Despite the many advances in our understanding of glaucoma, the only available treatments of the disease are aimed at lowering IOP, and IOP-lowering medications are usually our initial therapy. Consequently, unmet needs in glaucoma treatment still exist. The clearest need is for therapeutic targets beyond IOP reduction. A recent report from the Low-Pressure Glaucoma Treatment Study (LoGTS) has raised this intriguing possibility. Although there are clearly IOP-independent risk factors, even with the LoGTS results, no glaucoma therapies targeted at neuroprotection or optic nerve perfusion are currently approved. Until these alternative therapies become available, we clinicians will continue to decrease IOP with topical medications.
SIDE EFFECTS OF PRESERVATIVES IN GLAUCOMA MEDICATIONS
We must be aware of the impact of therapy on the eye and its associated effect on patients' quality of life. Topical therapy can cause local side effects due to the active ingredient or the excipients. Since glaucoma is a chronic disease, medical therapy is usually a long-term prescription, often involving multiple ophthalmic medications. The prevalence of ocular surface disease (OSD) in the medically treated glaucoma population is high.1 A relatively overlooked opportunity in glaucoma treatment is the availability of more medications formulated to additionally minimize side effects like OSD.
In a study of 630 patients with primary open-angle glaucoma or ocular hypertension on topical IOP-lowering medication regimens, nearly half had OSD index scores indicating at least mild OSD symptoms. More than a quarter were classified as having moderate or severe OSD.2
In the aging American population, age itself (along with commonly taken medications) can be associated with dry eye and OSD. There is accumulating evidence that some preservatives used in glaucoma eye drops to maintain a microbe-free environment aggravate dry eye and OSD conditions. Although preservatives are of less concern with the short-term use of topical ophthalmic medications, long-term use may cause problems. In vitro and animal studies have shown that preservative agents have toxic effects, compromising tear film stability and causing damage to corneal, conjunctival, and trabecular cells.3-14 These ocular side effects can translate into symptoms such as stinging, burning, and dryness.1 Preservatives are less commonly associated with allergic reactions that can occur when the eye is hypersensitized by the repeated use of preserved eyedrops.15
The incidence of dry eye and other OSDs in glaucoma patients increases with the dose and duration of use of antiglaucoma treatments containing preservatives.1,16,17 A cross-sectional study of glaucoma patients reported that, for each additional eye drop preserved with benzalkonium chloride prescribed, there was a twofold increase in the likelihood of experiencing OSD.16 Another prospective epidemiologic survey investigated the use of preserved and preservative-free eye drops in 4,107 patients with glaucoma and found that ocular side effects were significantly more prevalent among patients treated with preserved eyedrops.18
REDUCING THE PRESERVATIVE LOAD
While at the present time it is impossible to remove preservatives completely from every glaucoma patient's treatment regimen, it is possible to lower the preservative burden by prescribing preservative-free medications or medications with less toxic preservatives when OSD is present.
New preservatives such as SofZia (Alcon Laboratories, Inc.) and Purite (Allergan, Inc.) have been called vanishing preservatives, because they convert to nontoxic substances once in the eye. Purite is a stabilized oxychloro complex (sodium chlorite) with a long history of use in water purification systems; it degrades to chloride ions and water upon exposure to ultraviolet light. This proprietary preservative is used in Alphagan P (Allergan, Inc.), a brimonidine tartrate preparation for glaucoma. SofZia is a proprietary, ionic, buffered solution consisting of zinc, borate, propylene glycol, and sorbitol— substances that are not significantly toxic to the ocular surface but maintain an antimicrobial environment in the container. SofZia is the preservative system used in Alcon's prostaglandin analogue Travatan Z (travoprost ophthalmic solution).
The only topical glaucoma medication completely free of preservatives that is available in the United States is Timoptic (timolol maleate ophthalmic solution) in Ocudose (Aton Pharma, Inc.). Timoptic in Ocudose is available in two dosage strengths, 0.25% and 0.5%.
Preservative-free pilocarpine and Cosopt (fixed-combination timolol 2%-dorzolamide 0.5%; Merck & Co., Inc., Whitehouse Station, NJ) are available outside the United States. Tafluprost is a new preservative-free prostaglandin for the reduction of IOP in open-angle glaucoma and ocular hypertension. This drug is available in some countries outside the United States and is under study for approval in the United States.
CONCLUSION
Many glaucoma patients are able to tolerate a single medication regardless of the preservative.17 However, at least half of our patients will advance beyond monotherapy. Topical glaucoma medications that contain alternative preservatives or that are free of preservatives offer the potential to preserve the health of the ocular surface as therapy advances. This consideration is particularly valuable when patients are sensitive to preservatives or have concomitant OSD. Several studies have suggested that switching from a preserved to a preservative-free medication can benefit the tear film, conjunctiva, cornea, and eyelids.19-21
We should keep in mind the association between preservatives and OSD and be aware of the alternatives for our patients being treated with IOP-lowering medications.
Robert D. Fechtner, MD, is the director of the Glaucoma Division at UMDNJ, and is a professor of ophthalmology at the Institute of Ophthalmology, both at New Jersey Medical School in Newark. He is a consultant to and has received research support from Alcon Laboratories, Inc.; Allergan, Inc.; and Merck & Co., Inc. Dr. Fechtner may be reached at (973) 972- 2030; fechtner@umdnj.edu.
