A Randomized, Double-Masked Trial of Topical Ketorolac versus Articial Tears for Treatment of Viral Conjunctivitis

Yichieh Shiuey, MD, Balamurali K. Ambati, MD, Anthony P. Adamis, MD, the Viral Conjunctivitis Study Group*
Objective: To determine if topical ketorolac 0.5% relieves the symptoms and signs of viral conjunctivitis better than articial tears. Design: Randomized, controlled trial. Participants: One hundred seventeen patients with a clinical diagnosis of viral conjunctivitis were randomized to the treatment group or control group. Methods: Physicians and patients were masked to treatment. Patients in the treatment group received topical ketorolac 0.5% four times daily. Patients in the control group received articial tears four times daily. Symptom and sign scores were recorded on the day of recruitment and at the time of a follow-up examination 3 to 4 days later. Main Outcome Measures: Change in six symptoms of conjunctivitis (overall discomfort, itching, foreign body sensation, tearing, redness, and lid swelling) and four signs of conjunctivitis (conjunctival injection, conjunctival chemosis, conjunctival mucus, and lid edema). Adverse effects were also studied. Results: A total of 105 patients returned for their 3- to 4-day follow-up. Both the articial tear and ketorolac groups showed improvement in all symptom scores at their 3- to 4-day follow-up visit. There was no statistically signicant difference between the change in symptom scores between the treatment group and control group in any symptom category except redness. Patients in the control group were more likely to report improvement in redness than those in the treatment group, P 0.012. There was no statistically signicant difference between the change in sign scores between the treatment and control groups. Ketorolac 0.5% was more likely to produce stinging than articial tears, 59.2% versus 18.8%, P 0.001. Conclusions: Topical ketorolac 0.5% used four times daily is no better than articial tears at relieving the symptoms or signs of viral conjunctivitis and produces more stinging than articial tears. Ophthalmology 2000; 107:15121517 2000 by the American Academy of Ophthalmology. Viral conjunctivitis is a common problem encountered by ophthalmologists. It may be caused by a wide array of viruses including adenovirus, herpes simplex virus, varicella zoster virus, enterovirus, picornavirus, inuenza A virus, Epstein-Barr virus, and Newcastle disease virus. Viral conjunctivitis causes redness, tearing, swelling, and irritation of the eyes that typically lasts from 1 to 3 weeks. Current management of this condition focuses on supportive care while the viral infection completes its course and resolves.1,2 However, many patients still experience substantial discomfort despite standard treatments with cool compresses, articial tears, topical vasoconstrictors, ointment, or a combination thereof. Inammation of the conjunctiva is an essential feature of viral conjunctivitis, and this inammation is believed to cause many of the symptoms of the infection. At present, the most commonly used form of anti-inammatory treatment in viral conjunctivitis is topical steroids. Topical steroids may be indicated to treat severe adenoviral conjunctivitis in the setting of visually signicant subepithelial opacities or when conjunctival membrane formation occurs. However, topical steroids are not recommended for the routine treatment of viral conjunctivitis because of a variety of possible side effects.1 The use of topical steroids may aggravate herpes simplex viral conjunctivitis and may predispose the eye to corneal involvement.1 Animal models of
ISSN 0161-6420/00/$see front matter PII S0161-6420(00)00177-9

Originally received: October 14, 1999. Accepted: March 29, 2000. Manuscript no. 99710. Massachusetts Eye and Ear Inrmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. *Sherleen Chen, MD, Mary Coday, MD, Ronald Farkas, MD, PhD, Jeffrey Finer, MD, PhD, Kenneth Graham, MD, Melanie Graham, MD, Lynn Halpern, MD, PhD, Eddie Harris, MD, Deeba Hussain, MD, Eugene Lit, MD, Subhransu Ray, MD, PhD, Ivana Kim, MD, Rosa Kim, MD, Stella Kim, MD, Tueng Shen, MD, PhD, Kimberly Sippel, MD, Eric Strauss, MD, PhD, Michael Tolentino, MD, Lynette Watkins, MD. Presented in part as a poster at the American Academy of Ophthalmology annual meeting, Orlando, Florida, October 1999. Supported in part by an unrestricted grant from Allergan Pharmaceuticals, Irvine, California. The authors have no proprietary interest in any of the products mentioned in this study. Reprint requests to Yichieh Shiuey, MD, 331 Bloomeld Avenue, Nutley, NJ 07110.

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2000 by the American Academy of Ophthalmology Published by Elsevier Science Inc.

Shiuey et al Topical Ketorolac versus Articial Tears for Viral Conjunctivitis

viral conjunctivitis have shown that topical steroids enhance virus replication and prolong the duration of virus shedding.3 There have also been reports of chronic adenoviral conjunctivitis in patients who have been treated with steroids.4 Other potential side effects of topical steroids include increased intraocular pressure, cataract formation, delayed wound healing, and promotion of infections. Because of the many possible adverse effects of topical steroids in the treatment of viral conjunctivitis, we explored the possibility of using a nonsteroidal anti-inammatory agent to treat the signs and symptoms of viral conjunctivitis. Topical ketorolac, a nonsteroidal anti-inammatory agent, has previously been shown to be safe and effective in the symptomatic treatment of seasonal allergic conjunctivitis and has approval for this indication by the United States Food and Drug Administration. However, it has not been previously studied for the treatment of human viral conjunctivitis.5 Ocular application of topical ketorolac has been shown to have anti-inammatory effects without the side effects of topical steroids.6 11 In contrast to topical steroids, animal models of viral conjunctivitis have not demonstrated enhanced virus replication with administration of topical ketorolac.12 For these reasons, we chose to study the efcacy of topical ketorolac in treating the symptoms and signs of viral conjunctivitis.
investigators and patients until the study was closed. At the end of the study, the code for the randomization scheme was obtained from the DEllis Group. This study was approved by the institutional review board, and written informed consent was obtained from all patients. A nominal fee was paid to each of the patients to cover their expenses for participating in the study.

Efcacy Variables
Patients were evaluated at baseline and were asked to return either 3 or 4 days later for a follow-up evaluation. The principal efcacy variables were six symptoms of viral conjunctivitis: overall discomfort, itching, foreign body sensation, tearing, redness, and lid swelling. Four signs of viral conjunctivitis were also evaluated: conjunctival injection, conjunctival chemosis, conjunctival mucus, and lid edema. Each of the symptoms was rated by the patient at presentation and at follow-up on a 4 point scale: none (0), mild (1), moderate (2), or severe (3). In addition, each patient was asked to report their opinion on the usefulness of the treatment in relieving their symptoms on a 4 point scale: did not help (0), unsure (1), think it helped (2), and sure it helped (3). After the 3 to 4 day follow-up evaluation, patients were given a questionnaire to mail in that reported on their overall symptoms at 7 and 14 days after their initial evaluation (Fig 1). Each of the signs was rated in the more badly affected eye by the examiner at presentation and at the 3 to 4 day follow up visit on a 4 point scale: none (0), mild (1), moderate (2), or severe (3). For the sign of conjunctival injection, a grade of none (0) indicated no detectable hyperemia of the conjunctiva, a grade of mild (1) indicated conjunctival hyperemia that was barely detectable, a grade of moderate (2) indicated conjunctival hyperemia that was readily detectable, and a grade of severe (3) indicated intense conjunctival hyperemia that could be mistaken for subconjunctival hemorrhage without slitlamp examination. For the sign of chemosis, a grade of none (0) indicated no detectable conjunctival edema, a grade of mild (1) indicated conjunctival edema that was barely detectable, a grade of moderate (2) indicated conjunctival edema that was readily detectable in the form of swollen redundant conjunctiva, and a grade of severe (3) indicated conjunctival edema sufcient to cause protrusion of swollen redundant conjunctiva through closed lids. For the sign of conjunctival mucus, a grade of none (0) indicated no detectable mucus discharge, a grade of mild (1) indicated mucus discharge that was barely detectable, a grade of moderate (2) indicated mucus discharge that was readily detectable, and a grade of severe (3) indicated mucus discharge associated with an inammatory conjunctival pseudomembrane or true membrane. For the sign of lid edema, a grade of none (0) indicated no detectable eyelid swelling, a grade of mild (1) indicated barely detectable eyelid swelling, a grade of moderate (2) indicated readily detectable eyelid swelling, and a grade of severe (3) indicated eyelid swelling sufcient to cause partial or complete ptosis. Examiners of each patient were the same at the initial and follow-up evaluations.

Methods
The study was designed as a prospective, double-masked, controlled study of the efcacy of ketorolac 0.5% ophthalmic solution (Acular, Allergan, Irvine, CA) compared with articial tears (Moisture Drops, Allergan). Patients were recruited from the eye emergency room of the Massachusetts Eye and Ear Inrmary, Boston, Massachusetts. Eligible patients were required to have an acute unilateral or bilateral conjunctivitis of less than 2 weeks. In addition, they were required to have at least one of the following features compatible with viral conjunctivitis: unilateral or asymmetric conjunctivitis, follicles on the inferior tarsal conjunctiva, preauricular lymphadenopathy, an associated upper respiratory infection, and recent contact with a person with a red eye. Exclusion criteria included history of seasonal allergic conjunctivitis, use of ocular medication after the beginning of symptoms, contact lens wear, history of herpetic eye disease, history of ocular surgery, history of chronic ocular disease other than refractive error, allergy to aspirin or nonsteroidal anti-inammatory drugs, pregnancy, age less than 18 years, bleeding disorder, signicant blepharitis or dry eyes on slit lamp examination, purulent ocular discharge, corneal epithelial staining with uorescein, or intraocular inammation. Patients were also required to grade their overall symptoms from the conjunctivitis as none, mild, moderate, or severe. Only patients reporting initial overall discomfort as moderate or severe were asked to participate in the study. Patients who met the study criteria and who agreed to participate in the study were randomly assigned to receive either ketorolac 0.5% or articial tears. Sealed, randomly numbered opaque manila envelopes containing unlabeled bottles of either ketorolac or articial tears were given to the patient. Patients were instructed to put one drop into each symptomatic eye four times daily for 7 days. The manila envelopes containing the eyedrops were prepared professionally by the DEllis Group, Irvine, California. The randomization scheme was created using a computer program by the DEllis Group. The identity of the drops was masked to both the

Safety Variables
Patients were instructed to contact one of the principal investigators by telephone if they were experiencing any signicant side effect from the study eyedrops. If the investigator was unavailable, the patients were to report to an eye emergency room that was open 24 hours a day. In addition, patients were asked to report any side effects at the 3 to 4 day follow-up evaluation.

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Figure 1. Mail-in questionnaire for grading of symptoms on days 7 and 14.

Statistical Methods
At the completion of the study, the identity of the drops given to each patient was unmasked and the data analyzed. Fishers exact test and the Wilcoxon ranksum test were used to look for differences in demographics, baseline symptoms, and clinical scores in the articial tear and ketorolac groups. Fishers exact test was also used to see if the patients perception of benet was related to treatment with ketorolac. Fishers exact test was used to examine whether paired changes in symptom and clinical scores between baseline and follow up were different in the articial tear and ketorolac groups. Fishers exact test was also used to see if the likelihood of having an adverse effect was related to the articial tear or ketorolac group.

Results
A total of 117 patients met eligibility criteria and were initially enrolled in the study. Twelve patients did not return for follow up,

seven of whom had been assigned to the articial tears group and ve of whom had been assigned to the ketorolac group. One hundred ve patients returned for the 3 to 4 day follow up examination. Of the these patients, 55 returned the questionnaire that reported on their symptoms at days 7 and 14. The baseline characteristics of the 105 patients who completed the 3 to 4 day follow up examination are shown in Table 1. The articial tear and ketorolac groups were similar at baseline with regard to demographic and clinical characteristics. One examination nding that was of borderline statistical signicance was of a palpable preauricular node, which was more common in the articial tear group, P 0.05. The comparison of symptom scores between the initial evaluation and follow up at day 3 or 4 has been summarized as the number and percentage of patients whose conditions were worse, did not change, or were better after treatment (Table 2). There was no statistically signicant difference between the change in symptom scores between the articial tear group and the ketorolac group in any symptom category except for redness. Patients were more likely to report improvement in red-

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Table 1. Patient Characteristics
Articial Tears (n 48) Median age (yrs) Male (%) White (%) Median days with symptoms Bilateral symptoms (%) Unilateral or asymmetric symptoms (%) Associated upper respiratory infection (%) Follicles on inferior tarsal conjunctiva (%) Preauricular node (%) Contact with person with a red eye (%) 31 46 66 2 46 73 52 96 27 19 Ketorolac (n 57) 31 53 65 2 49 65 42 98 12 30 P value 0.96 0.31 0.54 0.98 0.44 0.25 0.44 0.44 0.05 0.14 *Fishers exact test.

Table 3. Patients Perception of Benet of Treatment at Day 3 or 4

Patient Response Did not help Unsure Think it helped Sure it helped Total Articial Tears 5 (10.4%) 6 (12.5%) 19 (40.6%) 18 (37.5%) 48 (100.0%) Ketorolac 0.5% 8 (14.0%) 5 (8.8%) 21 (36.8%) 23 (40.4%) 57 (100.0%) P Value* 0.867

ness in the articial tear group than in the ketorolac group, P 0.012. The opinions of the patients on day 3 or 4 regarding the usefulness of their treatment is summarized in Table 3. There was no statistically signicant difference between the responses of the patients who received articial tears and of those who received ketorolac. The comparison of sign scores between the initial evaluation and follow up at day 3 or 4 is summarized in Table 4. There was no statistically signicant difference between the change in sign scores between the articial tear group and the ketorolac group in any sign category. A comparison of the overall symptom scores at the initial evaluation and from the questionnaire at days 7 and 14 is summarized in Table 5. Nearly 90% of the patients who returned the Table 2. Summary of the Change in Patient Symptom Scores, Baseline Compared with Day 3 or 4
Conjunctivitis Symptom Overall Worse No change Better Itching Worse No change Better Foreign body sensation Worse No change Better Tearing Worse No change Better Redness Worse No change Better Lid swelling Worse No change Better *Fishers exact test. Articial Tears 0 (0.0%) 5 (10.4%) 43 (89.6%) 0 (0.0%) 17 (35.4%) 31 (64.6%) 4 (8.3%) 13 (27.1%) 31 (64.6%) 4 (8.3%) 8 (16.7%) 36 (75.0%) 0 (0.0%) 5 (10.4%) 43 (89.6%) 5 (10.4%) 11 (22.9%) 32 (66.7%) Ketorolac 0.5% 1 (1.7%) 10 (17.5%) 46 (80.7%) 5 (8.8%) 16 (28.1%) 36 (63.2%) 4 (7.0%) 17 (29.8%) 36 (63.2%) 3 (5.3%) 12 (21.1%) 42 (73.7%) 6 (10.5%) 12 (21.1%) 39 (68.4%) 5 (8.8%) 19 (33.3%) 33 (57.9%) P Value*

questionnaire in both the articial tear and ketorolac groups reported an improvement in their overall symptom score by day 7. At day 14, nearly all patients reported improvement in their overall symptom score. There was no statistically signicant difference between articial tears group and ketorolac group at either day 7 or 14. A comparison of the reported adverse effects is shown in Table 6. Ketorolac was found to cause stinging in 59.2% of patients as compared with 18.8% in the articial tear group. This was statistically signicant, P 0.001. There was one patient in the study who reported at the 3 day follow up examination that she believed that the drops were worsening her symptoms. The study medication was discontinued and unmasked. It was identied as ketorolac. By slitlamp examination, there was no appreciable change in the patients examination ndings from the initial evaluation. This patients conjunctivitis resolved without sequelae by 2 weeks after the initial visit.

Discussion
We studied the effect of topical ketorolac, a nonsteroidal antiinammatory drug, on the symptoms and signs of viral conjunctivitis. We chose to test topical ketorolac because of its known antiinammatory effects when administered to the eye and its lack of serious side effects. Our
Table 4. Summary of the Change in Investigator Sign Scores, Baseline Compared with Day 3 or 4
0.107 Injection Worse No change Better Chemosis Worse No change Better Mucus Worse No change Better Lid edema Worse No change Better *Fishers exact test. Articial Tears 1 (2.1%) 9 (18.8%) 38 (79.2%) 3 (6.3%) 19 (39.6%) 26 (54.2%) 1 (2.1%) 19 (39.6%) 28 (58.3%) 0 (0.0%) 23 (47.9%) 25 (52.1%) Ketorolac 0.5% 3 (5.3%) 13 (22.8%) 41 (71.9%) 7 (12.2%) 28 (49.1%) 22 (38.6%) 5 (8.8%) 15 (26.3%) 37 (64.9%) 3 (5.3%) 20 (35.1%) 34 (59.6%) P Value*

0.404

0.953

0.692

0.786

0.266

0.012

0.206

0.481

0.179

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Table 5. Overall Patient Symptom Score at Day 7 and 14 Compared with Initial Evaluation
Articial Tears Day 7 Worse No change Better Day 14 Worse No change Better *Fishers exact test. 1 (3.9%) 2 (7.7%) 23 (88.5%) 0 (0.0%) 0 (0.0%) 26 (100.0%) Ketorolac 0.5% 0 (0.0%) 3 (10.3%) 26 (89.7%) 0 (0.0%) 1 (3.4%) 28 (96.6%) P Value*

0.822

1.000

hypothesis was that ketorolac would relieve some of the symptoms of viral conjunctivitis through its antiinammatory effects. Both the articial tear and ketorolac groups showed improvement in all symptom scores after using the drops four times daily for 3 to 4 days. However, we found that there were no statistically signicant differences between the articial tear and ketorolac groups with respect to overall discomfort, itching, foreign body sensation, tearing, or eyelid swelling. There was a statistically signicant difference in the symptom of redness. Patients who received ketorolac were less likely to experience improvement in redness, P 0.012. Patients were also more likely to experience stinging with instillation of the ketorolac drops, P 0.001. There were no statistically signicant differences between the conjunctivitis sign scores of the two groups at the 3 to 4 day follow-up. Patients were not reexamined at day 7 after initiation of treatment. We chose not to have a second clinical examination at day 7 because we anticipated that the number of patients returning for follow up would be unacceptably low. Our patients were young, working class persons with a median age of 31 years who could not easily take time off. We believed that at day 7 a signicant proportion of the study patients would have minimal symptoms and, as a result, would be less likely to return for follow up. Because we did not reexamine patients at day 7, it is unknown if topical ketorolac has any benet in reducing the signs of viral conjunctivitis after 1 week of treatment. However, we do know that we could not detect a difference in the overall symptom score of patients receiving topical ketorolac or articial tears at either day 7 or 14 after initiation of treatment. Our study did not show any benet to the use of topical ketorolac 0.5% as compared with articial tears in relieving
Table 6. Adverse Events
Adverse Events Stinging Headache Photophobia *Fishers exact test. Articial Tears 9 (18.8%) 0 (0%) 0 (0%) Ketorolac 0.5% 34 (59.6%) 1 (1.7%) 1 (1.7%) P Value* 0.001

the symptoms of viral conjunctivitis. Moreover, there was a greater likelihood of stinging with the use of ketorolac. Topical ketorolac is also substantially more expensive than articial tears. For these reasons, our study does not support the use of topical ketorolac for the treatment of patients with a clinical diagnosis of viral conjunctivitis. We are aware of only one other study addressing the use of a topical nonsteroidal antiinammatory drug in the treatment of viral conjunctivitis.13 This was a randomized study of the effects of topical piroxicam on the symptoms and signs of patients with a clinical diagnosis of coxsackie virus infection. The authors concluded that topical piroxicam reduced foreign body sensation, pain, tearing, and mean time to recovery in these patients. A potentially signicant confounder of the results and conclusions of this piroxicam study was that neither the investigators nor patients were masked to the treatment. Therefore, both the patients and the investigators may have been subject to bias. Our study is unlikely to be biased. It was a prospective, randomized, double-masked study. It is also unlikely that there was a substantial benet to ketorolac that could not be detected with the number of patients in the study. For each of the symptom categories, overall, itching, redness, foreign body sensation, tearing, and lid swelling, patients using articial tears were more likely to report improvement than those using ketorolac. This was only statistically signicant for redness, but indicates an overall trend favoring articial tears. Thus it would be unlikely that a larger study would demonstrate a benecial effect of ketorolac. We used clinical criteria to diagnose acute viral conjunctivitis. This is the method by which most ophthalmologists diagnose viral conjunctivitis, because laboratory testing for the multiple types of viral conjunctivitis is not widely available and is also expensive. Ninety-seven percent of our patients were found to have an acute follicular conjunctivitis of less than 2 weeks in duration in the absence of any use of topical medications. In addition, patients who had a history or examination ndings suggestive of either seasonal allergic conjunctivitis or bacterial conjunctivitis were excluded. Therefore, by using these strict clinical criteria, the diagnosis of viral conjunctivitis was most likely correct in the great majority of patients in our study. It is unclear why topical ketorolac does not relieve the symptoms of viral conjunctivitis when it has been shown to be efcacious in seasonal allergic conjunctivitis. In a rabbit model of adenovirus keratoconjunctivitis, topical prednisolone was found to inhibit immune corneal inltrates, whereas topical ketorolac did not.12 This may indicate that the inammation of viral conjunctivitis is qualitatively different from that found in seasonal allergic conjunctivitis and is not effectively suppressed by topical ketorolac. Based on the results of this study, we do not recommend the use of topical ketorolac 0.5% for the symptomatic relief of viral conjunctivitis. Further studies to nd safe and effective treatments for the symptoms of this very common condition should be pursued.

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References
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ketorolac tromethamine solution 0.5% in reducing postoperative inammation after cataract extraction and intraocular lens implantation. Ophthalmology 1988;95:1279 84. Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol 1992;36:259 84. Flach AJ. Nonsteroidal anti-inammatory drugs in ophthalmology [review]. Int Ophthalmol Clin 1993;33:17. Fraser-Smith EB, Matthews TR. Effect of ketorolac on herpes simplex virus type one ocular infection in rabbits. J Ocul Pharmacol 1988;4:321 6. Fraser-Smith EB, Matthews TR. Effect of ketorolac on Pseudomonas aeruginosa ocular infection in rabbits. J Ocul Pharmacol 1988;4:1019. Fraser-Smith EB, Matthews TR. Effect of ketorolac on Candida albicans ocular infection in rabbits. Arch Ophthalmol 1987;105:264 7. Gordon YJ, Araullo-Cruz T, Romanowski EG. The effects of topical nonsteroidal anti-inammatory drugs on adenoviral replication. Arch Ophthalmol 1998;116:900 5. Kosrirukvongs P. Topical piroxicam and conjunctivitis. J Med Assoc Thai 1997;80:28792.

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