March 2014




Pharmaceutical focus

A clear-eyed view of preservatives in tears

by Maxine Lipner EyeWorld Senior Contributing Writer

Lissamine green

Lissamine green (LG) staining of the conjunctiva in a patient with mild dry eye. LG is a valuable vital dye to use because it is very sensitive and highlights even early devitalization of conjunctival epithelium.

Fluorescein staining of a cornea Fluorescein staining of a cornea in a patient with moderate dry eye. Broken tear film over the central cornea (decreased tear film break-up time) and fluorescein staining of the inferior cornea. Fluorescein stains epithelial cells in more advanced disease, as well as absent areas (erosions) on the corneal surface.

Source (all): Vincent P. de Luise, MD

Taking the sting out for patients

Using artificial tears is a fact of life for many patients with dry eye disease, according to Vincent P. de Luise, MD, assistant clinical professor of ophthalmology, Yale University School of Medicine, New Haven, Conn. Debra Schaumberg, ScD, OD, from the Harvard School of Public Health, has reported that between 25 and 40 million Americans have some level of dry eye, Dr. de Luise said, and virtually all of these patients are using artificial tears, if not daily then certainly during their week. With preservatives in many such tears on the drugstore shelves, EyeWorld asked leading practitioners to take a closer look at these and at potential alternatives for dry eye patients. Dr. de Luise noted that practitioners can offer patients some environmental strategies for keeping the ocular surface moist. For example, they can suggest putting a cold mist humidifier near the computer. Blink rates dramatically decrease and tears evaporate more rapidly during computer use, and a humidifier can be very helpful. Another useful recommendation is placing a pillow on the desk chair. "Sitting on a pillow raises your body an inch or two, resulting in the upper lid lowering about 1 mm as the patient is now looking down a tiny bit on the computer screen," Dr. de Luise said. "Lowering the upper eyelid about 1 mm covers the cornea 1 mm and thus reduces evaporation up to 15%."

Still, use of artificial tears looms as the next step in the treatment of most patients. Both the FDA and the US Pharmacopeia mandate use of preservatives for nearly all ophthalmic drops in bottles or multi-dose vials. Such eye drops have active ingredients as well as inactive ingredients, the latter of which are called "excipients." Dr. de Luise described excipients as including the preservatives, the buffers that keep the PH of the eye drop within a certain range, and viscosity agents that help increase the contact time of the eye drop on the ocular surface.

"The more inactive ingredients in an eye drop, the more worried I get as far as patient comfort and ocular toxicity are concerned," Dr. de Luise said. "Over the decades of managing dry eye patients, I have preferred going immediately to non-preserved tears."

Preservative types

There are two major types of preservatives to considerchemical and oxidative. "Chemical preservatives are older science, tend to be more irritating and toxic to the conjunctiva and corneal epithelium, but are still found in many bottled artificial tear drops," Dr. de Luise said. "Oxidative preservatives are newer science, less toxic, and thus friendlier to the surface of the eye, but they're still preservatives and still have some toxicity."

Chemical preservatives in tears include benzalkonium chloride (BAK) and chlorobutanol. Of the two, Dr. de Luise observed, the latter is considered friendlier to the ocular surface. "Chlorobutanol is an alcohol-based chemical preservative," he said. "It works by disorganizing the lipid structure of the microbial cell membrane and thereby increasing its permeabilitythe cell loses salt, potassium and sodium, other molecules ingress, and the cell is destroyed that way." BAK is a cationic surfactant quaternary ammonium detergent and works by breaking open cell membranes, lysing the cytoplasm, and destroying intracellular structures, Dr. de Luise explained. Other chemical preservatives include sorbate, which has been around for decades, and Polyquad, which is a newer and much gentler quaternary ammonium preservative. Polyquad is found in Tears Natural II (Alcon, Fort Worth, Texas) and in some contact lens solutions.

"Polyquad is less toxic to the corneal and conjunctival epithelium, which means it is friendlier to the surface of the eye," Dr. de Luise said. "Yet after studying and using these agents for three decades, it remains evident that all chemical preservatives have some degree of toxicity to the corneal and conjunctival epithelium."

Dr. de Luise views oxidative preservatives as newer science with the advantage of less ocular surface toxicity. Sodium perborate is one such oxidative preservative. It is sometimes nicknamed a "vanishing preservative" because the sodium perborate rapidly decomposes into hydrogen peroxide, which ultimately breaks down into salt and water. GenTeal (Novartis, Basel, Switzerland) is one artificial tear that contains sodium perborate, Dr. de Luise said.

Another oxidative preservative, known as stabilized oxychloro complex (SOC), has good antimicrobial activity and is more apt to kill fungi than some of the others, Dr. de Luise said. "It's safer than the chemical preservatives, even when dosed more than four times a day," he said. He cited bottled Refresh Tears (Allergan, Irvine, Calif.) as an example of an SOC-containing artificial tear. "I consider eye drops that contain oxidative preservatives several notches better than those with chemical preservatives, but they are still eye drops with preservatives," Dr. de Luise said. Meanwhile, anything on the store shelves that has the letters "PF" is preservative free and comes in single-dose vials.

Current recommendations

In Dr. de Luise's view, artificial tears with chemical preservatives are the most worrisome choices. Those with vanishing preservatives are much better, and the preferred strategy would be the use of preservative-free artificial tears.

When prescribing preservative-free tears, it is important to describe for patients exactly the type of packaging for which to look, he said. "Patients tend to get confused. They will end up buying the bottle if you don't tell them to look for the vial." To avoid confusion, many practices give patients sheets with photographs of the preservative-free artificial tear boxes that are recommended.

John D. Sheppard, MD, professor of ophthalmology, microbiology, and molecular biology, Eastern Virginia Medical School, Norfolk, Va., likewise views preservatives in tears as detrimental for dry eye patients. "Preservatives are fine for short-term use," Dr. Sheppard said. He pointed to antibiotic drops, which may be taken for a brief period, as a case where preservatives are not only non-problematic, but may provide a synergistic antimicrobial effect. But he stressed that in dry eye and glaucoma, use of chronic preservatives has a cumulative effect.

He doesn't recommend any tears with chemical preservatives, although he does sometimes suggest those with the vanishing alternative, which change their character from antimicrobial to benign tear electrolytes. "I don't see any reason when we have these good products on the market to use a tear with chemical preservatives in it," Dr. Sheppard said. For routine patients he relies on tears with vanishing preservatives. Even younger patients who would be more resistant to issues of surface damage are often at risk with preservatives since many wear contact lenses, which may prolong preservative contact time with the ocular surface. In addition to the eye being relatively hypoxic in such cases, the contact lens itself may compound the problem. "The tears and therefore the preservatives will become trapped underneath the contact lens and you've got a physiologically sustained release delivery situation," Dr. Sheppard said.

When it comes to more advanced dry eye cases, Dr. Sheppard advises patients to use completely preservative-free tears only. Christopher J. Rapuano, MD, chief of the cornea service, Wills Eye Hospital, Philadelphia, agreed that those with particularly compromised ocular surfaces should avoid preservatives. "The more compromised the ocular surface, whether it's damage from dry eye, blepharitis, chemical burns, or whatever, the less it tolerates preservatives," Dr. Rapuano said. Also, he said it's important to keep in mind the total amount of preservatives that get into the eye each day. If patients' eyes are pretty healthy and they're using drops just a few times a day, this is not a big problem, he observed. "But if their eyes are somewhat compromised and they're on tears three or four times a day it may become a problem," Dr. Rapuano said. "If their eyes are somewhat compromised and they're on tears 10 times a day, that is potentially a big problem." In addition, he said it's not just the amount of preserved tears to be concerned about but also factors such as preserved glaucoma medications, which are also taken chronically. "If they're on three glaucoma medications and each of those medications has a preservative in it, then you've got to add that to the amount of preservatives that they're getting with the tears," Dr. Rapuano said. He switches such patients to preservative-free tears and finds that their eyes often do much better.

"The downside of preservative-free tears is that they're more expensive and they're less convenient," he said. With this in mind, Dr. Rapuano tells patients when possible to use one vial for the entire day instead of throwing the vial away after one use. Meanwhile, not everyone thinks that the preservative-free approach is necessary. Robert A. Latkany, MD, associate professor, New York Eye and Ear Infirmary, New York, views these as essentially hype. "For the last decade or so, there has been a lot of talk on artificial tears, and I am now fairly convinced that there is not a whole lot of merit to the claim that preservatives are damaging to the surface of the eye," Dr. Latkany said. In his dry eye practice, he has had many patients who have had reactions to the preservative-free tears. Dr. Latkany thinks this may be some sort of allergic reaction. He has not, however, seen anyone who has had a reaction to the preservative itself. "How many people have I seen in the last 15 years who had what appeared to be a reaction to the preservative found in the artificial tear dropzero," he said. "It's a sensitive populationsensitive population patients have reactions to chemicals you put in their eyes. It doesn't necessarily mean it's the BAK."

It's very expensive to use preservative-free drops. "It could be hundreds of dollars a year for patients over the price of a preserved bottle," Dr. Latkany said. His goal is to get patients off of tears altogether. "I'll dig deep and try to find out where this inflammation is coming from," he said.

Dr. de Luise acknowledges the added expense but views the preservative-free option as necessary for all but the very mild dry eye patient. "There are no magic bulletsdry eye disease is a diagnosis that is often made in a patient's 30s or 40s that is chronic and may get worse as the patient gets older," he said. He urged practitioners to take the time and talk to patients about this. "Say, 'This is a lifetime disease, you're not going to go blind, but I recommend that you use single-dose drops as opposed to those with preservatives,'" Dr. de Luise said. "They'll spend a bit more but they'll be better served by medicines and drops that are more soothing to the surface."

Editors' note: Dr. de Luise has no financial interests related to this article. Dr. Latkany has no financial interests related to this article. Dr. Sheppard has financial interests with AbbVie (North Chicago), Alcon, Allergan, Bausch + Lomb (Rochester, N.Y.), TearScience (Morrisville, N.C.), TearLab (San Diego), and Nicox (Sophia Antipolis, France). Dr. Rapuano has financial interests with Allergan, Bausch + Lomb, BioTissue (Doral, Fla.), Nicox, TearLab, and TearScience.

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