The New Science Behind Artificial Tears
A discussion on the use of artificial tears in various patient populations.
JOSEPH MUSSOLINE, M.D.

Dry eye syndrome remains one of the most widespread and underdiagnosed ophthalmic disorders, affecting 11%-22% of the general population.¹ Causative factors for dry eye syndrome include age, gender, environmental stressors, systemic medications with drying effects, postsurgical conditions and prolonged visual tasking. Dry eye is also associated with various systemic diseases including Sjögren's syndrome, lupus and rheumatoid arthritis. The presence of dry eye syndrome in a patient is marked by a chronic breakdown of the tear film involving one or more of its primary layers (lipid, aqueous and/or mucin). Severe dry eye often involves an inflammatory response. The common signs and symptoms of dry eye include dryness, burning, stinging, grittiness, foreign body sensation, blurred vision and photophobia.

In addition to the patient population with clinical signs determined by the clinician to merit a diagnosis of dry eye (patients with dry eye), there are also those patients who experience relatively frequent ocular discomfort similar to that present in some patients with dry eye, but have no clinical signs definitively indicative of dry eye. Unmasking these patients may prove to be a difficult task. However, a simple questionnaire is a useful tool for identifying these patients. Questionnaires can quantify frequency and severity of symptoms for each type of patient with dry eye. They can be used for diagnostic purposes, as well as for assessing treatment benefits. It is also important to obtain a complete medical history, ensuring that the patient is queried regarding the presence of other ocular conditions, systemic diseases, the use of any medications that cause drying effects such as systemic antihistamines, and questions about the patient's daily activities.² Since dry eye is affected by so many factors, a full medical history may reveal the cause of a dry-eye condition. A patient with dry-eye symptoms (and not necessarily signs) should generally be treated with products similar to those prescribed to patients with dry eye.

When choosing a treatment to combat signs and/or symptoms of dry eye syndrome, it is important to consider the microenvironment of the ocular surface. In a healthy eye, the microvilli of the corneal epithelial cells hold the mucus layer of the tear film to the ocular surface with a glycocalyx lattice. In patients with dry eye, exposed epithelial cells become desiccated and the microvilli that extend from these cells are worn down until they are incapable of producing or supporting the mesh of glycocalyx molecules, without which the mucin and subsequent phases cannot adhere to the eye. The lipid layer floats on top of the tear film, preventing evaporation, but it is the mucin layer that anchors the tear film to the surface of the eye.

Results of Clinical Trials

It may seem difficult to distinguish between the available dry-eye products. A lot has changed since the standard polymer drop. Over the past few years, many artificial tears and one prescription product have been approved for treating dry-eye symptoms. As we try to determine which treatments are best for our patients, it is helpful to consider the results from various recent clinically relevant comparative trials.

As more and more is learned about the tear film, products are being developed that are scientifically attuned to enhancing certain portions of it by different mechanisms of action. Restasis (cyclosporine 0.05%, Allergan), the only approved prescription product thus far, is indicated to increase tear production presumed to be suppressed due to ocular inflammation. Restasis utilizes an emulsion system featuring cyclosporine 0.05% that increases tear production by acting on the t-cells that cause inflammation, and in turn, suppression of the lacrimal glands; however, the mechanism of action of Restasis is not yet fully understood.³ This product is recommended for moderate to severe dry eye patients, specifically aqueous-deficient ones.⁴

The available artificial tears may be more difficult to distinguish, but each one has its own unique formulation and mechanism of action. Allergan's Refresh line of artificial tears exemplifies the development of different formulations and viscosities to treat varying severities of dry eye. These drops include Refresh Tears and Refresh Liquigel, both of which contain the mucoadhesive carboxymethyl cellulose (CMC), which is designed to replace and enhance the mucin layer of the tear film in order to retain the aqueous phase longer and more fully.

The Genteal line (Novartis) comes in varying product formulations similar to Refresh, and all utilize the active ingredient hydroxypropylmethyl cellulose (HPMC), a lubricating polymer. Genteal contains the preservative perborate, which turns into pure water and oxygen upon contact with the eye. Refresh Endura makes use of a castor oil emulsion system containing components that separate upon instillation and enhance the three layers of the tear film respectively, as does the artificial tear Soothe (Alimera), which focuses on reconstructing a continuous lipid layer. In a study that included five normal and 10 dry-eye subjects, Refresh Endura significantly increased patients' lipid layer thickness, as measured by kinetic tear interference analysis.⁵ It is important to note that this effect is only relevant to those products that specifically target the lipid layer.

Systane (Alcon) has a demulcent binding system that features a mechanism by which the artificial tear meshes with and strengthens a patient's tear film rather than just temporarily replacing it, as is the case for most artificial tears. Systane can be used in one formulation for all levels of dry-eye severity. Hydroxypropyl (HP)-Guar, the gelling agent in Systane, has a neutral pH of 7.0. When instilled in the human eye (pH~7.5), the guar bonds with borate ions, increasing the viscosity of the artificial tear and providing the ocular surface with greater lubricity. When the binding system in Systane is triggered by the pH alteration upon instillation, the bonded guar and borate, along with the active demulcents, polyethylene glycol (PEG) and propylene glycol (PG), form a cross-linked mesh that is, in essence, a synthetic glycocalyx lattice. This lattice attaches smoothly to the actual glycocalyx, thereby generating a grip for the mucin layer that is continuous across the ocular surface, which allows for longer retention of the tear film and facilitates corneal epithelial repair by protecting the otherwise exposed cells.⁶

Refresh Tears and Systane were compared in their ability to relieve dry eye in a recent 6-week study. The study assessed corneal and conjunctival staining, as well as subject-rated symptoms. Systane achieved an overall decrease in conjunctival staining scores, and at Days 14 and 28, demonstrated statistically significant improvements in conjunctival staining compared to Refresh Tears. Refresh Tears showed no significant change in conjunctival staining. Both treatments lowered corneal staining significantly from baseline, with Systane recording better, though not significant, scores at all time points. With regard to symptoms, subjects treated with Refresh were more likely to agree that their eyes felt drier in the morning and at the end of the day than were Systane-treated subjects. Among the other symptoms recorded, Systane showed a trend in easing the frequency of ocular dryness relative to Refresh, and demonstrated a significant decrease from baseline in frequency of foreign body sensation at all time points.⁶

One tool for assessing dry-eye signs and symptoms, the ocular protection index (OPI), was recently developed by Ophthalmic Research Associates.⁷ The OPI, calculated by dividing tear film break-up time (TFBUT) by inter-blink interval (IBI), is also an accurate and reproducible means by which to determine treatment efficacy. A TFBUT greater than a corresponding IBI (OPI�1) implicitly suggests that the tear film remains intact until it can be replenished with a blink, whereas an IBI higher than TFBUT (OPI<1) indicates the ocular surface will be exposed for the time between the tear-film breakup and the blink. Use of the OPI helps to understand that extending the TFBUT beyond the IBI is a clinically relevant increase we want to achieve in patients with dry eye.

In a recent study, Systane, Refresh Tears and Refresh Endura were compared in their abilities to relieve DES as measured by the OPI. Ocular protection index and TFBUT were evaluated at 5, 10, 15, 20, 30, 45 and 60 minutes following the instillation of the eye drop. Systane resulted in a higher percentage of OPI scores above 1.0 at all time points versus both Refresh Tears and Refresh Endura, with statistical significance at 15 and 45 minutes against Refresh Tears, and at 5 minutes against Refresh Endura. Systane also achieved greater baseline-adjusted TFBUTs at every time point than both of the control formulas. The differences were statistically significant at 5, 10, 15, 20 and 60 minutes versus Refresh Tears and at 5, 10, 15, 20 and 30 minutes versus Refresh Endura (for both comparisons, there were P-values below .001 at three or more time points).⁸

Combination Therapy

While artificial tear monotherapy is sufficient for mild to moderate dry-eye sufferers, the possibility of combination treatment is arising for more advanced DES patients. In the more severe cases when Restasis is used, a concomitant product can be added to help improve the discomfort associated with Restasis instillation. The NSAID Acular LS (ketorolac tromethamine 0.4%, Allergan) was tested for concomitant use with Restasis, which helped reduce initial discomfort without hindering the efficacy of the treatment.⁹

Another study evaluated the concomitant use of standard artificial tears with Restasis in order to facilitate its effects.¹⁰ This study looked at trends in three dry-eye treatment groups: Restasis and Refresh Tears in conjunction, Restasis and Systane in conjunction and Systane alone. The study recorded changes at Days 7, 14, 28, 42 and at 4 and
6 months in corneal and conjunctival staining and TFBUT. Changes in subject assessment of seven symptoms (ocular burning, dryness, stinging, blurriness, grittiness, scratchiness and foreign-body sensation) were also assessed. Though all treatments initially saw improvements in staining, the Restasis and Refresh combination failed to further decrease staining after 2 weeks, and even saw some relative increases later in the study. There was a statistical difference in staining observed in favor of the Restasis/Systane treatment vs. the Restasis/Refresh treatment. The Restasis/Systane treatment group reported statistically significant improvement, when compared to Restasis/Refresh, in frequency of burning, stinging, grittiness and dryness, and displayed trends indicating less frequent scratchiness and blurriness. Across all symptoms, Restasis/Systane provided significantly more effective relief than Restasis/Refresh, and there was a trend observed in favor of the Systane-only treatment versus Restasis/Refresh for symptom-relief. This study suggests that the use of an artificial tear in conjunction with Restasis is a beneficial treatment modality in some of our patients with dry eye.

When choosing a treatment for dry eye, it is important to first determine the frequency and severity of a patient's symptoms. Even chronic complainer patients who do not have clinical signs of dry eye can benefit from artificial tear therapy. If the patient has more severe dry eye, the combination of Restasis and an artificial tear will provide the best treatment option. This is especially important since it may take up to 6 months before the benefits of Restasis can be fully realized, and the concomitant product may be able to reduce the discomfort associated with Restasis instillation. As practitioners, we rely on our own clinical experiences to guide our prescribing habits. However, it is also important to be up-to-date on recent clinically relevant study results. OM

References

1. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45:199-201.

2. Ousler GW, Wilcox KA, Gupta G, Abelson MB. An evaluation of the ocular drying effects of 2 systemic antihistamines: loratadine and cetirizine hydrochloride. Annals of Allergy, Asthma and Immunology. 2004;93:460-464.

3. Perry HD, Donnenfeld ED, Perry AR, et al. Evaluation of topical cyclosporine A 0.05% in dry eye disease. Paper presented at: American Academy of Ophthalmology annual meeting. New Orleans, La.; October 24, 2004.

4. Sall K, Stevenson OD, Mundorf TK, Reis BL, CsA Phase 3 Study Group. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107:631-639.

5. Di Pascuale MA, Goto E, Tseng SC. Sequential changes of lipid tear film after the instillation of a single drop of a new emulsion eye drop in dry eye patients. Ophthalmology. 2004;111:783-791.

6. Christensen MT, Cohen S, Rinehart J et al. Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye. Current Eye Research. 2004; 28: 55-62.

7. Ousler GW, Emory TB, Welch D, Abelson MB. Factors that Influence the Inter-Blink Interval (IBI) as Measured by the Ocular Protection Index (OPI). Invest Ophthalmol Vis Sci. 2002;43:E-Abstract 56.

8. Pollard S, Stone RP, Christensen MT, Ousler GW, Abelson MB. Extensions in tear film break-up time after instillation of HP-guar artificial tear substitute. Invest Ophthalmol Vis Sci. 2003;44:E-Abstract 2489.

9. Schechter BA, Wittpenn JR. Evaluation of ketorolac (Acular LS) during the induction phase of cyclosporine a (Restasis) therapy to improve patient comfort. Poster presented at: Association for Research in Vision and Ophthalmology annual meeting. Fort Lauderdale, Fla.; May 2, 2005.

10. Sall KN, Cohen SM, Christensen MT. Efficacy and compatibility of an HP-guar based lubricant eye drop when used as supportive therapy with a cyclosporine-based ophthalmic emulsion. Invest Ophthalmol Vis Sci. 2005;46:E-abstract 2020.