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Itching to Find a Solution: The Community Pharmacist’s Role in Ocular Allergy Treatment (Monograph)

INTRODUCTION

The conjunctiva is a thin, transparent mucous membrane that covers the outer surface of the eye and lines the inside surface of eyelids.¹ The conjunctiva is comprised of two key surfaces, a clear epithelium and substantia propria. The substantia propria is a highly vascularized area and noted to be the site for a significant amount of immunologic activity (FIGURE 1).^1,2 Conjunctivitis, specifically, is the inflammation of the conjunctiva.^1,2

Conjunctivitis is typically classified as infectious (bacterial or viral) or noninfectious (allergic, mechanic/irritative/toxic, immune-mediated, or neoplastic).^3,4 The most commonly reported or managed forms of conjunctivitis are listed in TABLE 1; however, the list is not fully inclusive.

TYPES OF ALLERGIC CONJUNCTIVITIS

While all types of conjunctivitis vary in their prevalence in different patient populations, forms of allergic conjunctivitis (AC) are commonly encountered in the outpatient setting.^3,5

AC is classified as a form of conjunctivitis that is caused when allergens directly contact the eye and trigger immunologic activity.^3,5 Ultimately, local mast cells degranulate and cause the significant release of various immune mediators (eg, histamine, platelet-activating factor).¹ In the United States (US), over 20% of the population experiences symptoms of AC on an annual basis. In addition, 15% to 40% of the population have reported experiencing AC-related symptoms at least once in their lifetime.⁵ The most commonly reported forms of AC are acute seasonal and perennial allergic conjunctivitis. Seasonal allergic conjunctivitis (SAC) corresponds primarily with outdoor allergens during airborne pollen seasons. For example, many patients report symptoms associated with SAC after being near tree pollens during the spring. Perennial allergic conjunctivitis (PAC) corresponds primarily with environmental exposure to indoor allergens. Many patients report symptoms associated with PAC after being near dust mites or animal dander.⁶ Most patients are unaware of AC being different than allergic rhinitis, which has resulted in many patients being under diagnosed and undertreated.⁷

Other relatively uncommon forms of allergic eye disease include vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).⁸

VKC is known as a chronic and severe form of conjunctivitis that occurs during the spring (ie, vernal) time of the year. The exact pathogenic mechanism for VKC is not fully understood; however, researchers suspect the role of T-helper 2 (Th2) and immunoglobulin E (IgE) cells in response to nonspecific stimuli, warmer climates during typical seasonal patterns, or when around perennial forms.⁸

Comparable to VKC, AKC is considered a perennial form of conjunctivitis that occurs in patients who have a history of atopic dermatitis. Researchers suspect that various cytokines and inflammatory cells are released into the conjunctival tissues in patients with AKC.⁸ AKC is considered to involve symptoms within the eyelid, cornea, and conjunctiva. While both of these forms of AC are uncommon, they can cause severe damage and vision loss if their initial symptoms are not appropriately managed.^1,3,4

CLINICAL PRESENTATION

The hallmark symptoms of most forms of conjunctivitis are bilateral ocular itching, redness, watery discharge, and physical discomfort. However, there are no universal sign or symptoms that can clearly differentiate all the various types of conjunctivitis. TABLE 2 lists common types of conjunctivitis and their general symptom presentations.^3,4

While common forms of conjunctivitis (eg, AC) rarely causes permanent visual loss, symptoms of conjunctivitis can significantly reduce quality of life, work productivity, and increase utilization of health care services.¹⁰

GUIDELINES

Pharmacists should consider following the 2018 American Academy of Ophthalmology Preferred Practice Pattern Recommendations³ or 2017 European Academy of Allergy and Clinical Immunology (EAACI) Guidelines on Allergen Immunotherapy: Allergic Rhinoconjunctivitis⁴ to help treat patients with symptoms of conjunctivitis—namely specific forms of AC.

NONPHARMACOLOGIC TREATMENTS FOR CONJUNCTIVITIS

Basic Eye Care

There are several nonpharmacologic interventions pharmacists can consider to ensure that patients are able to physically remove any causative agent (eg, allergen) immediately or treat the immediate conjunctivitis symptoms of inflammation or eyelid periorbital edema discomfort.^6,11 Patients should consider implementing the following basic eye care recommendations^{3,4, 6,11}:

• Avoid eye rubbing to prevent further mast cell degranulation
• Use cold compresses for at least 5 minutes as needed (PRN)
• Use ocular irrigation with refrigerated artificial tears PRN.

The efficacy of these interventions has been supported by the findings of Bilkhu et al.¹² In 2014, Bilkhu et al conducted a randomized, masked clinical trial of 18 patients to determine whether the use of artificial tears or cold compresses, alone or in combination, would provide a benefit. Patients were exposed to grass pollen for 5 minutes in a computer-controlled environmental chamber, then given artificial tears and/or cold compresses to help remove the synthetic allergens. Artificial tears were applied to the temporal conjunctiva of the eyes, and the cold compress was applied to the closed eyelids for 5 minutes after exposure to an allergen. Overall, researchers found that the combination of the cold compress and artificial tears significantly reduced hyperemia, lowered antigen-raised ocular surface temperature, and provided a cooling effect in patients.¹²

Ocular irrigation with refrigerated artificial tears or saline solution is also recommended to dilute or remove the triggering agent.^3,4 Refrigeration of the artificial tears or saline solution has been purported to improve comfort and improve physical awareness of drop instillation.¹³ In 1997, Fujishima et al conducted a preliminary study of 24 patients to evaluate the relationship between artificial tear temperature, ocular surface sensation, and patient comfort. Researchers placed artificial tears, which were stored at 4 temperatures (36°C, 25.2°C, 4°C, and -10°C), into the right eyes of the patients to evaluate corneal temperature and patient comfort. Overall, researchers found that artificial tears stored at 4°C (39.2°F) provided the most comfortable relief.¹³ The temperature at 4°C (39.2°F) would be considered refrigeration. The most commonly recommended over-the-counter (OTC) brand preparations of artificial tears, by pharmacists, include the following¹⁴:

• Refresh
• Systane
• Tears Naturale
• Visine
• GenTeal
• TheraTears
• Blink Tears
• Soothe
• Hypo Tears
• Advanced Eye Relief
• Clear Eyes Pure Relief.

Basic Allergen or Miscellaneous Trigger Avoidance

After implementing basic eye care recommendations, identifying consistent external triggers is a major step of managing most types of conjunctivitis.^3,4 By identifying external triggers, patients may use simple actions (listed below) to prevent contact with external vectors. Lifestyle interventions include wearing sunglasses, avoiding eye rubbing while hands are possibly exposed to allergen, purchasing hypoallergenic bedding, bathing or showering before bedtime, and washing clothes and sheets on a weekly to monthly basis.

Patients who experience specific forms of AC (eg, SAC or PAC), may consider following the additional lifestyle interventions described below^3,4,11:

To Limit Exposure to Pollen and Outdoor Molds

• Use mobile apps and internet websites to monitor pollen levels and plan outdoor activities accordingly
• Close windows and use air conditioning while driving a vehicle
• Stay home/indoors.

To Limit Exposure to House Dust Mites

• Dust and vacuum the entire home on a weekly basis, especially areas that typically gather dust
• Substitute materials that have a higher risk of trapping allergens (eg, rugs/carpets) for materials that have a lower risk (eg, wood flooring)
• Use a dehumidifier to reduce humidity within the home
• Use protective covers for all mattresses, pillows, duvets, and chairs.

To Limit Exposure to Animal Dander

• Limit animal contact by recommending that all pets stay out of bedrooms
• Avoid rubbing the nose or eyes following contact with an animal.

PHARMACOLOGIC TREATMENTS FOR CONJUNCTIVITIS

Pharmacologic treatment is recommended to be directed at the specific cause of conjunctivitis versus indiscriminate use of topical antibiotics or corticosteroids.^3,4 However, various forms of conjunctivitis can be treated with topical antihistamines with mast cell stabilizer activity, first-generation antihistamine/vasoconstrictor agents, mast cell stabilizers, topical glucocorticoids, and topical calcineurin inhibitors. Oral antihistamines are recommended in patients who experience systemic symptoms (ie, nonocular) with conjunctivitis.^3,4,6

Antihistamine With Mast Cell Stabilizer Activity

Antihistamines with mast cell stabilizing properties or “dual-acting agents” are recommended for first-line therapy for the intermittent or chronic treatment of SAC, PAC, VKC, and AKC.^3,4,6 Dual-acting agents are preferred since they provide better and quicker symptom control when compared to mast cell stabilizers alone.^3,4,6 Their antihistamine component reversibly inhibits histamine receptors, which provides temporary relief of ocular pruritus, redness, and congestion. These specific antihistamines also have mast cell stabilizer activity in which they inhibit mast cell degranulation and leukocyte activity. The mast cell inhibition results in the significant limitation of the release of histamine, tryptase, and prostaglandin D2 (PGD2). In addition, by limiting leukocyte activity, these antihistamines are able to limit the mediator release from basophils, eosinophils, and neutrophils.¹⁵

The efficacy of antihistamines with mast cell stabilizing properties has been supported by several systematic reviews in patients with AC.^16-18 In 3 systematic reviews of 34 randomized controlled trials, antihistamines with mast cell stabilizing properties (eg, olopatadine and alcaftadine) were both seen as safe and effective in significantly improving symptoms of ocular itching and redness in 4330 patients with AC. However, alcaftadine was seen as slightly superior to olopatadine.^16-18

In another systematic review of 40 randomized controlled trials of 4344 patients with SAC/PAC, researchers evaluated the effects of using topical antihistamines and mast cell stabilizers, alone or in combination.¹⁹ The most prominent topical antihistamines that were evaluated included olopatadine, ketotifen, azelastine, emedastine, levocabastine, and bepotastine. Researchers found that all of the previously listed agents significantly reduced signs and symptoms of SAC/PAC within 24 to 72 hours; however, olopatadine was seen as being superior to ketotifen.¹⁹

Pharmacists should consider recommending olopatadine or ketotifen first-line agents due to their availability as OTCs. However, other available antihistamines (eg, alcaftadine, azelastine, bepotastine) would be appropriate prescription alternatives. While no systematic review data were found addressing the use of these antihistamines in patients with VKC, AKC, or contact blepharoconjunctivitis (CBC), pharmacists can still consider using them to manage the symptoms of itching and other key signs and symptoms in such patient groups.^3,4,15

These antihistamines do not have any specific contraindications. While systemic side effects are quite rare, patients should be advised to discontinue the agent if the patient experiences ocular pain or irritation or if symptoms worsen or persist after 72 hours.¹⁵ Like most ocular medications, the most common adverse effects are burning and stinging upon administration.¹⁵

The specific dosing for the antihistamines with mast cell stabilizing properties are listed in TABLE 3.^6,15 Guidelines suggest that patients may use these agents on a daily basis for up to 6 weeks.^3,4 Olopatadine and alcaftadine are dosed once daily, which may improve adherence in most patients.¹⁵

Topical Antihistamine/Vasoconstrictor Combination Agents

Current guidelines recommend the combination of antihistamines and vasoconstrictors as alternatives to antihistamines with mast cell stabilizing properties for SAC.^3,4 However, antihistamines and vasoconstrictors are recommended to be used in combination with mast cell stabilizers as alternatives to antihistamines with mast cell stabilizing activity for PAC, VKC, and AKC.⁴ The antihistamine component works in conjunction with the vasoconstrictor. The vasoconstrictor/decongestant component acts as an agonist to postjunctional, alpha-adrenergic receptors, therefore causing vasoconstriction, which improves ocular inflammation and redness.^3,15

The efficacy of antihistamine/vasoconstrictor combinations has been supported by a single clinical trial in patients with SAC/PAC. In a single multicenter, clinical trial, topical antihistamine/vasoconstrictor agents were shown to be comparable to antihistamines with mast cell stabilizer activity in reducing symptoms of SAC/PAC.²⁰ However, the antihistamine/vasoconstrictor combination demonstrated a significantly faster onset of action (ie, within 30 minutes). No specific antihistamine/vasoconstrictor combination has been shown to be superior when compared to each other; however, the use of naphazoline/antazoline has been associated with a poorer tolerability,² suggesting naphazoline/pheniramine being the preferred combination agent to use in patients with SAC/PAC.

Pharmacists should consider recommending the naphazoline/pheniramine combination due to its availability as an OTC agent within the US. Naphazoline/pheniramine does not have any listed contraindications; however, use is limited by rebound conjunctival hyperemia after 7 days of use.^1,2,10 In addition, while systemic side effects are quite rare, patients should be advised to discontinue the agent if the patient experiences ocular pain or irritation or if symptoms worsen or persist after 72 hours.¹⁵ The most common adverse effects are burning and stinging upon administration.¹⁵

The specific dosing recommendation for the antihistamine/vasoconstrictor combination is listed in TABLE 4. Guidelines suggest that patients may use this medication can be used up to 4 times per day for up to 7 to 14 days consistently or they may be used for episodes of SAC/PAC, VKC, and AKC.^3,4,6,15

While no systematic review data were found addressing the use of antihistamine/vasoconstrictor agents in patients with VKC, AKC, or CBC, pharmacists can still consider using them to quickly manage the symptoms of itching and other key signs and symptoms in combination with mast cell stabilizers.^3,4

Mast Cell Stabilizers

Mast cell stabilizers are not commonly recommended for acute symptoms of conjunctivitis due to their slow onset of action, inconvenient dosing, and lack of direct antihistamine or vasoconstrictor activity.^3,4 Mast cell stabilizers inhibit mast cell degranulation and leukocyte activity, therefore limiting mediator release.¹⁵ Mast cell stabilizers have been seen as safe and effective for frequently recurrent or persistent SAC/PAC, VKC, and AKC when used in combination first-generation antihistamines/vasoconstrictors.

The efficacy of mast cell stabilizers for SAC has been supported by a systematic review. In 2004, Owen et al conducted a systematic review of 40 randomized control trials in 790 patients and a meta-analysis of 6 trials to assess the effectiveness of topical treatments for the management of SAC.²¹ Overall, researchers found that the use of topical mast cell stabilizers (lodoxamide, nedocromil, sodium cromoglycate) were 4.9 times more likely to perceive a benefit in improving symptoms of SAC versus those taking placebo (95% CI, 2.5-9.6). In addition, a US-available mast cell stabilizer (nedocromil) was specifically shown to improve the odds of patients reporting that their allergies were moderately or totally controlled by 1.8 times when compared to placebo in a meta-analysis of 5 trials (95% CI, 1.3-2.6).²¹ Therefore, pharmacists should consider recommending lodoxamide or nedocromil as an appropriate mast cell stabilizer for SAC/PAC in combination with first-generation antihistamine/vasoconstrictor preparations (ie, naphazoline/pheniramine).

The efficacy of mast cell stabilizers for VKC has been supported by a systematic review. In 2007, Mantelli et al conducted a systematic review of 27 randomized control trials in 1092 patients and a meta-analysis of 10 trials to assess the effectiveness of topical treatments for the management of VKC.²² Overall, researchers found that all researched agents (cromolyn, cyclosporine, flurbiprofen, lodoxamide, mitomycin, nedocromil, sodium cromoglycate, disodium cromoglycate, mipragoside) were effective in reducing the signs and symptoms of VKC. In addition, US-available mast cell stabilizers (cromolyn, lodoxamide, and nedocromil) were documented to significantly reduce the sign and symptoms of VKC in all of their respective randomized control trials (RCTs). Therefore, pharmacists should consider recommending cromolyn, lodoxamide, or nedocromil as appropriate mast cell stabilizers for VKC in combination with first-generation antihistamine/vasoconstrictor preparations (ie, naphazoline/pheniramine).

The efficacy of mast cell stabilizers for AKC has been supported by a lower quality case series. In 1981, JL Jay wrote a case series of 17 patients with AKC to address the use of sodium cormoglycate.²³ Overall, Jay documented that 10 out of 15 patients reported significant improvement in symptoms after using sodium cromoglycate. A major limitation to applying these results is that sodium cromoglycate is not available within the US. However, researchers have noted that sodium cromoglycate has the same mechanism of action (MOA) of other available agents (cromolyn and nedocromil).²⁴ Therefore, pharmacists should consider recommending nedocromil, cromolyn, or lodoxamide as an appropriate mast cell stabilizer for AKC in combination with first-generation antihistamine/vasoconstrictor preparations (ie, naphazoline/pheniramine). However, further data from RCTs are needed to further strengthen confidence regarding the efficacy of these agents for AKC.

These mast cell stabilizers do not have any listed contraindications, suggesting that they are relatively safe to use in most patients. In addition, while systemic side effects are quite rare, patients should be advised to discontinue the agent if the patient experiences ocular pain or irritation or if symptoms worsen or persist after 72 hours.¹⁵ The most common adverse effects are burning and stinging upon administration.¹⁵

The specific dosing recommendations for mast cell stabilizer combinations are listed in TABLE 5. Guidelines recommend dosing up to 4 to 6 times per day chronically for the management of the various forms of conjunctivitis.^3,4,6,15

Topical Corticosteroids

Ocular topical corticosteroids are recommended after the failure of antihistamines with mast cell stabilizing properties or failure of the combination of antihistamines/vasoconstrictors and mast cell stabilizers for AC, VKC, and AKC.^3,4 In their nature, corticosteroids inhibit phospholipase A2 (PLA2), which ultimately results in a reduction in the formation of various mediators from arachidonic acid.¹⁵ The significant reduction in mediators from arachidonic acid results in less leukocyte migration, fibroblast growth, and changes in vascular permeability, which ultimately reduces inflammation in the ocular space.¹⁵

The efficacy of ocular topical corticosteroids for AC has been supported by a systematic review. In 2015, Wu et al conducted a systematic review and meta-analysis of 8 randomized controlled trials to evaluate the safety and efficacy of loteprednol etabonate for managing AC.²⁵ Overall, researchers found that that the low potency loteprednol etabonate was effective in significantly reducing sign scores of AC symptoms by a standardized mean difference (SMD) of 0.48 (SMD - 0.48; 95% confidence interval [CI], -0.65 to -0.32) and improving rates of signs by 53% (Relative risk [RR] 1.53; 95% CI, 1.26-1.86) and symptoms by 29% (RR 1.29; 95% CI, 1.15-1.46). However, loteprednol etabonate significantly increased the likelihood of patients having an elevated intraocular pressure (IOP) by 3 times (Odds ratio [OR] 3.03; 95% CI, 1.04-8.80) when compared to placebo.²⁵ Therefore, pharmacists should consider recommending a very brief course (7-14 days) of low potency topical corticosteroids (ie, loteprednol etabonate) in patients with AC.^3,4

The efficacy of ocular topical corticosteroids for VKC has been supported by 1 RCT. In 2012, Oner et al conducted a RCT in VKC patients to compare the safety and efficacy of loteprednol etabonate to prednisolone and to fluorometholone.²⁶ Patients were given a corticosteroid (loteprednol etabonate, prednisolone, and fluorometholone) for 4 times a day for 28 days to evaluate major signs and symptoms of VKC. Overall, researchers found that loteprednol etabonate and prednisolone significantly improved the signs and symptoms of VKC. However, fluorometholone had less of an effect when compared to the other 2 agents. In addition, use of prednisolone was associated with a significantly higher incidence of IOP elevations.^3,26 Therefore, pharmacists should consider recommending a very brief course (7-14 days) of low- and mid-potency topical corticosteroids (ie, loteprednol etabonate or prednisolone) in patients with VKC.^3,4

No systematic reviews or RCTs were found evaluating the safety and efficacy of ocular topical corticosteroids for CBC. However, guidelines recommend low potency ocular topical corticosteroid creams/ointments as first-line agents to manage acute phases of eyelid eczema in patients with CBC.³

Ocular topical corticosteroids are contraindicated in patients with most types of active viral infections of the cornea and conjunctiva (eg, epithelial herpes simplex [dendritic] keratitis, vaccinia, varicella).¹⁵

TABLE 6 lists the available topical corticosteroids and are ranked based upon their potency.^3,4,6,15 Guidelines recommend dosing up to 3 to 4 drops per day and to be used for short “pulse therapy” (ie, 3-5 days) due to the life-threating ocular side effects, including cataract formation, elevated IOP, glaucoma, and secondary infections.^3,4 “Soft” steroids, such as loteprednol, have a lower incidence of causing an increased IOP when compared to older generation agents such as prednisolone acetate and dexamethasone phosphate. Soft steroids are designed for medication delivery near their site of action with lower systemic absorption.²⁷ Due to previously mentioned safety concerns, newer, less systemically absorbed ocular topical corticosteroids are preferred.^3,4 In a narrative review of 40 clinical studies, researchers found that a common soft steroid, loteprednol, was associated with having a favorable IOP safety profile.²⁸

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (ie, cyclosporine) are recommended to be used in steroid-dependent or severe cases of VKC and AKC.² Calcineurin inhibitors bind to specific immunosuppressant-binding proteins that inhibit the calcineurin enzyme, therefore inhibiting transcription of various immune proteins (nterleukin [IL]-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor [GM-CS]).^15]

The efficacy of cyclosporine for AKC and VKC has been supported by 2 systematic reviews.^22,29 In 2012, González‐López et al conducted a systematic review of 3 randomized controlled trials in 58 patients with AKC to determine the safety and efficacy of topical calcineurin inhibitors (ie, cyclosporine). Overall, researchers found that use of topical cyclosporine was associated with improving symptoms of various symptoms of AKC (itching, tearing, discomfort, mucous discharge, photophobia or pain) and lowering the use of ocular topical corticosteroids.²⁹ Therefore, pharmacists should consider using topical cyclosporine in patients with AKC after the failure of ocular topical corticosteroids.^3,4

In a previously highlighted systematic review by Mantelli et al,²² cyclosporine was also noted to being effective for the management of VKC. Specially, use of cyclosporine was shown to significantly improve total signs, total symptoms, and specific symptoms related to tarsal papillae, corneal involvement, limbal disease, and hyperemia.²² Therefore, pharmacists should consider using topical cyclosporine in patients with VKC after the failure of ocular topical corticosteroids or after long-term use of such corticosteroids.^3,4

Topical cyclosporine should also be considered in VKC or AKC patients who appear dependent on ophthalmic corticosteroid preparations to lower their risk of dependence and other steroid-related adverse events (eg, cataract formation, intraocular hypertension, glaucoma,).³ In a previously highlighted systematic review, researchers concluded that the use of topical cyclosporine was associated with lowering the concurrent use of ocular topical corticosteroids.²⁹ However, further research from higher quality studies will likely clarify the true effect.

Topical cyclosporine does not have any listed contraindications, suggesting it is relatively safe to use in most patients for VKC or AKC. In addition, while systemic side effects are quite rare, patients should be advised to discontinue the agent if the patient experiences ocular pain or irritation or if symptoms worsen or persist after 72 hours.¹⁵ The most common adverse effects are burning and stinging upon administration.¹⁵ TABLE 7 lists the dosing for topical cyclosporine for the highlighted forms of conjunctivitis.^6,15

Miscellaneous Agents

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDS are effective in the short-term for reducing ocular itching and redness in SAC/PAC conjunctivitis in combination with other agents.^6,15 NSAIDs inhibit both cyclooxygenase enzymes (COX-1 and COX-2), which ultimately reduces levels of ocular prostaglandins. This inhibition prevents ocular inflammation, vasoconstriction, lowering vascular permeability, inhibiting leukocytosis, and lowering IOP.¹⁵

One systematic review of 8 RCTs found that topical NSAIDs (ketorolac, diclofenac, flurbiprofen, piroxicam ) are effective in reducing ocular itching and redness when compared to placebo in patients with AC.³⁰ Diclofenac, flurbiprofen, and ketorolac are the only NSAIDs available in the US as ophthalmic formulations and may be considered for use. Specifically, the ketorolac formulation is the only FDA-approved agent for AC; therefore, it should be the preferred NSAID formulation.¹⁵ However, NSAIDs have consistently been shown to be inferior to antihistamines with mast cell activity; thus, pharmacists should only recommend NSAIDs in patients with limited access to such antihistamines.^31,32 Also, while topical NSAIDs are also safe to administer, they are rarely used due to a higher rate of causing burning/stinging upon application when compared to other ophthalmic agents.^3,6,15,31,32 TABLE 8 lists the dosing for topical NSAID formulations for AC.^6,15

Dietary Supplements/Homeopathic Agents

No specific dietary supplement or homeopathic agent was recommended within the guidelines or practice standards.^3,4 However, promising data were found addressing the use of the Euphrasia rostkoviana Hayne supplement.^33,34E rostkoviana Hayne has been used since the 14th century to treat any disease associated with the eye. Historians have associated its use with stimulating perfusion within the nasal membranes and lachrymal apparatus to reduce inflammation within the eye.³³ To assess the efficacy and tolerability of E rostkoviana Hayne, Stoss et al conducted a prospective, open-label, one-armed, multicentered, multinational cohort trial in 65 patients with inflammatory conjunctivitis.³⁴ Overall, Stoss et al found that using one drop of Euphrasia single-dose eye drops 1 to 5 times a day resulted in recovery in 81.5% of patients and no serious adverse events. However, a major limitation of this study was that it was not a RCT comparing E rostkoviana Hayne with a placebo. Therefore, it is unclear whether patients naturally improved their symptoms of conjunctivitis or experienced a benefit after starting the E rostkoviana Hayne supplement. Pharmacists should counsel patients to avoid such supplements until further data from RCTs emerge.

Adjunctive Therapies for Conjunctivitis

Adjunctive therapies are recommended for patients with who have additional systemic symptoms with conjunctivitis.^3,4

Oral Antihistamines

Oral systemic antihistamines are highly effective for the treatment of AC in patients with systemic symptoms. In a 2013 systematic review of 4 randomized control trials involving 2573 patients with AC, systemic antihistamines (ie, desloratadine, ebastine, rupatadine) were shown to significantly relieve allergy symptoms, nasal symptoms, and ocular symptoms when compared to placebo.³⁵ Therefore, oral antihistamines are recommended to be used in most cases of AC if a patient has systemic allergic symptoms (eg, rhinorrhea, urticaria) that needs to be addressed with the ocular symptoms.^3,4 While no systematic review data were found addressing the use of oral antihistamines agents in patients with VKC, AKC, or CBC, pharmacists can still consider using them to adjunctly manage the systemic allergic symptoms.^3,4

Guidelines suggest that newer oral antihistamines (eg, cetirizine, desloratadine, fexofenadine) should be used in combination with ophthalmic agents in patients complaining of itching and watery eye symptoms since they have a lower incidence of drowsiness and greater drying effect when compared to early generation antihistamines (eg, diphenhydramine). TABLE 9 lists the dosing for the newer oral antihistamines for systemic allergic symptoms.^1,2,6,15

Leukotriene Inhibitors

Montelukast is the only leukotriene receptor antagonist that has been shown to improve ocular symptoms in patients with SAC/PAC.² Montelukast acts as a potent antagonist to leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT₁, found in the human respiratory systems. This inhibition results in lower amounts of inflammatory mediators such as mast cells and eosinophils when stimulated by an allergen.¹⁵

Montelukast’s efficacy was evaluated in a 2013 systematic review of 18 randomized control trials with 9192 patients to evaluate its efficacy for AC.³⁶ Overall, researchers found that montelukast was significantly more effective than placebo but less effective when compared to oral antihistamines. Montelukast does not have any listed contraindications, suggesting that they are relatively safe to use in most patients. However, montelukast has a black box warning suggesting neurologic events with use. Therefore, it should be considered a possible option in patients unable to tolerate oral antihistamines due to the lack of superiority and safety concerns. TABLE 10 lists the dosing for leukotriene inhibitors for systemic allergic symptoms.^1,2,6,15

PHARMACIST’S ROLE IN OCULAR ALLERGY TREATMENT

Pharmacists can act as initial screeners for patients to determine whether they should seek further care from an ophthalmologist. Pharmacists can use the QuEST/SCHOLAR-MAC method to quickly assess the patient. The QuEST/SCHOLAR-MAC acronyms consist of the following³⁷:

• Quickly and accurately assess the patient by asking about:
  • Symptoms
  • Characteristics
  • History
  • Onset
  • Location
  • Aggravating factors
  • Remitting factors
  • Medication use (including prescription and nonprescription products)
  • Allergic reactions
  • Coexisting conditions
• Establish that the patient is able to use a self-care product
• Suggest an appropriate self-care product
• Talk with the patient about the product.

In addition, pharmacists should conduct an ocular history evaluating the following factors^3,4,8,38:

• Vision: Identify if the patient reports symptoms of impaired vision
• Contact Lens Wear History: Identify if the patient reports repeatedly using contact lenses
• Conjunctiva: Evaluate for any discolorations, inflammation, masses, or discharge (FIGURE 2)
  • Bacterial infection = Yellow discharge discoloration
  • Viral infection = Red/pink discoloration of sclera
  • Allergic = Red discoloration of sclera without additional corneal involvement
• Number of Eyes: Evaluate number of eyes with symptoms
  • Bacterial infection = Primarily unilateral, however, patients may experience involvement with additional eye within 48 hours
  • Viral infection = Primarily unilateral, however, patients may experience involvement with additional eye after 48 hours
  • Allergy = Primarily bilateral
• Eyelid Margins: Evaluate for inflammation, edema, hyperpigmentation, or discharge
  • Yellow discharge: Suggestive of bacterial/viral infection or blepharitis (FIGURE 2)
• Warning Signs suggesting sight-threatening conditions³⁸:
  • Decrease in visual acuity
  • Ciliary flush
  • Photophobia
  • Severe foreign body sensation that prevents the patient from keeping the eye open
  • Corneal opacity
  • Fixed pupil
  • Severe headache with nausea.

Pharmacists should refer the patient to an ophthalmologist if they suspect an infection, conjunctivitis secondary to a nonallergic vector, or a sight threatening condition. However, if the pharmacist suspects AC, they should recommend OTC treatments (as previously discussed) for swift treatment of the ocular discomfort.

Finally, pharmacists should counsel patients about how to properly administer eye drops, especially when taking multiple formulations. Research has found that only 48.67% of patients correctly administer the eye drops on their first attempt;³⁹ therefore, many patients may require counseling. Some key counseling points are detailed below.

How to Administer Eye Drops^6,15,40,41:

• Wash both hands before administering eye drops
• Gently clean eyelids—if they have solid discharge—using a cotton ball dampened with warm water
• Look upward to the ceiling while pinching and pulling the lower eyelid outward to form a pocket with the lower eyelid
• Place the eye drop into the open “pocket” formed in the lower eyelid. If placed directly onto the eye, the drop will likely run down a cheek or into the tear duct. Occlude the nasolacrimal duct to prevent the drop from draining into the tear duct
• Close the eye gently for at least 5 to 10 seconds to improve the absorption of medication.
• Wait at least 5 to 10 minutes before coadministering another eye drop to optimize the absorption of the first ophthalmic medication.

How to Administer Drops Using the Closed Eye Technique for Patients Who Cannot Self-Administer Eye Drops^40,41:

• Ask patient to lie flat on bed or ground
• Direct the patient to tilt their head back
• Administer drop of medication onto the closed eyelid via nasal corner
• Direct the patient to open their eye and close the eye gently for at least 5 to 10 seconds to improve the absorption of medication.

Other Helpful Recommendations to Provide to Patients^{6,15,38,40,41}:

• Consider refrigerating the eye drops to help allow the cool sensation to provide comfort for administration
• Avoid repetitive blinking to avoid washing out the topical medications
• Avoid allowing the tip of the dropper to touch the eye, fingertips, or any other susceptible surface
• Consider having a partner administer the eye drop on a patient’s behalf to allow optimal administration of the medication
• Consider using a tissue or swab to recover excess medications from the cheek.

CONCLUSION

Conjunctivitis is a key symptom that presents with inflammation of the conjunctiva within the eye. Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are one of the most common forms of conjunctivitis—namely allergic conjunctivitis (AC). Nonpharmacologic treatments include applying cold compresses, using refrigerated artificial tears, and avoiding known triggers. Pharmacists should consider using antihistamines with mast cell stabilizer activity, first-generation antihistamine/vasoconstrictor agents, mast cell stabilizers, topical corticosteroids, and/or topical calcineurin inhibitors to primarily manage various forms of conjunctivitis.

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