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A wide range of agents is available to fight allergens when patients cannot
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The ocular allergy realm is far reaching. It comprises several conditions ranging from the relatively benign, seasonal conjunctivitis to the more insidious vernal variety, from the difficult-to-treat atopic keratoconjunctivitis to the contact lens wearer's bane: giant papillary conjunctivitis.
Ocular allergy treatment spans a wide range, as well, from the simplicity of cold compresses, artificial tears and over-the-counter anti-inflammatories to the complexity of cyclo-oxygenase blockers and mast cell stabilizers.
The common denominator throughout is the itch. All of those accurately diagnosed with ocular allergy have it; and all effective therapies fight it.
"Classically, the hallmark of allergy-type conjunctivitis is itching, but many other situations, such as dry eye, blepharitis and other topical ocular surface diseases or lid diseases, can mimic various types of conjunctivitis, particularly the allergic-type of conjunctivitis," said Robert Ryan, OD, in private group practice in Rochester, N.Y.
Because of this, Dr. Ryan's initial treatment is always to evaluate the ocular surface and lids to make sure there is no underlying disease masquerading as an allergic-type problem. "When there is attending lid disease, the body's defenses against environmental-type allergies are reduced," he explained.
Tear film combats allergy
Some helpful components of normal tear film help combat infection and allergic-type responses. The tears themselves are very good at diluting allergens and flushing them away from the surface of the eye to reduce the amount of contact time. The lids act as a protective mechanism by both their shearing action and their mechanical protection, as well as by the cilia acting as filters to help keep debris out of the tear film.
Immunoglobulins are also present in normal tears, and these can be mediators of the allergic-type response. A person with a normal, plush tear film with all of its components intact and working well is better able to defend against allergy insult. A person with a compromised tear film is more susceptible to environmental factors.
"My treatment is always to make sure that the normal homeostasis is in line and to ensure that the lids, glands and tear film are functioning adequately," Dr. Ryan said. "Then, if we can get to that baseline and the symptoms persist, it is clear we need to move along to a therapeutic regimen."
Synergistic agents
Ocular allergy is ubiquitous. Between 5% and 10% of the population will experience at least a single episode. In response, new and improved products that fight redness, block burning and reduce wateriness are making their way into the marketplace at a rapid clip. Meanwhile, optometrists are prescribing or recommending prescription or over-the-counter antihistamines — the strongest itch medicine — alone or in combination with anti-inflammatories, mast cell stabilizers and decongestants.
According to Jimmy D. Bartlett, OD, professor of optometry in the School of Optometry and professor of pharmacology in the Department of Pharmacology at the University of Alabama School of Medicine, "All of these drugs can be used either alone or in combination. You just need to titrate what the patient needs and try to treat for the shortest amount of time possible."
"We used to think that we should use one agent or the other, because they all work on different parts of the pathway," said Mark Abelson, MD. It turns out, however, that the agents are not mutually exclusive.
"You can expect to have synergy by using more than one medication," said Dr. Abelson, a clinical senior scientist at Schepens Eye Research Institute in Boston. "We are starting to gain some experience using different combinations of these agents, and I think for the more-than-really-simple allergies we will probably be doing add-on therapy for some time to come."
Different degrees of treatment
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Dr. Bartlett compares the levels of ocular allergy treatment to the rungs on a ladder. "Think of the therapy as a step ladder whereby the lower rungs of the ladder are very simple, easy, safe steps," he said. "Then, as you go up higher, you get to more sophisticated levels and are dealing with agents that have a little more danger associated with them in terms of side effect potential."
Decongestants and artificial tears represent the lower end of the rungs. According to Dr. Bartlett, the greatest risk associated with decongestants is rebound hyperemia. "With long-term or repeated use of decongestants, your eye can actually end up redder than it was initially," Dr. Bartlett said.
Because of the possibility of rebound hyperemia, he said, most practitioners today typically do not recommend decongestants. "Decongestants are useful for mild cases where a patient is sporadically irritated by occasional itching and there's no cosmetic problem involved," Dr. Bartlett said. "For occasional redness, we typically use artificial tears, because the artificial tear is even safer than a decongestant and can wash out the pollen or antigen that is stimulating the problem. This makes the patient feel better without the risk of rebound hyperemia."
Second rung: antihistamines
Antihistamines are one rung up from decongestants. Dr. Bartlett said many of the antihistamines that are now available over the counter such as Naphcon-A (pheniramine maleate 0.3%, naphazoline HCl 0.025%, Alcon), Opcon-A (pheniramine maleate 0.315%, naphazoline HCl 0.027%, Bausch & Lomb), and Vasocon-A (naphazoline HCl 0.05%, antazoline phosphate 0.5%, Ciba Vision) remain very popular. "They are excellent products, and we still like to recommend them because they are very inexpensive and cost-effective. We recommend an over-the-counter antihistamine for patients on whom we have tried an artificial tear and it is just not providing enough relief," he said.
Dr. Bartlett prescribes Livostin (levocabastine HCl 0.05%, Ciba Vision) for "patients who have a little more significant involvement: the eyes are really red, the patient is very uncomfortable and itching, and it is really debilitating."
Two functions of topicals
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Topical antihistamines offer a "double whammy," Dr. Bartlett said, because they provide relief by both inhibiting the H1 receptor and diluting the antigen. "Topical delivery of these drugs is usually very effective, but we also have the option of prescribing an oral antihistamine," he said.
Dr. Bartlett said he usually reserves oral delivery for patients who have angioneurotic edema. "In patients who have a lot of swelling around the eyes, it's the best way to get the drug inside the eyelids. If you get the drug deep within the lid tissue, it can resolve the swelling faster," he said.
Using orals does not preclude the use of topicals, Dr. Bartlett stressed. "If you use both, you have both routes of administration working for you." Dr. Bartlett does not generally recommend oral antihistamine treatment for chronic ocular conditions because of the increased toxicity potential.
The future: single dose
Single-dose, nonsedating antihistamines are where the short-term future of ocular allergy treatment lies, according to Dr. Bartlett. "The trend is toward a drug that the patient can take once a day without experiencing any drowsiness, dizziness or sedation," he added. Allegra (fexofenadine, Hoechst Marion Roussel), a derivative of terfenadine, is a nonsedating antihistamine new to the marketplace last year. Unlike Seldane (terfenadine, Marion Merrell Dow), Allegra is safe to use for patients taking erythromycin or antifungal medications.
Hismanal (astemizole, Janssen Pharmaceutica) and Seldane may interact with erythromycin and cause potentially fatal heart arrhythmias, Dr. Bartlett warned. Claritin (loratadine, Schering), another nonsedating antihistamine, is safe in these patients, as well. Claritin was recently made available in a syrup form for children or patients unable to swallow pills.
Another nonsedating antihistamine called Zyrtec (cetirizine, Pfizer) became available last year. Studies of the once-a-day drug comparing it to Seldane suggest that Zyrtec may work a bit faster, said Dr. Bartlett.
Role of mast cell stabilizers
Mast cell stabilizers represent one of the higher rungs on the ladder of ocular allergy treatments. "Mast cell stabilizers are commonly used and are very effective, particularly for chronic use," Dr. Bartlett said.
Crolom (cromolyn sodium), the first ophthalmic mast cell stabilizer, is now made by Bausch and Lomb. Alcon makes Alomide (lodoxamide tromethamine), another mast cell stabilizer.
"It is very important to remember that both of those drugs are Food and Drug Administration approved only for vernal conjunctivitis. They are not approved for routine, seasonal allergic conjunctivitis," said Dr. Bartlett. "They have been shown to be effective for that in clinical studies, but they have yet to be approved for that."
Dr. Bartlett, as well as others interviewed for this article, said off-label use of Crolom and Alomide for seasonal allergic conjunctivitis is common. "There is enough anecdotal information, as well as a few clinical studies, to support the safety of that use," Dr. Bartlett said.
The most recent ocular allergy pharmaceutical to gain Food and Drug Administration market approval is Alcon's Patanol (olopatadine HCl ophthalmic solution 0.1%). Patanol has both histamine blocking and mast cell stabilizing properties. It is the first dual-action product in the marketplace indicated for ocular allergy, and it is the first ocular allergy agent with twice-daily dosing.
Dr. Abelson said Patanol is a real step forward in that "we are finding drugs that are working for longer periods of time."
A water-soluble solution, the agent has a rapid onset of action — from 15 to 30 minutes — and maintains an 8-hour duration of action.
The top rung
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The steroidal anti-inflammatory drugs represent the last rung on the ladder and the last resort for treatment, according to Siret D. Jaanus, PhD, chair of biological science at the State University of New York College of Optometry. "Steroids are not the drug of first choice because of the potential side effects, but sometimes you have no choice, such as when you have severe allergic conjunctivitis, vernal conjunctivitis or giant papillary conjunctivitis where you have severe cellular hypertrophy."
Dr. Jaanus pointed out that the problem with nonsteroidal anti-inflammatory drugs (NSAIDs) is that studies indicate several different allergic mediators are involved in conjunctivitis. "Both the cyclo-oxygenase pathways and the lipoxygenase pathways are involved," Dr. Jaanus said. "The NSAIDs act against the prostaglandins but do not act against the lipoxygenase mediators. Some of the studies have shown that if you use an NSAID you are actually making the other pathway worse by inducing the formation of more lipoxygenase mediators, that is, leukotrienes."
According to Dr. Jaanus, the strength of steroids over NSAIDs is that steroids inhibit both pathways.
Contact lens concerns
Dr. Ryan said optometrists need to make sure contact lens wear is doing as little as possible to contribute to ocular allergy findings. "Soiled lenses are more likely to bind allergens, keeping them in contact with the surface of the eye longer and, therefore, exacerbating the situation," he said. "So with patients who are prone to allergic-type response, we need to be concerned about clean, fresh materials including disposable lenses or rigid gas-permeable lenses.
"We also need to be cautious with regard to topical agents that we use in conjunction with soft contact lenses," Dr. Ryan continued, "and particularly those using benzalkonium chloride (BAK), because BAK has been shown to bind to the soft lens matrix. It can stay in contact with the ocular surface longer and cause more hypersensitivity."
The other concern with contact lens patients is a greater susceptibility for giant papillary conjunctivitis. "It is a fairly common condition in soft contact lens wearers, whereby the tarsal conjunctiva develops an allergic, mediated reaction to a soiled contact lens or the allergens that are adhered to that lens," Dr. Ryan continued. "If the patient has a real problem with this, he or she should be wearing rigid gas-permeable lenses."
Future directions
Several sources interviewed for this article believe the future of ocular allergy treatment lies in prevention via mast cell stabilizers; others believe that is just the beginning.
Dr. Abelson foresees continued work on blocking receptors more efficiently and stabilizing the mast cell more vigorously. "The problem is that there is nothing significantly intrinsic that we're aware of, to date, in the mast cell that we've been able to exploit toward differentiating it from other cells so that we can stabilize the mast cell and not stabilize other cells that are needed to protect us," he said.
According to Dr. Abelson, the future of allergy treatment lies beyond prophylactic therapy. "That could mean de sensitizing individuals so they don't respond to allergens," he explained.
Another avenue for exploration with regard to ocular allergy is gene manipulation. "Some of our work that intrigues me the most is finding that people who tend to be the most allergic in terms of ocular disease tend to have histaminase deficiencies," Abelson continued. "This histaminase deficiency suggests that gene therapy is the next step, and that's something that we're currently examining."
The study is funded by a private foundation grant.
Dr. Abelson also pointed to the lipoxygenase blockers as a hot ticket toward allergy relief. "Keep your eyes open for agents that are now in the pipeline that stop neutrophils specifically from coming in without affecting any other parts of the immune system," he said. "They play a good role in antibiotic combinations for bacterial conjunctivitis, for treating corneal ulcers and for modulating conditions such as marginal infiltrates."
Mitchell H. Friedlaender, MD, sees ocular allergy treatment research as becoming far more targeted than it has been previously. "There are efforts to develop products that interfere with specific mediators and are much more targeted at the receptors on cells for those mediators. An example would be levocabastine, which targets the H1 histamine receptor, and emedastine difumarate (Alcon's as-yet-unapproved antihistamine), which also targets the H1 receptor. There is also interest in platelet-activating factor antagonists (PAFs) — allergy drugs that interfere with PAF — a potent mediator of allergy," Dr. Friedlaender said.
For Your Information:
- Robert Ryan, OD, can be contacted at 1972 S. Clinton Ave., Rochester, NY 14618; (716) 271-2990; fax: (716) 244-3416. Dr. Ryan has no financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Jimmy D. Bartlett, OD, can be reached at the University of Alabama at Birmingham School of Optometry, Birmingham, AL 35294; (205) 934-3036; fax: (205) 934-6758. He has equity interest in Schering-Plough Corporation and is a paid consultant for Alcon.
- Mark Abelson, MD, is a clinical senior scientist at Schepens Eye Research Institute, Boston. He can be reached at fax: (617) 248-0366. He has no financial interest in any of the products in this article, nor is he a paid consultant for any companies mentioned.
- Siret D. Jaanus, PhD, can be reached at 100 East 24th St., New York, NY 10010; (212) 780-4900; fax: (212) 780-5174. Dr. Jaanus has no financial interest in any of the products mentioned in this article, nor is she a paid consultant for any companies mentioned.
- Mitchell Friedlaender, MD, has no financial interest in any of the products mentioned in this article, nor is he a paid consultant for any companies mentioned.