The Preservative Paradox: Navigating Artificial Tear Selection in Chronic Dry Eye

Key Takeaways:

• Long-term exposure to benzalkonium chloride (BAK) induces mitochondrial stress, often triggering the inflammatory cycle it is intended to soothe.
• Per the TFOS DEWS III (2025) guidelines, any patient requiring tear supplementation more than 4 times daily must be transitioned to preservative-free (PF) formulations to protect epithelial integrity.
• PF artificial tear drops are the standard for post-cataract and refractive recovery, significantly accelerating corneal nerve healing and improving patient satisfaction compared to preserved alternatives.

For clinicians managing chronic dry eye (CDE), the therapeutic goal is simple: restore tear film homeostasis. However, the very tools often used to achieve this – artificial tears – can inadvertently trigger a cycle of inflammation and ocular surface damage.¹

The distinction between preserved and preservative-free (PF) formulations has transitioned from a matter of "patient preference" to a critical clinical decision backed by a deepening understanding of cellular toxicity.¹

BAK and mitochondrial stress

The most common preservative, benzalkonium chloride (BAK), remains a staple in multi-dose bottles due to its potent antimicrobial properties. However, recent evidence highlights its cumulative cytotoxic nature.^2,3

Recent research demonstrates that even at sub-micellar concentrations, BAK induces significant mitochondrial dysfunction in human corneal epithelial cells, inhibiting ATP production and leading to irreversible barrier failure over time.^2,3

For patients with CDE, the "detergent effect" of BAK is particularly damaging. Not only does it destabilize the lipid layer, but it also actively reduces goblet cell density and promotes the expression of pro-inflammatory cytokines like MCP-1 and IL-6. This creates a clinical paradox where the patient seeks relief from dryness but the tears intended to provide relief exacerbate the issue.²

PF artificial tears: The standard for frequent use

The clinical consensus, reinforced by the TFOS DEWS III management guidelines, is clear: If a patient requires lubrication more than 4 times daily, preservative-free formulations are essential.⁴

PF drops offer several key advantages for the CDE patient:^1,5

• Corneal epithelial integrity – A 2026 study comparing preserved vs. PF tears found that patients using PF options maintained significantly better corneal epithelial thickness compared to those on BAK-preserved drops.
• Reduced stinging and burning – Research has shown higher drug satisfaction and lower dropout rates in patients using PF formulations, largely due to the absence of the "stinging" sensation associated with preservative-induced toxicity.
• Advanced delivery systems – The rise of multi-dose preservative-free (MDPF) bottles, which use one-way valves, has helped to maintain sterility without the use of preservatives.

Using artificial tears strategically

When treating CDE, clinicians must weigh the "toxicity threshold." While occasional use of a preserved drop (1 to 2 times daily) may be tolerated by mild sufferers, the chronic patient is rarely in this category.¹

Post surgery considerations

For patients undergoing cataract or refractive surgery, the use of PF tears is no longer optional. A 2024 study revealed that PF artificial tears containing hyaluronic acid (HA) significantly reduced the incidence of post-operative DED and accelerated corneal nerve recovery compared to preserved alternatives.⁶

Cost vs. compliance

Clinicians often face pushback regarding the higher cost of PF drops. However, the long-term management of Ocular Surface Disease (OSD) caused by BAK – including the need for prescription anti-inflammatories or punctal plugs – far outweighs the incremental cost of starting a patient on a high-quality PF lubricant initially.

Prioritizing PF formulations

The transition from preserved to preservative-free artificial tears is a fundamental shift in dry eye management. By prioritizing PF formulations, especially in patients with MGD or those requiring frequent dosing, clinicians can break the inflammatory cycle of CDE and provide a more stable foundation for advanced therapies.