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Ocular Allergy Treatment

Probably the greatest challenge in treating patients with ocular itching is separating dry eyes (which can have a mild itchy component) from allergy (which can occasionally present with some burning). The differential diagnosis becomes rather clear in most all cases when the clinical findings are reflected against the subjective complaints. A sizable minority of patients have mild itching as an expression of opportunistic allergy resulting from primary precorneal tear film dysfunction, commonly called dry eyes. For these patients, simply addressing their dry eyes will eliminate secondary allergy expression. Always bear in mind that dysfunctions of the precorneal tear film represent the most common treatable eye condition in North America.

There are only two noteworthy allergy updates since last year. Allergan has reformulated Acular 0.5% (ketorolac tromethamine) and now offers a more patient-friendly 0.4% solution, marketed as Acular LS. Allergan has also thrown its hat into the ring of the already crowded “antihistamine-mast cell stabilizer” market with Elestat (epinastine HCl 0.05%) ophthalmic solution. These drugs are discussed in more detail later in this chapter.

Managing patients with symptomatic, seasonal allergic conjunctivitis is a routine part of optometric practice. Following is a practical/clinical look at this class of drugs.

Allergy Pathophysiology
Most all of the allergy drugs work well in managing seasonal allergic conjunctivitis. More and more, it comes down to determining which is the least expensive medicine, since there can be up to a $25-per-bottle difference among these medications.

Conventional wisdom holds that if it itches, it’s allergy. As simple as it sounds, this truth is borne out in clinical reality. However, it remains highly virtuous to attempt to discover the inciting cause, or circumstances that lead to allergy expression. Furthermore, are the patient’s complaints of itching primary, or secondary to precorneal tear film dysfunction? Keep in mind, a poorly functioning tear film can set the stage for allergy expression by failing to properly dilute and wash away environmental allergens.

Since dry eye syndrome is the most common eye disease, it often plays a complicating adjunctive role in many, if not most all, ocular surface maladies. The acknowledgement of this clinical reality comes center stage when the patient presents with a chief complaint of “itching and burning.” With this history, the astute clinician must perform a decisive slit lamp examination. The issue at hand is, “Does this patient have mainly dry eyes (burning) with secondary allergic (itching) expression, or perhaps a somewhat equal affliction of both?”

Whichever the case, it is the good doctor who makes an exquisite diagnosis prior to determining a management plan. Many, if not most all, of these mixed histories (i.e., itching/burning) are opportunist expression of dry eyes. Appropriately frequent instillation of a premium quality artificial tear will make most of these patients asymptomatic.

Now, let’s move into absolute allergy—the patient with itchy eyes. It is well known that allergic conjunctivitis can present as an isolated clinical entity, or as a component of allergic rhinitis and/or allergic sinusitis. The patient’s history can fairly easily paint the picture. Obviously, if the allergic expression is limited to the eye, management is clear cut. Extraocular tissue involvement may dictate the need for an intranasal corticosteroid spray, or a systemic antihistamine in addition to the eye drop therapy.

A quick look at pathophysiology shows the mast cells to be the cellular machinery that makes allergy happen. Initial exposure to an allergen sensitizes mast cell membranes via immunoglobin E (IgE). Subsequent exposure to this allergen causes these mast cell-affixed IgE molecules to react so as to cause destabilization and degranulation of the mast cells. Mast cells contain thousands of microvacuoles which contain many chemical mediators of allergy, most notably histamine. These chemical mediators in turn react with other cell membrane receptors, which result in clinical disease. Histamine stimulates both type 1 and type 2 receptors; the first subserves itch and partial vasodilation, the latter only vasodilation. Antihistamine medicines block the histamine type 1 receptors, stopping itch more so than vasodilation. Type 2 receptor blockers, such as ranitidine (Zantac) and cimetidine (Tagamet), are not used in combating allergy since blocking the H1 receptors seems to sufficiently quell the allergic cascade in the eye.

It should be evident that if mast cell membranes can be prevented from degranulating, itch would not occur. This is indeed clinical reality. However, the problem is, when the patient in your examination room is complaining of itching, the horse is already out of the barn—mast cells have degranulated. Such acute itching must be treated with an appropriate acute care drug, such as an antihistamine, antihistamine/mast cell stabilizer or steroid. The duration of such therapy depends upon the unique circumstances of each patient presentation. For example, is this a first time event, or a chronic, recurrent problem? Is the causative agent known? How intense are the symptoms? Is the allergic expression localized to the eye/eyelids, or is there concurrent sinusitis and/or rhinitis? If the allergy expression is localized to the eye and is a new occurrence of mild to moderate severity, then any antihistamine or antihistamine/mast cell stabilizing drug, or topical steroid would be an excellent choice. If the itching is more severe, we would choose a steroid, such as Alrex or Lotemax, and instruct the patient on the proper use of cold compresses. If there is also non-ocular allergic expression, we would consider prescribing an oral antihistamine, such as Claritin or Zyrtec.

If the patient tells us this episode of itching is a flare-up of long term, chronic, recurrent allergic disease, employ the above-mentioned acute therapy for five to ten days, then prescribe one of the newer mast cell stabilizers, such as Alamast or Alocril, used for months at a time if the history dictates. All of these non-steroidal products are incredibly safe, so long-term use is no problem. We generally use Alrex or Lotemax up to a couple of months comfortably, but prefer a mast cell stabilizer for protracted therapy.

You might ask, “Why not use an antihistamine mast cell stabilizing drug instead of a pure mast cell stabilizer for long term care?” This would likely do fine, but think about it—if the mast cells are being pharmacologically stabilized, is there a need for an antihistamine? The logic follows that it would have little or no clinical role. Furthermore, it is our clinical judgment that a pure mast cell stabilizer is more effective at stabilizing mast cell membranes than antihistamine drugs that have some mast cell stabilizing properties.

One final note about itch: Keep in mind the less common causes of allergy, such as atopic and vernal disease. These are more severe and long term afflictions that must be treated with a balance of potent steroids and mast cell stabilizers. Numerous, excellent reference texts detail the management of these uncommon conditions.

Let’s look at the different classes of allergy drugs, as well as each individual product, according to two main categories: acute and chronic.

Acute Care Drugs

First, discourage patients from using OTC anti-allergy drugs, the kind that include vasoconstrictors. At least one study has found that vasoconstrictors, alone or combined with antihistamines, can cause acute and chronic inflammatory conjunctivitis, which usually takes several weeks to resolve upon discontinuation of the drug.1 The authors state, “although previous experience suggests that vasoconstrictors never or rarely incite conjunctival hyperemia, the 50 cases in this series clearly demonstrate that ophthalmic decongestants containing phenylephrine, naphazoline, or tetrahydrozoline can cause rebound dilation of conjunctival vessels.”

A careful history in patients with chronic conjunctivitis has often revealed the etiology of the problem in the long term use of these products containing vasoconstrictors. Furthermore, it has long been known that topical ophthalmic antihistamines themselves can, paradoxically, cause allergic reactions and ocular irritation. Thus, encouraging patients, either passively or actively, to use OTC anti-allergy preparations may not be in their best interest since they may continue to self-medicate for a long time. We much prefer to write a prescription for a drug in which we have scientific and clinical knowledge of effectiveness and for which we, not the patient, have control over drug exposure duration.

There are eight products that nicely meet the clinical challenge of acute allergic suppression:

• Acular LS (ketorolac tromethamine 0.4%, Allergan)
  
• Alrex (loteprednol etabonate 0.2%, Bausch & Lomb)
  
• Elestat (epinastine hydrochloride 0.05%, Allergan)
  
• Emadine (emedastine difumarate 0.05%, Alcon)
  
• Livostin (levocabastine 0.05%, Novartis Ophthalmics)
  
• Optivar (azelastine hydrochloride 0.05%, Bausch & Lomb)
  
• Patanol (olopatadine hydrochloride 0.1% and 0.2%, Alcon)
  
• Zaditor (ketotifen fumarate 0.025%, Novartis Ophthalmics)

Acular LS (ketorolac tromethamine) is a recently-improved formulation of the original Acular. Ketorolac is a non-steroidal anti-inflammatory drug which raises the sensory threshold of peripheral nerve endings such that the sensation of itch is abated. The package insert states Acular LS, “is indicated for the reduction of ocular pain and burning/stinging following corneal refractive surgery.” It is interesting that the package insert for Acular states it is indicated for “ocular itch due to seasonal allergic conjunctivitis, post-op inflammation after cataract extraction.” The truth is, both of these formulations perform exactly the same, only the LS formulation has little or no sting upon instillation, making it a much more patient-friendly drug.

Acular LS is generally used four times daily for a week or two, then two to three times daily thereafter as needed for itching. Symptomatic relief is usually achieved in an hour or so. Ketorolac tromethamine is also available in a preservative-free, unit-dose system, which is mainly used in post-operative refractive surgery management. Unit-dose delivery systems are always more expensive, so it would be the exceedingly rare patient who would merit this preservative-free formulation for allergy therapy.

Alrex (loteprednol etabonate 0.2%) ophthalmic suspension is approved for the treatment of ocular allergy. Its more potent partner, Lotemax (loteprednol etabonate 0.5%), is approved to treat more advanced ocular and postoperative inflammatory conditions. (A comprehensive discussion of loteprednol etabonate is found in the corticosteroid section.)

Other than HMS (Allergan), which was marketed many years ago, Alrex is the first topical corticosteroid to be FDA-approved for the treatment of ocular allergy. Because of the uniqueness of this “site-specific” steroid, the active drug resides at the target tissue long enough to render a therapeutic effect, but rarely long enough to cause secondary rises in IOP and, presumably, posterior subcapsular cataracts. A review of the literature shows this to be a safe and effective therapy for allergic conjunctivitis. It is to be used four times a day as needed to control itching.

Alrex, a corticosteroid, has the unique advantage of being able to suppress the entire inflammatory cascade which addresses all the signs and symptoms of the allergic response. Conjunctival vascular involvement in allergic eye disease can range from subclinical to marked. While Alrex can be used in all cases of allergic conjunctivitis, it is particularly effective when there is considerable conjunctival inflammation. As a suspension, it needs to be shaken prior to instillation.

Emadine (emedastine difumarate 0.05%) ophthalmic solution is virtually identical to levocabastine. Emadine is a topical antihistamine approved for temporary relief of the signs and symptoms of allergic conjunctivitis. It is to be used four times a day as needed and, like all antihistamines, is safe and effective.

Livostin (levocabastine 0.05%), a potent histamine type 1 (H1) receptor blocker, has gained great popularity and is an effective suppressor of itching. As a topical antihistamine, it competes with histamine for the H1 receptor binding site. If these H1 receptors are preemptively bound by an antihistamine, then histamine is denied the opportunity to produce or propagate allergic expression. It is generally prescribed just like emedastine: q.i.d. for a week or two, then one to three times per day thereafter as needed for itching. Since it is a suspension, shaking is required.

Patanol (olopatadine hydrochloride) is a topical antihistamine with some mast cell stabilizing properties. It is available in two concentrations; 0.1% for b.i.d. use, and 0.2% for once-daily use. Notice how increased concentration tends to prolong the pharmacologic effect. Of practical note, we have observed that many patients using any of these wonderful antihistamine/mast cell stabilizers can remain comfortable using them once daily after a week or two of b.i.d. use. Currently, however, Patanol 0.2% is the only antihistamine/mast cell stabilizer FDA-approved for once-daily use.

Highly successful drugs in the ophthalmic market rarely remain without competition. Patanol’s awesome dominance of the allergy market caught the attention of Novartis Ophthalmics, Bausch & Lomb and Allergan. They have developed three excellent products which stand side by side with Patanol. Novartis Ophthalmics brought Zaditor (ketotifen fumarate 0.025%) ophthalmic solution to market in 1999, Bausch & Lomb launched Optivar (azelastine hydrochloride 0.05%) ophthalmic solution in 2000, and Allergan received approval to market Elestat (epinastine hydrochloride 0.05%) ophthalmic solution in 2004. Like Patanol, they are all antihistamine/mast cell stabilizing medicines, which are highly effective at b.i.d. dosing, and are approved for use in pediatric and adult patients. While each of these four products are touted to have small advantages over their competitors, the main difference we have discovered is the cost of these drugs. Check with pharmacies in your community to get a feel for drug costs. Interestingly, Optivar comes in a 3ml and 6ml bottle sizes. Since these four drugs are all used b.i.d., they pretty much eclipse Acular LS, Livostin, Emadine, the cromolyn sodiums, and Alomide, since these are generally prescribed for use q.i.d.

It is well known that contact lens wearers are disproportionately bothered by allergy. This begs the question of safety and efficacy of using Patanol, Zaditor, Optivar or Elestat with contact lenses. No problem. Just to be conservative, have the patient instill the morning drop a few minutes prior to insertion; the afternoon drop can go right on top of the contact lens.

To quell hyperacute allergic reactions, use potent topical corticosteroids (Lotemax, Inflamase Forte, Vexol, fluorometholone acetate 0.1%, or prednisolone acetate 1%) every hour or two for a day or two. In these more marked expressions, cold compresses can be immensely helpful in restoring calm.

Once you’ve neutralized the marked inflammatory response using one of the potent corticosteroids, then, if indicated, switch to an appropriate anti-allergy medication to continue to suppress any chronic expression of disease.

Chronic Care Drugs
Chronic allergic eye disease is the less prevalent subset of allergy expression. This category of drugs is exclusively represented by agents that can stabilize mast cell membranes. Keep in mind, however, that all of these medicines can give some degree of acute symptomatic relief by virtue of their dilution and washing away of allergens resident in the precorneal tear film.

Since mast cell stabilizing drugs have little or no direct anti-histaminic nor anti-inflammatory properties, they are poorly suited to address acute allergic disease. However, these are excellent drugs for long-term preventive and maintenance therapy. They are well suited for multiple-week therapy for patients afflicted with allergies at known times (e.g., “every March and April”) or when anticipating exposure to known allergens (visiting a home with cats).

Mast cell stabilizers, when used appropriately, can virtually eliminate the outbreak of allergic reactions. These drugs work by inhibiting the degranulation of mast cells, preventing them from releasing histamine and other allergy mediators. They are completely safe medications that can be used for weeks or months without any significant side effects. Since they are preserved, there is a low risk of toxicity, especially in patients with compromised tear function.

All of these drugs are excellent and generally perform well. It should be noted that Alocril has a slight yellow color. This is the nature of the formulation and should be explained to patients so they won’t think it’s “gone bad.” Although Alocril is recommended as b.i.d. therapy, its identical counterpart in Canada suggests it can be increased to q.i.d. with advanced disease.

Stress to patients that mast cell stabilizers must be used regularly throughout their “at risk” season. They only perform properly when mast cell membranes remain stabilized. Giant papillary conjunctivitis (GPC) is routinely treated with a mast cell stabilizing agent. Such therapy is generally adjunctive to some of the following traditional therapeutic maneuvers: switching to disposable lenses; decreasing contact lens wearing time; enhancing daily lens hygiene; and using artificial tears with lens wear. When indicated in GPC, we prescribe a mast cell stabilizing drug q.i.d. for a month, then b.i.d. for a month or longer if indicated.

The question is always asked, “Can you use these drugs with soft contact lenses?” With disposable and GP lenses, no problem. These can be used with soft contact lenses replaced at least monthly, or GPs. Because of long-term potential toxicity from solution preservatives with conventional soft lenses, we try to limit use of topical ophthalmic medicines with annual replacement lenses. With yearly replaced conventional soft lenses, we have never had problems using these drugs as follows: one drop a few minutes before lens insertion, one drop at midday, and one drop in the evening after lens removal.

While there are other topical eye drops available to treat ocular allergy, we recommend one of the drugs discussed in this section. But, lastly, don’t forget the benefit of cold compresses for acute flare-ups, or oral adjunctive therapy (e.g. Claritin, steroid nasal sprays, etc.) when indicated.

In summary, there are now eight excellent acute care, and five excellent chronic care allergy products. They all work well when used properly by the patient.

Oral Antihistamines
While these drugs are less commonly used by eye doctors, there are times when oral therapy nicely augments topical therapy. These are for patients who most commonly have allergic conjunctivitis concurrently with allergic sinusitis and/or allergic rhinitis. They can occasionally be helpful in treating eyelid myokymia (lid twitch) should a topical antihistamine fail to break the orbicularis fasciculation.

There are two main categories of oral antihistamines: OTC and prescription. The two most common OTCs are diphenhydramine (e.g., Benadryl) and chlorpheniramine (e.g., Chlor-Trimeton).

Now that Claritin has gone OTC, almost all drug plans disallow prescription antihistamines unless the doctor feels (and requests in writing) that a specific brand is required for an individual patient. It may be that corticosteroid nasal sprays (of which there are several) give greater relief from allergic rhinitis without the many potential side effects of oral antihistamines.

There are also several prescription antihistamines which are minimally sedating although dryness-inducing. For safety and effectiveness, only four are recommended: Claritin (loratadine) 10mg q.d., Clarinex (desloratadine) 5mg q.d., Zyrtec (cetirizine) 5mg and 10mg, and Allegra (fexofenadine) 60mg b.i.d. or 180 mg q.d. n

1. Ciprandi G, Cosentino C, Milanese M, Tosca MA. Rapid anti-inflammatory action of azelastine eyedrops for ongoing allergic reactions. Ann Allergy Asthma Immunol 2003 Apr;90(4):434-8.

2. Abelson M. 2000 Year in Review: Pharmaceuticals—Anti-allergics. Rev Opthalmol 2000 Nov:7(11):57-58.

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