Impact of Preservative-Free Travoprost on Intraocular Pressure and Ocular Surface in Primary Open-Angle Glaucoma Patients

Abstract

Background: The present study assesses the effectiveness and tolerability of preservative-free travoprost in patients with primary open-angle glaucoma (POAG), focusing on intraocular pressure (IOP) reduction and ocular surface health over a six-month period. Methods: The study was prospectively designed and conducted at the University General Hospital of Alexandroupolis, Greece. A total of 45 patients diagnosed with either POAG or ocular hypertension (OHT) were included in the study; all were either newly diagnosed or had previously discontinued prostaglandin therapy due to intolerance. Of these, 39 participants completed the study. All subjects were administered preservative-free travoprost once daily. Clinical evaluations were conducted at baseline (T0), and at 1 month (T1), 3 months (T3), 6 months (T6) and 12 months (T12) following treatment initiation. The primary outcomes encompassed reductions in intraocular pressure (IOP), Schirmer test values, tear break-up time (TBUT), conjunctival hyperemia, as well as measurements of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness. Visual field parameters were also assessed. Results: A significant reduction in IOP was observed at T1, T3, T6 and T12 compared to baseline (p < 0.01). Schirmer test scores improved significantly from T0 to all subsequent time points (p < 0.01). Conjunctival hyperemia decreased significantly across follow-ups, while TBUT showed no significant change (p > 0.05). No significant changes were noted in mean deviation (MD), pattern standard deviation (PSD), RNFL, or GCC thickness over six months. Conclusion: Preservative-free travoprost effectively reduces IOP while improving ocular surface health, particularly in tear production and conjunctival hyperemia.

1. Introduction

Glaucoma, a progressive optic nerve disorder, is among the top causes of irreversible blindness, affecting over 76 million people globally—a figure expected to rise to 111.8 million by 2040 [1,2]. Glaucoma can be classified into several types, with primary open-angle glaucoma (POAG) being the most prevalent form. POAG is characterized by an increase in intraocular pressure (IOP), resulting in optic nerve degeneration and subsequent visual impairment [3]. Among the risk factors for POAG, elevated IOP is the most significant and the only one that can currently be modified through treatment [3].

Recent epidemiological analyses indicate that the global prevalence of POAG continues to rise, with approximately 57.5 million individuals affected worldwide in 2020 and projections estimating more than 100 million cases by 2040, disproportionately affecting Asian and African populations [1,2]. This growing prevalence underscores the importance of optimizing therapeutic strategies that effectively lower intraocular pressure while minimizing treatment-related adverse effects [3].

The principal objective of glaucoma management is the reduction in IOP, thereby preventing or slowing further optic nerve damage [4,5,6]. Pharmacological therapy remains the first-line treatment for POAG, with prostaglandin analogs being the most frequently prescribed class of drugs due to their efficacy in lowering IOP [4,7,8,9]. Travoprost, a prostaglandin F2-alpha analog, enhances aqueous humor outflow via both the trabecular meshwork and the uveoscleral pathway [10,11,12,13].

Although prostaglandin analogs are highly effective in lowering intraocular pressure, many formulations include preservatives like benzalkonium chloride (BAK), which are used to prevent microbial growth and prolong shelf life [14,15,16]. However, preservatives such as benzalkonium chloride (BAK) have been linked to a range of ocular surface side effects, especially in patients receiving long-term therapy [17,18]. Long-term exposure to BAK may cause ocular surface disease (OSD), presenting symptoms such as dry eye syndrome, conjunctival hyperemia, damage to the corneal epithelium, and instability of the tear film. OSD not only reduces quality of life for patients but can also lead to poor adherence to treatment and subsequent glaucoma progression [19].

BAK is a cationic surfactant commonly used as a preservative in ophthalmic preparations. Its surface-active properties can interact with lipid components at the aqueous–lipid interface and, in vitro and in vivo, have been associated with reduced tear-film stability. However, BAK’s clinically important effects are multifactorial: direct epithelial cytotoxicity, induction of subclinical inflammation, and loss of conjunctival goblet cells with consequent reduction in mucin production—all of which impair tear-film homeostasis and promote evaporative dry eye. Clinically, these mechanisms contribute to tear film instability, conjunctival hyperemia, and corneal epitheliopathy, which not only worsen ocular surface disease but also reduce patient adherence and tolerance to therapy. The clinical relevance of minimizing or eliminating BAK exposure is therefore particularly significant in glaucoma patients requiring lifelong treatment [20,21].

In response to the growing impact of preservative-induced ocular surface toxicity, preservative-free formulations of prostaglandin analogs, including travoprost, have been developed [19,20,21,22]. These preservative-free formulations aim to reduce the risk of OSD while maintaining the IOP-lowering effects of the medication [19,22,23,24].

Travoprost was selected for this study because, among prostaglandin analogues, it has demonstrated robust IOP-lowering efficacy through dual mechanisms of action (enhancing both trabecular and uveoscleral outflow). Previous formulations of travoprost contained BAK or alternative preservatives, both of which may still exert ocular surface toxicity. Evaluating a completely preservative-free travoprost formulation therefore provides an opportunity to determine whether the proven efficacy of travoprost can be maintained while eliminating the risks associated with preservatives. This distinction sets it apart from other prostaglandins, where preservative-free options have been more extensively investigated [25,26,27].

While earlier studies have primarily investigated BAK-free travoprost formulations containing alternative preservatives such as polyquaternium-1 or SofZia^® (Novartis AG, Basel, Switzerland), there is limited evidence regarding formulations completely devoid of preservatives. To our knowledge, the present study is the first to specifically evaluate the dual impact of a preservative-free travoprost formulation on both intraocular pressure control and ocular surface health in patients with primary open-angle glaucoma. By focusing on these complementary outcomes, this work seeks to address an important gap in the literature and provide new evidence supporting the clinical value of preservative-free prostaglandin therapy [25,26,27].

Within this context the current study seeks to assess the efficacy and safety of preservative-free travoprost in a group of patients with POAG, focusing on both IOP reduction and improvements in ocular surface.

2. Materials and Methods

2.1. Study Design

This prospective observational study was conducted to assess the efficacy and safety of preservative-free travoprost in patients with POAG. It aimed to evaluate the IOP-lowering effect of preservative-free travoprost while monitoring its impact on ocular surface health over a twelve-month period. The study complied with the principles of the Declaration of Helsinki, and all participants provided written informed consent before enrollment. The study protocol was approved by the Institutional Review Board of the University Hospital of Alexandroupolis in Greece, where the research took place (protocol code ES3/03-02-2022 and date of approval 3 February 2022). ClinicalTrials.gov identifier: NCT05319470.

2.2. Study Population

Patients were recruited from the outpatient service of the Department of Ophthalmology of the University General Hospital of Alexandroupolis. Inclusion criteria consisted of (i) patients with a diagnosis of POAG or ocular hypertension (OHT) who were either treatment-naive or had discontinued previous prostaglandin medications due to intolerance for at least 2 weeks, (ii) central corneal thickness (CCT) ≥ 500 μm and CCT ≤ 600 μm and (iii) in both eyes 22 mmHg ≤ IOP < 34 mmHg. This range was chosen because values below 22 mmHg may not reliably indicate pathological elevation requiring pharmacological intervention, whereas values above 34 mmHg are generally considered advanced or at high risk of rapid progression, making such patients less suitable for short-term safety and tolerability evaluation. Central corneal thickness (CCT) between 500 μm and 600 μm was required to minimize the confounding effect of corneal thickness on Goldmann applanation tonometry readings, as thinner corneas can lead to underestimation and thicker corneas to overestimation of IOP. This restriction ensured greater accuracy and consistency of IOP measurements within the study population. Exclusion criteria included patients, (i) with advanced visual field loss (mean deviation (MD) < −18 dB), a total defect (complete loss of visual sensitivity within the tested area) within the central 10 degrees of the visual field, and a potential risk of further visual field deterioration based on the investigator’s assessment for study eligibility, (ii) with significant worsening of the 2 last visual fields (6 months between them), (iii) with psychiatric conditions, (iv) receiving additional anti-glaucoma medications, (v) with a history of allergic reactions to similar medications, and (vi) with recent ocular surgery. All patients underwent a complete slit-lamp examination to ensure corneal integrity. Subjects with active or chronic corneal disease (e.g., keratitis, keratoconjunctivitis sicca, corneal dystrophies or ectasias, scarring) or history of corneal surgery were excluded, in order to prevent confounding factors affecting ocular surface evaluation or accuracy of IOP measurements.

2.3. Treatment Protocol

Patients received preservative-free travoprost (Trav-IOP, Cooper S.A., Athens, Greece) as a monotherapy once daily, administered in the evening. The preservative-free travoprost used was designed to reduce the potential for ocular surface irritation and toxicity while maintaining the IOP-lowering effects of the medication.

2.4. Assessment and Follow-Up

All patients were examined at five key time points: baseline prior to initiating treatment (T0), and subsequently at one (T1), three (T3), six (T6) months and twelve (T12) months following the start of preservative-free travoprost therapy. At each visit, several standardized clinical parameters were assessed to monitor treatment efficacy and ocular surface status.

Intraocular pressure (IOP) was measured using Goldmann applanation tonometry, widely regarded as the gold standard in IOP assessment for accuracy and reproducibility in clinical research, thereby allowing reliable comparisons with previous glaucoma trials. For each eye, three consecutive readings were obtained, and the mean value was recorded. To ensure consistency across visits, IOP measurements were performed at the same time of day (in the morning). The primary outcome of the study was the reduction in IOP over time, with measurements documented at T0, T1, T3, T6, and T12.

Tear production was evaluated through the Schirmer test, performed using filter paper strips inserted in the lower eyelid following instillation of tetracaine 0.5%. After five minutes, the length of wetting was measured, with a value below 10 mm considered indicative of tear deficiency. Schirmer testing was performed with topical anesthesia to suppress reflex tearing, thereby providing a more accurate measure of basal tear secretion. This test was administered at each follow-up point: T0, T1, T3, T6, and T12.

Tear film stability was assessed using the Tear Break-Up Time (TBUT) test. TBUT was evaluated using fluorescein dye instilled in the inferior conjunctival sac, and the interval between a complete blink and the first appearance of a dry spot on the corneal surface was recorded under slit-lamp examination. This standardized approach was selected, as it represents the most commonly accepted method for assessing tear film stability in clinical practice. A TBUT value of less than 10 s was interpreted as indicative of tear film instability. As with other assessments, TBUT was measured at T0, T1, T3, T6, and T12.

To evaluate ocular surface inflammation, conjunctival hyperemia was graded using the validated Efron scale, ranging from 0 (normal) to 4 (severe redness). Grades were assigned as follows: 0 = normal, 1 = trace, 2 = mild, 3 = moderate, and 4 = severe. Each patient was evaluated at all four time points. This scale is publicly available for educational and clinical use. No copyright permission is required [23].

Structural integrity of the optic nerve was monitored using spectral-domain Optical Coherence Tomography (OCT) imaging with the Avanti system (Optovue Inc., Fremont, CA, USA). Retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness were measured at baseline (T0), at the six-manth follow-up (T6) and at the final follow-up to detect any glaucomatous progression.

Visual field testing was performed using the Humphrey automated perimeter (Carl Zeiss Meditec, Inc., Dublin, CA, USA), employing the Swedish Interactive Threshold Algorithm (SITA) Standard with the 24-2 program. These assessments were conducted at baseline, at six months and at the final follow-up (T0, T6 and T12) to monitor functional changes related to glaucoma progression.

2.5. Statistical Analysis

Statistical analysis was performed using the Medcalc 20.1.4 statistical software package (MedCalc Software, Ostend, Belgium). A priori power analysis was performed to determine the necessary sample size, indicating that 28 patients were needed to complete the study in order to achieve power 80% at a 0.05 significance level with effect size at 0.23. For normally distributed repeated measures, ANOVA for repeated measures was applied, whereas the Friedman test was used for non-normally distributed repeated measures. Paired-sample t-tests were employed for comparisons between two time points. p-values < 0.05 were regarded as statistically significant. Missing data from patients who did not complete all follow-ups were excluded from the longitudinal analyses (complete-case analysis).

3. Results

3.1. Patient Demographics

Out of the 45 patients initially enrolled in the study, 3 patients developed an allergic reaction to the medication and withdrew from the study and 3 lost one of their follow-ups, 39 completed the full twelve-month follow-up period. A total of 78 eyes were examined over a period of 12 months following the initiation of treatment with preservative-free travoprost. Demographic data of the patients recruited in the study are presented in

Table 1. Demographic Data.

Parameters
Age (years, Median [IQR])	75 [73, 82]
Gender (n)	22 male, 17 female
Duration of disease (years, Median [IQR])	6.5 [1, 15]
Previous medication (n)	15 latanoprost, 13 tafluprost

IQR—interquartile range.

.

3.2. Intraocular Pressure (IOP)

A Friedman Test revealed a statistically significant reduction in IOP over time (x²(4) = 43, p < 0.001). Pairwise comparisons showed significant reductions in mean IOP from baseline (T0) to all subsequent visits (T1, T3, T6, and T12 p < 0.001), with no significant differences between T1, T3, and T6 (p > 0.05), indicating a sustained IOP-lowering effect. Significant differences were also detected between T12 and T0,T1 and T3 timelines (p < 0.01). Median baseline IOP was 18 [15, 20] mmHg, which decreased to 14 [12.8, 15] mmHg at 12 months, corresponding to a mean reduction of 4 mmHg (approximately 22.2% decrease from baseline; p < 0.001). These findings are illustrated in

Table 2. IOP comparisons.

Follow-Up	Number of Patients	Median (mmHg) [IQR]	p < 0.05 (Mean Difference)	p-Value
IOP Τ0	39	18 [15, 20]	IOP Τ1 (3)	p < 0.001
			IOP Τ3 (2)	p < 0.001
			IOP T6 (3)	p < 0.001
IOP Τ1	39	15 [14, 16]	IOP Τ0	p < 0.001
IOP Τ3	39	16 [14.75, 17]	IOP Τ0	p < 0.001
IOP Τ6	39	15 [13.5, 15]	IOP Τ0	p < 0.001
IOP T12	39	14 [12.8, 15]	IOP T0 (4)	p < 0.001
			IOP T1 (3)	p = 0.007
			IOP T3 (2)	p < 0.001

IQR—interquartile range. IOP—intraocular pressure.

and Figure 1.

3.3. Ocular Surface Parameters

Statistical comparisons across the follow-up period demonstrated notable improvements in ocular surface health after the initiation of preservative-free travoprost. Tear production, as assessed by the Schirmer test, showed a statistically significant increase over time, with Friedman Test revealing a significant main effect (x²(3) = 27.4, p < 0.001). Pairwise analysis confirmed that Schirmer scores were significantly higher at all follow-up visits (T1, T3, T6 and T12) compared to baseline (T0) (p < 0.001), and a further significant improvement was observed between T1 and T6 (p = 0.003) and T3 and T12 (p < 0.001). Conjunctival hyperemia also improved significantly, with a Friedman test indicating a reduction in scores over time (χ²(4) = 34.5, p < 0.001). Pairwise comparisons demonstrated statistically significant decreases in hyperemia from baseline to each follow-up until T6 (p < 0.05), with additional improvements detected between T1 and T6 (p < 0.038), between T3 and T6 (p < 0.007), between T1 and T12 (p = 0.003) and between T3 and T12 (p < 0.001). In contrast, tear film stability, as measured by Tear Break-Up Time (TBUT), remained stable throughout the study period. Repeated measures ANOVA yielded no statistically significant differences in TBUT across visits (F(4) = 2.06, p = 0.1). Post hoc analysis after Bonferroni correction showed no statistical differences between each follow-up timeline. These findings are further detailed in

Table 3. Ocular surface disease parameters comparison.

Follow-Up	Number of Patients	Median [IQR]	Statistically Significant Difference Between the Time Points (p < 0.05) (Mean Difference)	p-Values
Schirmer test Τ0 (mm)	39	7 [5, 12.25]	Schirmer Τ1 (3)	p < 0.001
			Schirmer Τ3 (5.5)	p < 0.001
			Schirmer Τ6 (5.5)	p = 0.013
Schirmer test Τ1 (mm)	39	10 [6, 15]	Schirmer T0(3)	p < 0.001
			Schirmer T6 (2.5)	p = 0.013
Schirmer test Τ3 (mm)	39	12.5 [10, 15.5]	Schirmer T0 (5.5)	p < 0.001
Schirmer test Τ6 (mm)	39	12.5 [10, 16.5]	Schirmer T0 (5.5)	p < 0.001
			Schirmer T1 (2.5)	p = 0.013
Schirmer test Τ12 (mm)	39	13.5 [11, 17.3]	Schirmer T0 (6.5)	p < 0.001
			Schirmer T1 (3.5)	p < 0.001
			Schirmer T3 (1)	p < 0.001
TBUT T0 (s)	39	14 [10, 19.5]	N/A	p > 0.05
TBUT T1 (s)	39	16 [11.5, 19]	N/A	p > 0.05
TBUT T3 (s)	39	16 [14.5, 20]	N/A	p > 0.05
TBUT T6 (s)	39	16,5 [14, 20]	N/A	p > 0.05
TBUT T12 (s)	39	17 [15, 21]	N/A	p > 0.05
CH Τ0	39	2 [1, 2]	CH Τ1	p = 0.005
			CH Τ3	p = 0.027
			CH Τ6	p < 0.001
CH Τ1	39	1 [1, 2]	CH Τ0	p = 0.005
			CH Τ6	p = 0.038
CH Τ3	39	1 [1, 2]	CH Τ0	p = 0.027
			CH Τ6	p = 0.007
CH Τ6	39	1 [1, 2]	CH Τ0	p < 0.001
			CH Τ1	p = 0.038
			CH Τ3	p = 0.007
CH T12	39	1 [1, 2]	CH Τ0	p < 0.001
			CH Τ1	p = 0.003
			CH Τ3	p < 0.001

IQR—interquartile range. TBUT—tear break-up time. CH—conjunctival hyperemia.

and illustrated in Figure 2, Figure 3 and Figure 4.

3.4. Glaucoma Indices

Comparative analysis between baseline (T0), the six-month follow-up (T6) and the twelve-month follow-up revealed no statistically significant deterioration in either functional or structural parameters associated with glaucoma progression. The mean change from baseline in Visual Field Index (VFI) was −1.08 ± 0.84, which did not reach statistical significance (p = 0.218). Similarly, MD showed a minor shift of 0.141 ± 0.018 dB (p = 0.15), while Pattern Standard Deviation (PSD) changed by 0.072 ± 0.09 dB (p = 0.39). Structural metrics assessed via OCT also remained stable, with the RNFL decreasing from baseline by −2.5 ± 1.99 µm (p = 0.11), and the GCC by −1.8 ± 3.72 µm (p = 0.18). These results, presented in

Table 4. Glaucoma indices comparison.

Glaucoma Indices	Number of Patients	T0 (Mean ± SD)	T6 (Mean ± SD)	T12 (Mean ± SD)	Mean Difference (from Baseline) ± SD [95% CI]	p-Values
VFI (%)	39	84.55 ± 23.86	82.83 ± 24.26	82.4 ± 24.35	−1.083 ± 0.84 [−0.62, 2.79]	p = 0.218
MD (dB)	39	−6.54 ± 8.38	−6.66 ± 8.40	−6.69 ± 8.51	0.141 ± 0.018 [0.1, 0.177]	p = 0.15
PSD (dB)	39	3.88 ± 3.06	3.93 ± 3.33	3.95 ± 3.13	0.072 ± 0.095 [−0.245, 0.099]	p = 0.39
RNFL (μm)	39	87.17 ± 9.76	85 ± 8.38	84.4 ± 9.54	−2.5 ± 1.99 [−1.25, −1.96]	p = 0.11
GCC (μm)	39	89.68 ± 11.3	88.4 ± 11.31	87.9 ± 11.2	−1.8 ± 3.72 [−2.35, 0.15]	p = 0.18

VFI—visual field index. MD—mean deviation. PSD—pattern standard deviation. RNFL—retinal nerve fiber layer. GCC—ganglion cell complex. dB—decibel. μm—micrometers.

, indicate that treatment with preservative-free travoprost did not contribute to measurable glaucomatous progression over the twelve-month observation period.

Based on the study results, it is evident that IOP is better controlled with travoprost compared to the previous treatment. Specifically, IOP values before treatment with travoprost showed a statistically significant difference compared to all values during follow-up (p < 0.01), while no difference was observed between measurements at T1, T3, and T6 time points (p > 0.05). The twelve-month follow-up showed significant difference between T1 and T3 follow-ups.

Regarding the severity parameters of ocular surface disease, clear improvement was observed in the Schirmer test and conjunctival hyperemia, while no improvement was seen in TBUT. Schirmer test at treatment initiation showed significant difference compared to all time points (T1–T12) (p < 0.01), with a difference also noted between T1 and T6 (p < 0.05) and T3 and T12 (p < 0.001). Conjunctival hyperemia improved significantly, with differences observed between baseline and all time points (T1–T12), as well as between T1 and T6, T3 and T6, T1 and T12 and T3 and T12 time points. The TBUT index showed no significant change during patients’ follow-up (p > 0.05).

As for the clinical indices of glaucoma progression during treatment, results indicate that preservative-free travoprost can effectively control glaucoma progression in patients with mild or moderate glaucoma, based on non-significant differences indicated through the follow-ups between VFI, MD, PSD, RNFL and GCC.

4. Discussion

The findings of this study demonstrate that preservative-free travoprost is effective in significantly lowering IOP in patients with mild to moderate POAG, aligning with the efficacy reported in earlier clinical trials. This reinforces its potential role as a reliable first-line treatment. Crucially, the therapeutic benefits were achieved without exacerbating OSD, a common concern with preserved formulations, particularly those containing BAK.

A particularly noteworthy result was the significant improvement in Schirmer test scores, suggesting enhanced tear production in patients treated with preservative-free travoprost. This is especially important for individuals predisposed to or already experiencing dry eye symptoms. The elimination of preservatives appears to minimize ocular surface stress, a theory further supported by the reduction in conjunctival hyperemia observed throughout the study. This aligns with the hypothesis that preservatives, particularly BAK, may induce low-grade inflammation and epithelial toxicity, exacerbating OSD during long-term topical therapy. The observed improvement in Schirmer test values indicates enhanced basal tear secretion, suggesting that the switch to preservative-free travoprost may help restore tear film homeostasis in patients with ocular surface compromise. This finding is clinically relevant, as increased tear production can alleviate dry eye symptoms, improve visual comfort, and support better adherence to long-term glaucoma therapy. Similarly, the significant reduction in conjunctival hyperemia reflects decreased ocular surface inflammation and irritation, both of which are frequently associated with preserved formulations. Together, these outcomes underscore the ocular surface benefits of preservative-free travoprost, contributing not only to patient tolerability but also to overall quality of life and treatment compliance.

While TBUT remained unchanged, this outcome may reflect the chronic and multifactorial nature of tear film instability, which is unlikely to resolve rapidly. The lack of TBUT improvement could also be influenced by the limitations of the test itself, which primarily assesses the lipid layer rather than the mucin layer-possibly the primary site of preservative-induced damage. The concurrent improvement in hyperemia despite stable TBUT suggests that underlying mucin-related dysfunction may have improved even if not fully captured by TBUT measurements [29].

Importantly, no statistically significant changes were observed in glaucoma indices, including VFI, MD, PSD, RNFL, GCC thickness during the 12-month follow-up period. These findings suggest that preservative-free travoprost maintained effective IOP control sufficient to preserve both structural and functional stability. Although the study duration may not have been long enough to detect subtle progressive changes, the absence of deterioration across these parameters indicates stable disease under treatment, supporting the efficacy and safety of preservative-free travoprost in maintaining glaucomatous stability.

An additional aspect that warrants consideration is the cost–benefit profile of preservative-free formulations. Although preservative-free prostaglandin analogues are generally associated with higher acquisition costs compared with preserved alternatives, these expenses may be offset by potential long-term savings. Preservatives such as BAK contribute to ocular surface disease, which frequently leads to increased healthcare utilization through the need for additional lubricants, anti-inflammatory treatments, and even surgical interventions in severe cases. Moreover, ocular discomfort and intolerance can negatively affect adherence to glaucoma therapy, increasing the risk of disease progression and associated costs. In patients with pre-existing ocular surface disease, the use of preservative-free therapy may therefore not only improve comfort and adherence but also reduce secondary treatment burden and long-term expenditure. By minimizing preservative-related ocular surface complications and improving patient tolerance, preservative-free formulations may enhance both quality of life and long-term cost-effectiveness of glaucoma management. Future pharmacoeconomic studies are needed to quantify these potential savings and further inform treatment decisions [30].

The present findings are consistent with prior studies examining preservative-free glaucoma therapies. Pisella et al. (2002), in a large observational study, found a significantly higher prevalence of OSD symptoms in patients using preserved medications [31]. Switching to preservative-free drops led to symptom improvement in most cases. Similarly, Oddone et al. (2022) demonstrated that patients switching to preservative-free tafluprost/timolol experienced both improved IOP control and reduced OSD signs [32]. Jandroković et al. (2022) also reported improved ocular surface integrity and reduced hyperemia following a similar therapeutic switch [33]. Although other studies, such as those by Shedden et al. (2010) and Day et al. (2013), found comparable efficacy and tolerability between preserved and preservative-free treatments, the trend across multiple investigations supports a favorable safety profile for preservative-free agents, particularly in patients with ocular surface sensitivity [34,35].

Goldberg et al. in 2014 compared the efficacy of two bimatoprost/timolol formulations (with and without preservatives) [36]. A total of 561 patients with primary open-angle glaucoma and ocular hypertension were randomly assigned in this study. The study results showed the non-inferiority of the preservative-free formulation compared to the preservative-containing one in IOP control, with no significant differences observed in conjunctival hyperemia and punctate keratitis [36].

Aihara et al. (2012) provided long-term evidence for BAK-free travoprost, showing sustained IOP reduction and notable improvements in corneal and conjunctival health [27]. Collectively, the current study adds to a growing body of evidence suggesting that while preservative-free medications perform comparably to preserved ones in IOP control, they may offer superior ocular surface tolerability. Nevertheless, discrepancies in the literature highlight the need for larger, randomized, long-term studies directly comparing these formulations under standardized conditions.

Kumar et al. (2020) compared BAK-preserved travoprost with BAKfree travoprost in Indian glaucoma patients and reported that the BAC-free formulation was associated with significantly fewer ocular surface disease symptoms and better quality of life [37]. Ruangvaravate et al. (2020) studied patients switching from other prostaglandins to tafluprost or preservative-free tafluprost and demonstrated improvements in ocular surface parameters, with the preservative-free formulation providing the greatest benefit [38]. Muz et al. (2021) [39] compared BAK-preserved latanoprost with polyquad-preserved travoprost and observed superior ocular surface outcomes with the polyquad-preserved formulation, while intraocular pressure reduction remained comparable between groups. These findings are consistent with the present study, which further extends the literature by specifically evaluating a completely preservative-free travoprost formulation. Unlike formulations containing alternative preservatives such as polyquad, our results suggest that the elimination of all preservatives may provide additional advantages for ocular surface health, while maintaining robust efficacy in IOP control [37,38,39].

As mentioned above, our findings are consistent with yet expand upon, the growing body of evidence supporting the efficacy and tolerability of preservative-free prostaglandin analogues. Early studies, such as those by Pisella et al. (2002), demonstrated significant improvement in ocular surface symptoms following a switch from preserved to preservative-free glaucoma medications, while Oddone et al. (2022) and Jandroković et al. (2022) further confirmed improvements in ocular surface integrity and reduction in hyperemia with preservative-free tafluprost/timolol combinations [31,32,33]. These observations have been reinforced by more recent large-scale and phase III clinical trials.

Baudouin et al. (2025) conducted a phase III multicentre trial comparing preservative-free latanoprost emulsion with a preserved formulation, demonstrating non-inferiority in IOP control while achieving significantly better tolerability and fewer ocular surface adverse events [40]. Similarly, Czumbel et al. (2024) confirmed the therapeutic equivalence and enhanced comfort of preservative-free generic latanoprost compared with the preserved reference drug (Xalatan^®, Pfizer, Puurs, Belgium) [41]. Brinkman et al. (2024) reported improved tolerability profiles with preservative-free tafluprost compared to preserved latanoprost, while maintaining comparable IOP-lowering efficacy [42]. Consistent findings were observed in the COMfort Eye Trial (COMET) by Kandarakis et al. (2024), which confirmed the non-inferiority of preservative-free latanoprost versus Xalatan^® in patients with POAG or OHT, alongside a significant reduction in ocular surface discomfort [43]. Collectively, these studies confirm that removing preservatives enhances ocular surface safety without compromising antiglaucoma efficacy. The safety of preservative-free ophthalmic formulations has been widely discussed in the literature, as preservatives such as benzalkonium chloride (BAK) are known to induce or exacerbate ocular surface alterations, including epithelial toxicity, tear film instability, and ocular surface inflammation. Several studies have reported improved ocular surface tolerance with preservative-free formulations in comparison with their preserved counterparts [25,26,27].

Regarding prostaglandin analogues, earlier investigations primarily focused on BAK-free travoprost formulations, in which alternative preservatives (e.g., polyquaternium-1, SofZia^®) were used. These studies consistently demonstrated a more favorable ocular surface profile than BAK-preserved travoprost, but they did not evaluate a formulation completely free of preservatives [25,26,27].

To our knowledge, the present study is the first to specifically assess the impact of a preservative-free travoprost formulation on the ocular surface. This distinction is important, as even alternative preservatives may exert subclinical or long-term effects on the ocular surface. By eliminating preservatives altogether, preservative-free travoprost offers a potentially safer therapeutic option for patients at risk of ocular surface disease, such as those with concomitant dry eye or requiring long-term intraocular pressure–lowering therapy.

Our findings add to the existing body of evidence by demonstrating that preservative-free travoprost maintains efficacy in intraocular pressure control while minimizing ocular surface compromise. This is particularly relevant for glaucoma patients who often require chronic therapy, in whom ocular surface health is a critical determinant of treatment adherence and quality of life.

Despite these promising findings, the present study has certain limitations. The absence of objective biomarkers for ocular surface inflammation and the reliance on clinical grading scales may have restricted the sensitivity of surface assessments. A limitation of the present study is the absence of blinding, as it was conducted in an open-label design. Although standardized assessments by a single examiner reduced variability, some degree of observer bias cannot be excluded. An additional consideration is that our study population included both treatment-naïve patients and those who had previously experienced poor tolerability with preserved antiglaucoma therapies. While combining these subgroups follows the methodology of prior studies [25,26,27], it may have masked potential differences in response or tolerability between them. We acknowledge this as a limitation and emphasize that larger studies with sufficient statistical power are needed to perform separate analyses of these clinically relevant subgroups. Future studies incorporating randomized control groups, longer follow-up periods, and objective surface evaluation methods with patient-report outcome using quality of life questionnaires are warranted to validate and expand upon these findings, assess the sustained impact on ocular surface health, and determine whether the observed short-term benefits translate into long-term disease stability and improved patient outcomes. Missing data were handled using a complete-case approach, as the proportion of dropouts was low. It is acknowledged that sensitivity analyses, such as intention-to-treat-based methods, could further assess the robustness of our findings and should be incorporated in future larger, randomized studies to minimize bias related to loss-to-follow-up.

The findings of this study have meaningful implications for clinical practice, especially in patients with preexisting OSD. Given that these patients are more susceptible to preservative-induced epithelial toxicity and inflammation, the use of preservative-free travoprost offers a safer and more tolerable therapeutic alternative. Improved ocular surface comfort and reduced hyperemia can enhance treatment adherence and overall quality of life—key factors in successful long-term glaucoma management. Therefore, preservative-free prostaglandin formulations should be strongly considered as first-line therapy, including other preservative-free formulation with the same efficacy, for patients with OSD or those requiring chronic topical treatment.

5. Conclusions

In conclusion, preservative-free travoprost offers an effective and well-tolerated treatment for patients with primary open-angle glaucoma, reducing IOP while minimizing the risk of ocular surface disease. The absence of preservatives like BAK in travoprost appears to alleviate many of the adverse effects associated with long-term glaucoma treatment.