservative exposure. Preservative-free corticosteroid formulations offer a valuable alternative by maintaining anti-inflammatory efficacy while reducing ocular surface toxicity. Studies have shown improved symptoms and reduced signs of surface inflammation when comparing preserved to preservative-free corticosteroid therapies, with similar efficacies (88-91). Additionally, reducing dosing frequency when clinically appropriate, limiting treatment duration, and using adjunctive preservative-free lubricants can further support epithelial recovery and improve patient comfort.

In patients with significant ocular surface compromise, clinicians should maintain a low threshold for transitioning to preservative-free steroid formulations, particularly when symptoms worsen despite apparent control of inflammation. Careful monitoring is essential to balance the therapeutic benefits of corticosteroids with their potential to contribute to ocular surface toxicity, ensuring optimal outcomes in patients requiring anti-inflammatory therapy.

Topical ocular decongestants

Topical ocular decongestants, commonly used as over-the-counter “redness-relief” drops, represent an underrecognized source of ocular surface irritation and inflammation. Traditional formulations often contain vasoconstrictive agents such as tetrahydrozoline or naphazoline, which reduce conjunctival hyperemia through adrenergic stimulation. However, repeated use has been associated with tachyphylaxis and rebound hyperemia upon discontinuation (92). Low-dose brimonidine tartrate 0.025% represents a newer class of selective alpha-2 adrenergic agonists that preferentially constrict venules while sparing arterioles, thereby reducing the risk of rebound redness compared to traditional decongestants (92). Clinical studies have demonstrated improved tolerability and a lower incidence of tachyphylaxis with this formulation (92,93). Furthermore, brimonidine tartrate 0.025% preservative-free formulation has similar efficacy to the preserved option, with similar safety profiles (94). Importantly, chronic use of these agents may mask underlying ocular surface disease. As such, clinicians should counsel patients on the cautious use of redness-relief drops and consider discontinuation in cases of unexplained or refractory ocular surface symptoms.

Topical ocular cleaning agents

Povidone-iodine (PVP-I), or Betadine, is routinely applied to the ocular surface for antisepsis prior to intraocular surgery and intravitreal injections. Although short-term exposure is generally safe, studies demonstrate that PVP-I can induce transient ocular surface irritation and inflammation (95,96). This is particularly the case with repeated exposure or at higher concentrations (96,97). The ocular irritation associated with PVP-I is typically limited. Studies indicate that thorough irrigation of residual PVP-I from the ocular surface reduces surface irritation symptoms (98), and postinjection irrigation of residual PVP-I using sterile saline is part of recommended injection practice patterns (99).

Limitations

This review has several limitations. First, much of the available literature on medication-induced ocular surface inflammation is heterogeneous, consisting of a mix of randomized controlled trials, observational studies, case series, and case reports, with variable study designs and outcome measures. Many studies are limited by small sample sizes and a lack of standardized definitions for ocular surface disease, making direct comparisons across studies limited. Additionally, isolating the effects of individual medications is often difficult, as patients are frequently treated with multiple topical agents concurrently, particularly in glaucoma management, introducing confounding variables. For certain drug classes, including topical anesthetics and NSAIDs, the literature is heavily reliant on case reports and retrospective analyses, which may overrepresent more severe presentations. Furthermore, the narrative nature of this review introduces the potential for selection bias, as study inclusion was not performed through a formal systematic review protocol or quantitative synthesis.

Despite these limitations, this review has several strengths. It provides a comprehensive synthesis of ocular surface inflammation across a broad range of commonly used topical ophthalmic medications. By organizing findings according to drug class and underlying pathogenic mechanisms, this work offers a practical framework to guide clinicians in diagnosis and management. Additionally, the emphasis on mechanism-based treatment strategies and cross-comparison between medication classes helps bridge gaps between disparate areas of the literature and highlights opportunities for more individualized and preventive approaches to care.

Conclusions

Ocular surface inflammation secondary to topical ophthalmic medications represents a multifactorial process that can severely affect quality of life and treatment outcomes across various diseases. Effective management first requires identification and then modification or removal of the offending agent. Supportive measures to restore and protect the ocular surface are often necessary. Other key strategies include minimizing preservative exposure and drop burden, judicious use of anti-inflammatory agents or steroids when indicated, as well as the use of alternative delivery methods when available. Thoughtful treatment modification or augmentation can substantially improve ocular surface health while still achieving original treatment goals.

Importantly, this review highlights the need for a paradigm shift in the management of drug-induced ocular surface disease from reactive treatment to proactive prevention and mechanism-based care. By synthesizing evidence across multiple medication classes, this review provides a framework to guide clinicians in selecting better-tolerated therapies and optimizing long-term treatment strategies. These insights may also inform the development of next-generation ophthalmic formulations with reduced toxicity, as well as increased adoption of preservative-free and sustained-delivery systems.

Future research should focus on improving diagnostic tools for early detection and developing targeted therapies that mitigate surface disease without compromising efficacy. Ultimately, these efforts to combat ocular surface inflammation secondary to topical ophthalmic medications have the potential to improve patient adherence and enhance clinical outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roy S. Chuck, Joann J. Kang and Viral V. Juthani) for the series “Inflammatory Disorders of the Cornea and Ocular Surface” published in Annals of Eye Science. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-1-0012/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-1-0012/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-1-0012/coif). The series “Inflammatory Disorders of the Cornea and Ocular Surface” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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