Effects of topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium on corneal sensitivity in ophthalmologically normal cats

Jordan K. Roberts Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Jessica M. Meekins Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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James K. Roush Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Amy J. Rankin Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

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Abstract

OBJECTIVE

To investigate the effects of short-term and prolonged topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium on corneal sensitivity (CS) in ophthalmologically normal cats.

ANIMALS

12 healthy adult domestic shorthair cats.

PROCEDURES

In the first of 2 study phases, each cat received 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, 0.03% flurbiprofen sodium, and saline (0.9% NaCl; control) solutions (1 drop [0.05 mL]/eye, q 5 min for 5 treatments) in a randomized order with a 2-day washout period between treatments. For each cat, an esthesiometer was used to measure CS before treatment initiation (baseline) and at 15, 30, 45, and 60 minutes after the last dose. There was a 2-day washout period between phases. The second phase was similar to the first, except each treatment was administered at a dosage of 1 drop/eye, twice daily for 5 days and CS was measured before treatment initiation and at 15 minutes and 24 and 48 hours after the last dose. The Friedman test was used to evaluate change in CS over time.

RESULTS

None of the 4 treatments had a significant effect on CS over time in either study phase.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that neither short-term nor prolonged topical instillation of 3 NSAID ophthalmic solutions had any effect on the CS of healthy cats. Given potential differences in cyclooxygenase expression between healthy and diseased eyes, further investigation of the effects of topical NSAID instillation in the eyes of cats with ocular surface inflammation is warranted.

Abstract

OBJECTIVE

To investigate the effects of short-term and prolonged topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium on corneal sensitivity (CS) in ophthalmologically normal cats.

ANIMALS

12 healthy adult domestic shorthair cats.

PROCEDURES

In the first of 2 study phases, each cat received 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, 0.03% flurbiprofen sodium, and saline (0.9% NaCl; control) solutions (1 drop [0.05 mL]/eye, q 5 min for 5 treatments) in a randomized order with a 2-day washout period between treatments. For each cat, an esthesiometer was used to measure CS before treatment initiation (baseline) and at 15, 30, 45, and 60 minutes after the last dose. There was a 2-day washout period between phases. The second phase was similar to the first, except each treatment was administered at a dosage of 1 drop/eye, twice daily for 5 days and CS was measured before treatment initiation and at 15 minutes and 24 and 48 hours after the last dose. The Friedman test was used to evaluate change in CS over time.

RESULTS

None of the 4 treatments had a significant effect on CS over time in either study phase.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that neither short-term nor prolonged topical instillation of 3 NSAID ophthalmic solutions had any effect on the CS of healthy cats. Given potential differences in cyclooxygenase expression between healthy and diseased eyes, further investigation of the effects of topical NSAID instillation in the eyes of cats with ocular surface inflammation is warranted.

Introduction

In cats, the cornea is a highly sensitive and densely innervated tissue, with sensory nerves originating from the ophthalmic branch of the trigeminal ganglia.1 The corneal nerves provide sensory function and play an important role in maintaining the structure and function of the cornea and facilitating corneal wound repair. Consequently, damage to the corneal nerves subsequent to inflammation or trauma can lead to diminished corneal sensation and corneal disease.

Ocular surface diseases of the cornea and conjunctiva are common, painful, and potentially vision-threatening conditions. In cats, infection with feline herpesvirus-1 is the most common ocular surface disease, frequently leading to conjunctivitis and corneal ulceration.2 Specific treatment of the underlying disease (eg, topical and systemic antiviral drugs) is administered when possible. However, clinicians are often compelled to use symptomatic treatments to control clinical signs associated with ocular inflammation and discomfort. The most commonly used symptomatic treatments for ocular surface inflammation are topical anti-inflammatory medications (eg, corticosteroids and NSAIDs).

Abundant evidence suggests that topical corticosteroids may exacerbate herpetic disease, and their use should be avoided in most cases of ocular surface disease in cats and other species.2,3,4,5 When anti-inflammatory treatment is necessary, topical NSAID ophthalmic solutions (topical NSAIDs) may be used preferentially over corticosteroids in patients with corneal ulceration, trauma, or infection.6 Currently, there are no topical NSAIDs approved for use in veterinary patients; thus, topical NSAIDs approved for use in humans are used in an extralabel manner in veterinary practice. Various topical NSAIDs have been used to reduce signs of ocular pain caused by corneal injury,7,8 to decrease localized inflammation,6,9,10 to treat anterior uveitis,11,12,13 and following surgical procedures in humans14,15 and some veterinary species.7

Nonsteroidal anti-inflammatory drugs inhibit COX, which mediates the breakdown of arachidonic acid, a precursor of proinflammatory prostaglandins and other metabolic products including eicosanoids and thromboxane.11,13,16,17 In humans and some veterinary species, the inducible isoenzyme COX-2 has been associated with ocular inflammatory and pathological processes.18,19,20 Arachidonic acid metabolites contribute to the local inflammatory response and the sensitization and excitation of various nociceptors.21 Topical NSA IDs decrease nociceptor excitation in clinically normal (ie, noninflamed) eyes of both cats7,8 and humans.7,8,10,21 However, topical NSAIDs have variable efficacy for alleviation of ocular discomfort in humans.9,10,14,15,22

Although topical NSAIDs are commonly used to treat many ocular surface diseases, studies demonstrating their effects in cats are limited. In a randomized, placebo-controlled study involving 8 healthy cats,23 the CS following topical instillation of 0.1% diclofenac sodium (1 drop/eye, 4 times/d for 7 days) did not differ significantly from the CS following topical instillation of artificial tears at the same dosage.

To our knowledge, the immediate effects of topical instillation of 0.03% flurbiprofen sodium or 0.5% ketorolac tromethamine on the CS of cats with ophthalmologically normal eyes have not been investigated, nor have the effects of prolonged administration of topical NSAIDs. Thus, the goals of the study reported here were to evaluate the effects of short-term (immediate) and prolonged administration of 3 topical NSAIDs on the CS in healthy nonbrachycephalic cats. We hypothesized that the CS of healthy cats would not be affected by short-term or prolonged administration of any of the 3 topical NSAIDs evaluated.

Materials and Methods

Animals

All study protocols were reviewed and approved by the Kansas State University Institutional Animal Care and Use Committee. Twelve purpose-bred nonbrachycephalic domestic shorthair cats owned by the Kansas State University Comparative Medicine Group were enrolled in the study. Prior to study enrollment, each cat was determined to be healthy on the basis of results of a physical examination and an ophthalmic examination that included assessment of the anterior segment and adnexa of each eye for evidence of active or previous ocular surface disease, neuroophthalmic examination, fluorescein staining,a rebound tonometry,b and slit-lamp biomicroscopy.c All ophthalmic examinations were performed by a board-certified veterinary ophthalmologist (JMM). All cats were housed in a climate-controlled environment with a 12-hour light-dark cycle, room temperature between 20°C and 23°C, and humidity between 54% and 57%. Cats were individually housed in cages (0.61 × 0.61 × 0.7 m) for assessment of the effects of short-term administration of the topical NSAIDs (immediate-dosing phase) and housed as a group in their usual enclosure for assessment of the effects of prolonged administration of the topical NSAIDs (prolonged-dosing phase).

Treatments

Three commercially available topical ophthalmic NSAID solutions (0.1% diclofenac sodium,a 0.5% ketorolac tromethamine,a and 0.03% flurbiprofen sodiumd) and a placebo (saline [0.9% NaCl] solutione) were assessed in a prospective, randomized, blinded, crossover study. Each treatment solution was dispensed in a generic sterile eyedropper bottle designed to dispense a standard 0.05-mL drop. The treatment solutions were obtained from the Kansas State University Veterinary Health Center Dispensary. Dispensary personnel labeled the bottle containing each treatment solution with an A, B, C, or D so that study personnel remained unaware of (blinded to) the specific treatment administered during each experiment (cat-treatment combination). Study personnel remained blinded to treatment assignment until after data analyses were completed.

The cats were allowed to acclimate to the environmental conditions (ie, individual housing) for the immediate-dosing phase and general handling conditions for 3 days prior to study initiation (days 1 to 3). During the acclimation period, 1 drop (0.05 mL) of saline solution was topically applied to each eye of each cat twice daily. The CS of each eye of each cat was measured on the last day of the acclimation period and served as the baseline CS for the immediate-dosing phase of the study (Supplementary Figure S1, available at: avmajournals.avma.org/doi/suppl/10.2460/ajvr.82.1.81)

An online randomization toolf was used to randomly assign each cat to 1 of 4 treatment orders (ABCD, BCDA, CDAB, or DABC) immediately prior to initiation of the immediate-dosing phase of the study (days 4 to 15). Each cat received 1 drop (0.05 mL) of the first assigned treatment (0.1% diclofenac sodium, 0.5% ketorolac tromethamine, 0.03% flurbiprofen sodium, or 0.9% saline solution) in each eye every 5 minutes for a total of 5 applications. Beginning 15 minutes after instillation of the last dose, the CS was measured in both eyes every 15 minutes for a total of 4 times. After a washout period of 2 days, the process was repeated with the next designated treatment until all cats had received all 4 treatments. During each washout period, the CS was measured in both eyes once daily to confirm that it had returned to the baseline level before initiation of the next treatment. The CS for each eye on the last day of the final washout period served as a baseline for the prolonged-dosing phase of the study. A washout period of 2 days was selected on the basis of the elimination half-life of 0.1% diclofenac sodium, which has the longest half-life of the 3 topical NSAIDs assessed in the study.24,25,26

The prolonged-dosing phase (days 16 to 43) of the study began immediately after the 2-day washout period following the fourth and final treatment of the immediate-dosing phase. As in the immediate-dosing phase, an online randomization tool was used to randomly assign each cat to 1 of 4 treatment orders. For each cat, 1 drop of the assigned treatment was applied to both eyes every 12 hours for 5 days. The CS of each eye was measured 15 minutes after instillation of the last dose of each treatment. After a washout period of 2 days, the process was repeated with the next designated treatment until all cats had received all 4 treatments. During each washout period, the CS was measured in both eyes once daily to confirm that it had returned to the baseline level before initiation of the next treatment.

Measurement of CS

Corneal sensitivity measurements were obtained by use of a Cochet-Bonnet esthesiometer.g Starting with a filament length of 60 mm, the 12/100-mm nylon filament was advanced perpendicularly toward the axial aspect of the cornea until a slight deflection of the filament was observed following corneal contact (Figure 1), after which the filament was withdrawn slightly, and the process repeated 4 more times. If a blink reflex was not elicited by the filament on at least 3 of the 5 attempts, the filament length was shortened in 5-mm decrements and the procedure was repeated. The recorded filament length was the shortest length (in millimeters) that induced a blink response on 3 of the 5 attempts (ie, the shorter the filament length, the less sensitive the cornea). The recorded filament length was then converted to CTT, which was reported in grams per square millimeter, on the basis of information provided in a conversion table supplied by the manufacturer of the esthesiometer. Only the axial aspect of the cornea was evaluated because it is the most sensitive portion of the cornea.27

Figure 1
Figure 1

Photograph that depicts the use of a Cochet-Bonnet esthesiometer with a 12/100-mm nylon filament to measure the CS of the left eye of a domestic shorthair cat. Starting with a filament length of 60 mm, the filament was advanced perpendicularly toward the axial aspect of the cornea until a slight deflection of the filament was observed following corneal contact, after which the filament was withdrawn slightly, and the process repeated 4 more times. If a blink reflex was not elicited by the filament on at least 3 of the 5 attempts, the filament length was shortened in 5-mm decrements and the procedure was repeated. The recorded filament length was the shortest length that induced a blink response on 3 of the 5 attempts (ie, the shorter the filament length, the less sensitive the cornea). Filament length was then converted to CTT (reported in g/mm2) on the basis of information provided in a conversion table supplied by the manufacturer of the esthesiometer.

Citation: American Journal of Veterinary Research 82, 1; 10.2460/ajvr.82.1.81

For each experiment, data were collected in a longitudinal fashion, with the baseline CS measurement designated as time 0 for calculation of changes over time. To minimize environmental (eg, lighting conditions, temperature, and humidity) and procedural variability on esthesiometric measurements, all CS measurements were performed in the same examination room by 1 investigator (JK Roberts). Minimal and gentle manual restraint was used for all cats. Additionally, to eliminate concerns about effects of the manufacturer's date on the mechanical properties (eg, rigidity and flexibility) of filaments, a new filament was obtained and used throughout the study.28 The ambient temperature and humidity as determined by a commercial thermometer and hygrometerh were also recorded for all CS measurements.

Statistical analysis

Data for the right and left eyes were analyzed separately for both the immediate-dosing and prolonged-dosing phases. The outcome of interest was CTT. The Anderson-Darling test was used to assess the data distribution for normality within each measurement time. Data were not normally distributed for multiple measurement times within each eye. Therefore, for each eye and treatment, the Friedman test (a 1-way repeated-measures ANOVA by ranks) was used to compare the CTT over time and between baseline and each day of the washout period. The Tukey adjustment was used when multiple post hoc pairwise comparisons were necessary. Values of P < 0.05 were considered significant for all comparisons. Results were summarized as the median (range).

Results

The study population consisted of 10 castrated males and 2 spayed females and had a mean ± SD age of 3.3 ± 1.3 years. The median CTT did not differ significantly between the right and left eyes at any measurement time during the immediate-dosing (P ≥ 0.66 for all comparisons) and prolonged-dosing (P ≥ 0.82 for all comparisons) phases.

The median Cochet-Bonnet filament length and CTT for the right and left eyes of all cats at all measurement times during the immediate-dosing (Table 1) and prolonged-dosing (Table 2) phases of the study were summarized. The median CTT did not differ significantly over time or between baseline and each of the 2 washout days for any of the 4 treatments during either study phase.

Table 1

Median (range) Cochet-Bonnet filament length and CTT for 12 ophthalmologically normal adult cats at various times before (baseline) and after topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium ophthalmic solutions and saline (0.9% NaCl) solution (control) at a dosage of 1 drop (0.05 mL)/eye, every 5 minutes, for a total of 5 applications (immediate-dosing phase).

Time after instillation of last dose (min)
Treatment Eye Variable Baseline 15 30 45 60 P value*
0.9% saline Right Filament length (mm) 45.0 (40–50) 45.0 (35–60) 45.0 (35–60) 45.0 (35–55) 45.0 (35–50)
solution CTT (g/mm2) 0.70 (0.55–0.8) 0.70 (0.4–1.0) 0.70 (0.4–1.0) 0.70 (0.5–1.0) 0.70 (0.55–1.0) 0.09
Left Filament length (mm) 45.0 (40–50) 45.0 (35–60) 40.0 (35–55) 45.0 (30–50) 42.5 (35–50)
CTT (g/mm2) 0.70 (0.55–0.8) 0.70 (0.4–1.0) 0.80 (0.5–1.0) 0.70 (0.55–1.4) 0.75 (0.55–1.8) 0.11
0.1% diclofenac Right Filament length (mm) 45.0 (40–50) 45.0 (30–55) 45.0 (35–55) 45.0 (35–55) 45.0 (35–55)
solution CTT (g/mm2) 0.70 (0.55–0.8) 0.70 (0.5–1.4) 0.70 (0.5–1.0) 0.70 (0.5–1.0) 0.70 (0.5–1.0) 0.09
Left Filament length (mm) 45.0 (40–50) 42.5 (35–55) 45.0 (30–55) 45.0 (40–55) 45.0 (30–55)
CTT (g/mm2) 0.70 (0.55–0.8) 0.75 (0.5–1.0) 0.70 (0.5–1.4) 0.70 (0.5–0.8) 0.70 (0.5–1.4) 0.17
0.5% ketorolac Right Filament length (mm) 45.0 (40–50) 40.0 (35–55) 42.5 (30–55) 45.0 (30–55) 42.5 (35–55)
tromethamine CTT (g/mm2) 0.70 (0.55–0.8) 0.80 (0.5–1.0) 0.75 (0.5–1.4) 0.70 (0.5–1.4) 0.75 (0.5–1.0) 0.89
Left Filament length (mm) 45.0 (40–50) 40.0 (35–60) 40.0 (35–55) 45.0 (35–55) 42.5 (35–50)
CTT (g/mm2) 0.70 (0.55–0.8) 0.80 (0.4–1.0) 0.80 (0.5–1.0) 0.70 (0.5–1.0) 0.75 (0.55–1.0) 0.62
0.03% flurbiprofen Right Filament length (mm) 45.0 (40–50) 45.0 (35–50) 45.0 (30–50) 45.0 (35–55) 45.0 (30–50)
sodium CTT (g/mm2) 0.70 (0.55–0.8) 0.70 (0.55–1.0) 0.70 (0.55–1.4) 0.70 (0.5–1.0) 0.70 (0.55–1.4) 0.16
Left Filament length (mm) 45.0 (40–50) 40.0 (35–50) 40.0 (30–50) 42.5 (35–50) 45.0 (30–50)
CTT (g/mm2) 0.70 (0.55–0.8) 0.80 (0.55–1.0) 0.80 (0.55–1.4) 0.75 (0.55–1.0) 0.70 (0.55–1.4) 0.21

Each cat received each treatment in a randomized order with a 2-day washout period between treatments. Corneal sensitivity measurements were obtained by use of a Cochet-Bonnet esthesiometer. Starting with a filament length of 60 mm, the 12/100-mm nylon filament was advanced perpendicularly toward the axial aspect of the cornea until a slight deflection of the filament was observed following corneal contact, after which the filament was withdrawn slightly, and the process repeated 4 more times. If a blink reflex was not elicited by the filament on at least 3 of the 5 attempts, the filament length was shortened in 5-mm decrements and the procedure was repeated. The recorded filament length was the shortest length that induced a blink response on 3 of the 5 attempts (ie, the shorter the filament length, the less sensitive the cornea). Filament length was then converted to CTT on the basis of information provided in a conversion table supplied by the manufacturer of the esthesiometer.

Value for the Friedman test in which CTT was compared over time.

— = Not calculated.

Table 2

Median (range) Cochet-Bonnet filament length and CTT for the cats of Table 1 at various times before (baseline) and after topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium ophthalmic solutions and saline solution (control) at a dosage of 1 drop (0.05 mL)/eye, every 12 hours for 5 days (prolonged-dosing phase).

Time after instillation of last dose (h)
Treatment Eye Variable Baseline 0.25 24 48 P value*
0.9% saline Right Filament length (mm) 45.0 (35–55) 42.5 (35–55) 40.0 (35–55) 42.5 (35–55)
solution CTT (g/mm2) 0.70 (0.5–1.0) 0.75 (0.5–1.0) 0.80 (0.5–1.0) 0.75 (0.5–1.0) 0.25
Left Filament length (mm) 42.5 (35–55) 40.0 (30–55) 42.5 (30–50) 45 (30–55)
CTT (g/mm2) 0.75 (0.5–1.0) 0.80 (0.5–1.4) 0.77 (0.55–1.4) 0.70 (0.5–1.4) 0.44
0.1% diclofenac Right Filament length (mm) 45.0 (35–55) 45.0 (35–55) 40.0 (35–50) 40.0 (35–55)
sodium CTT (g/mm2) 0.70 (0.5–1.0) 0.70 (0.4–1.0) 0.80 (0.55–1.0) 0.80 (0.5–1.0) 0.06
Left Filament length (mm) 42.5 (35–55) 45.0 (30–60) 45.0 (35–55) 40.0 (35–55)
CTT (g/mm2) 0.75 (0.5–1.0) 0.70 (0.4–1.4) 0.70 (0.5–1.0) 0.80 (0.5–1.0) 0.47
0.5% ketorolac Right Filament length (mm) 45.0 (35–55) 40.0 (35–55) 42.5 (35–55) 40.0 (35–55)
tromethamine CTT (g/mm2) 0.70 (0.5–1.0) 0.80 (0.5–1.0) 0.75 (0.5–1.0) 0.80 (0.5–1.0) 0.71
Left Filament length (mm) 42.5 (35–55) 42.5 (35–55) 45.0 (35–55) 45.0 (30–50)
CTT (g/mm2) 0.75 (0.5–1.0) 0.75 (0.5–1.0) 0.70 (0.5–1.0) 0.70 (0.55–1.4) 0.80
0.03% flurbiprofen Right Filament length (mm) 45.0 (35–55) 42.5 (35–55) 45.0 (35–60) 40.0 (35–55)
sodium CTT (g/mm2) 0.70 (0.5–1.0) 0.75 (0.5–1.0) 0.70 (0.4–1.0) 0.80 (0.5–1.0) 0.05
Left Filament length (mm) 42.5 (35–55) 45.0 (40–55) 42.5 (30–60) 40.0 (35–55)
CTT (g/mm2) 0.75 (0.5–1.0) 0.70 (0.5–0.8) 0.75 (0.4–1.4) 0.80 (0.5–1.0) 0.26

Each cat received each treatment in a randomized order with a 2-day washout period between treatments. The CS measurement obtained on the second day of the final washout period for the immediate-dosing phase was used as the baseline measurement for the prolonged-dosing phase.

See Table 1 for remainder of key.

Discussion

Results of the present study indicated that topical instillation of 3 NSAID ophthalmic solutions (0.1% diclofenac sodium, 0.5% ketorolac tromethamine, and 0.03% flurbiprofen sodium) at 5-minute intervals for 5 applications (immediate-dosing phase) or at 12-hour intervals for 5 days (prolonged-dosing phase) had no effect on the CTT (ie, did not induce corneal hypoesthesia) of ophthalmologically normal cats. Those findings were contrary to results of similar studies involving dogs29 and humans9,10,14,15,21,30,31 that suggest topical instillation of diclofenac, ketorolac, and flurbiprofen induces corneal analgesia. For the cats of the present study, the median CTT at baseline for both the immediate-dosing and prolonged-dosing phases was lower than the CTT for cats of other studies1,23,27,32 but was considered within the recommended reference interval owing to the large variation in the CTTs reported for the cats of those studies.

The findings of the present study were similar to the results of another study33 in which neither 0.1% diclofenac sodium nor 0.03% flurbiprofen sodium had any effect on the CS of ophthalmologically normal dogs following administration of multiple drops over a short duration or twice-daily dosing for 30 days. In a study29 of ophthalmologically normal nonbrachycephalic dogs, topical instillation of 0.1% diclofenac sodium resulted in a decrease in CS at 75 and 90 minutes after administration, whereas topical instillation of 0.03% flurbiprofen sodium resulted in an increase in CS between 15 and 30 minutes after administration and topical instillation of 0.5% ketorolac tromethamine had no effect on CS. Conversely, in ophthalmologically normal human subjects, repeated topical instillation of many NSAIDs including 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, 0.3% nepafenac, and 0.07% bromfenac consistently causes immediate and transient decreases in CS.9,10,14,15,21,22,30,31 The conflicting results observed in regard to the effects of topical NSAIDs on CS among cats, dogs, and humans are likely attributable to species-specific differences in neurochemistry and the proportion and distribution of mechano-nociceptors and polymodal nociceptors in the cornea.

Only limited information is available about COX expression in the ocular tissues of cats, although arachidonic acid metabolites (eg, prostaglandins and thromboxane) have been detected in ocular tissues of healthy cats.34 In a study20 of healthy and uveitic feline eyes, COX-2 was not constitutively expressed in healthy corneas but was detected in nearly half of uveitic eyes, which suggests that COX-2 may be present in the cornea only during active inflammation. Those findings were consistent with results of another study19 in which COX-2 expression was upregulated in all layers of the cornea in dogs with keratitis but was not present in the corneas of healthy dogs. If COX-2 is not present in healthy corneas, that may explain why the topical NSAIDs did not induce any changes in CS for the ophthalmologically normal cats of the present study. Although all topical ophthalmic NSAIDs are considered nonselective COX inhibitors (ie, inhibit both COX-1 and COX-2), the relative ratio of inhibitory potential for each drug differs.13,35,36 Among the topical NSAIDs selected for evaluation in the present study, 0.5% ketorolac tromethamine is the most COX-1 selective and 0.1% diclofenac sodium is the most COX-2 selective.13,35 Additional research is necessary to evaluate COX isoenzyme expression in both healthy and diseased eyes of cats to better assess the potential efficacy of topically instilled COX isoenzyme–specific NSAIDs.

Even though the topical NSAIDs assessed in the present study did not induce any changes in the CS for ophthalmologically normal cats, they may alter CS in cats with ocular disease. Further research on the effect of topical NSAID instillation in inflamed eyes (eg, eyes with herpetic keratitis with and without ulceration) of cats is warranted. Results of a study9 involving human patients with corneal epithelial defects secondary to Sjögren syndrome, an autoimmune disorder with inflammatory effects on the cornea and conjunctiva, suggest that topical ophthalmic instillation of 0.1% indomethacin or 0.1% diclofenac sodium 3 times daily significantly reduces CS and ocular discomfort. To our knowledge, no studies have been conducted to evaluate the antinociceptive effects of topical NSAIDs in cats with active, naturally occurring ocular surface disease.

The benefits of the use of topical NSAIDs to decrease CS and ameliorate pain associated with ocular surface inflammation should not overshadow the potential risk for delayed corneal wound healing or alterations in neurotrophic influence, which could lead to the development of neurotrophic epitheliopathy.12 In an in vitro study37 conducted to investigate the effects of commonly used topical anti-inflammatory medications and their associated preservatives on the morphological characteristics and migration of canine corneal epithelial cells, suprofen caused no changes in cell morphology at the lowest concentrations evaluated, but at higher concentrations, it induced cell rounding and shrinking in a concentration-dependent manner. Additionally, thimerosal (a preservative used in some topical NSAIDs including flurbiprofen and suprofen) inhibited the migration of corneal epithelial cells.37 In cats with experimentally induced corneal and limbal wounds, the rate of wound healing did not differ significantly between cats that received topical instillation of 0.5% ketorolac tromethamine 3 times daily and control cats that did not receive a topical anti-inflammatory treatment.7

Species and target tissue are important factors when considering NSAID administration. Systemic NSAIDs should be administered cautiously in cats because of their low capacity for hepatic glucuronidation, which is the major mechanism by which NSAIDs are metabolized and excreted.11,38 In 1 study,23 topical instillation of 0.1% diclofenac sodium 4 times daily to both eyes of healthy cats resulted in only mild signs of ocular irritation including transient blepharospasm and conjunctival hyperemia, and detectable concentrations of the drug accumulated in the systemic circulation over the 1-week treatment period. Cats of another study39 likewise developed detectable systemic drug concentrations following topical instillation of 0.1% diclofenac sodium and 0.03% flurbiprofen sodium in both eyes twice daily for 2 weeks. In cats, systemic absorption of 0.1% diclofenac sodium following topical instillation into the eyes may be associated with a reduction in glomerular filtration rate, particularly in volume-depleted animals.23 Therefore, clinicians are encouraged to use topical 0.1% diclofenac sodium cautiously, especially in regard to prolonged administration in systemically ill cats.

The present study was not without limitations. The number of cats evaluated was small. It is possible that evaluation of a larger number of cats may have led to different results. All study subjects were purpose-bred cats owned by the Kansas State University Comparative Medicine Group; thus, the number of cats available for study enrollment was limited. Another limitation was the lack of a true control group. Although physiologic saline solution served as a control, a more appropriate control treatment would have been an ophthalmic solution that contained a preservative because results of another study29 indicate that preservatives within ophthalmic solutions can significantly affect CS. The selection of a control solution containing only 1 preservative would have been complicated because all 3 of the commercially available topical NSAIDs evaluated in this study contained different preservatives. The 0.1% diclofenac sodium solution contains boric acid, 0.5% ketorolac tromethamine solution contains benzalkonium chloride, and 0.03% flurbiprofen sodium solution contains thimerosal. It is also possible that the twice-daily dosing regimen used during the prolonged-dosing phase of the study was insufficient to alter CS in cats, especially given that the surface area of the feline cornea is fairly large, when compared with that of the human cornea. Finally, corneal esthesiometry has inherent limitations and observer subjectivity. All esthesiometric measurements were performed by the same investigator throughout the present study to minimize procedural variability.

For the ophthalmologically normal cats of the present study, CS was not affected by topical instillation of 0.1% diclofenac sodium, 0.5% ketorolac tromethamine, 0.03% flurbiprofen sodium, or 0.9% saline (control) solutions in accordance with an immediate-dosing regimen (1 drop/eye, q 5 min for 5 treatments) or prolonged-dosing regimen (1 drop/eye, twice daily for 5 days). Given the potential differences in COX expression between healthy and diseased eyes, further investigation of the effects of topical NSAID instillation in the eyes of cats with ocular surface inflammation is warranted.

Acknowledgments

This manuscript represents a portion of a thesis submitted by Dr. Jordan K. Roberts to the Kansas State University Department of Clinical Sciences as partial fulfillment of the requirements for a Master of Science degree.

Supported by the Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University.

The authors declare that there were no conflicts of interest.

Abbreviations

COX

Cyclooxygenase

CS

Corneal sensitivity

CTT

Corneal touch threshold

Footnotes

a.

Akorn Inc, Lake Forest, Ill.

b.

Tono-Vet, Icare Finland, Espoo, Finland.

c.

SL-17, Kowa, Torrance, Calif.

d.

Amici Pharmaceuticals, Melville, NY.

e.

Fresenius USA Manufacturing Inc, Walnut Creek, Calif.

f.

Research Randomizer, version 4.0, Urbaniak GC, Plous S. Available at: randomizer.org. Accessed Jul 7, 2019.

g.

Luneau Ophtalmologie, Chartres Cedex, France.

h.

Extech 445703, Extech Instruments Corp, Waltham, Mass.

References

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    Chan-Ling T. Sensitivity and neural organization of the cat cornea. Invest Ophthalmol Vis Sci 1989;30:1075 1082.

  • 2.

    Nasisse MP, Guy JS, Davidson MG, et al. Experimental ocular herpesvirus infection in the cat. Sites of virus replication, clinical features and effects of corticosteroid administration. Invest Ophthalmol Vis Sci 1989;30:1758 1768.

    • Search Google Scholar
    • Export Citation
  • 3.

    Maggs DJ. Update on pathogenesis, diagnosis, and treatment of feline herpesvirus type 1. Clin Tech Small Anim Pract 2005;20:94 101.

  • 4.

    Gould D. Feline herpesvirus-1: ocular manifestations, diagnosis and treatment options. J Feline Med Surg 2011;13:333 346.

  • 5.

    Haesaert SP. Drugs and recurrent ocular herpes. Am J Optom Physiol Opt 1986;63:223 228.

  • 6.

    Hendricks RL, Barfknecht CF, Schoenwald RD, et al. The effect of flurbiprofen on herpes simplex virus type 1 stromal keratitis in mice. Invest Ophthalmol Vis Sci 1990;31:1503 1511.

    • Search Google Scholar
    • Export Citation
  • 7.

    Barba KR, Samy A, Lai C, et al. Effect of topical anti-inflammatory drugs on corneal and limbal wound healing. J Cataract Refract Surg 2000;26:893 897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Chen X, Gallar J, Belmonte C. Reduction by antiinflammatory drugs of the response of corneal sensory nerve fibers to chemical irritation. Invest Ophthalmol Vis Sci 1997;38:1944 1953.

    • Search Google Scholar
    • Export Citation
  • 9.

    Aragona P, Stilo A, Ferreri F, et al. Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren's syndrome patients. Eye (Lond) 2005;19:535 539.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Szerenyi K, Sorken K, Garbus JJ, et al. Decrease in normal human corneal sensitivity with topical diclofenac sodium. Am J Ophthalmol 1994;118:312 315.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Giuliano EA. Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology. Vet Clin North Am Small Anim Pract 2004;34:707 723.

  • 12.

    Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf 2002;25:233 250.

  • 13.

    Gaynes BI, Onyekwuluje A. Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension. Clin Ophthalmol 2008;2:355 368.

  • 14.

    Sun R, Gimbel HV. Effects of topical ketorolac and diclofenac on normal corneal sensation. J Refract Surg 1997;13:158 161.

  • 15.

    Narváez J, Kroll P, Guzek JP. Effect of topical diclofenac and ketorolac on patient discomfort and corneal sensitivity. J Refract Surg 2002;18:145 148.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol 2010;55:108 133.

  • 17.

    Ahuja M, Dhake AS, Sharma SK, et al. Topical ocular delivery of NSAIDs. AAPS J 2008;10:229 241.

  • 18.

    Radi ZA, Render JA. The pathophysiologic role of cyclo-oxygenases in the eye. J Ocul Pharmacol Ther 2008;24:141 151.

  • 19.

    Sellers RS, Silverman L, Khan KN. Cyclooxygenase-2 expression in the cornea of dogs with keratitis. Vet Pathol 2004;41:116 121.

  • 20.

    Sim ZH, Pinard CL, Plattner BL, et al. Cyclooxygenase-2 expression in the eyes of cats with and without uveitis. Am J Vet Res 2018;79:90 97.

  • 21.

    Aragona P, Tripodi G, Spinella R, et al. The effects of the topical administration of non-steroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects. Eye (Lond) 2000;14:206 210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Acosta MC, Berenguer-Ruiz L, García-Galvez A, et al. Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci 2005;46:282 286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Hsu KK, Pinard CL, Johnson RJ, et al. Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats. Am J Vet Res 2015;76:253 265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Todd PA, Sorkin EM. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1988;35:244 285.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Tang-Liu DD, Liu SS, Weinkam RJ. Ocular and systemic bio-availability of ophthalmic flurbiprofen. J Pharmacokinet Biopharm 1984;12:611 626.

  • 26.

    Gillis JC, Brogden RN. Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997;53:139 188.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Blocker T, Van Der Woerdt A. A comparison of corneal sensitivity between brachycephalic and domestic short-haired cats. Vet Ophthalmol 2001;4:127 130.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Lum E, Murphy PJ. Effects of ambient humidity on the Cochet-Bonnet aesthesiometer. Eye (Lond) 2018;32:1644 1651.

  • 29.

    Cantarella RA, de Oliveira JK, Dorbandt DM, et al. Effects of topical flurbiprofen sodium, diclofenac sodium, ketorolac tromethamine and benzalkonium chloride on corneal sensitivity in normal dogs. Open Vet J 2017;7:254 260.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Seitz B, Sorken K, LaBree LD, et al. Corneal sensitivity and burning sensation. Comparing topical ketorolac and diclofenac. Arch Ophthalmol 1996;114:921 924.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Singer DD, Kennedy J, Wittpenn JR. Topical NSAIDs effect on corneal sensitivity. Cornea 2015;34:541 543.

  • 32.

    Binder DR, Herring IP. Duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in clinically normal cats. Am J Vet Res 2006;67:1780 1782.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Dorbandt DM, Labelle AL, Mitchell MA, et al. The effects of topical diclofenac, topical flurbiprofen, and humidity on corneal sensitivity in normal dogs. Vet Ophthalmol 2017;20:160 170.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Kulkarni PS, Fleisher L, Srinivasan BD. The synthesis of cyclooxygenase products in ocular tissues of various species. Curr Eye Res 1984;3:447 452.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin 2006;22:1133 1140.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Masferrer JL, Kulkarni PS. Cyclooxygenase-2 inhibitors: a new approach to the therapy of ocular inflammation. Surv Ophthalmol 1997;41(suppl 2):S35–S40.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Hendrix DV, Ward DA, Barnhill MA. Effects of anti-inflammatory drugs and preservatives on morphologic characteristics and migration of canine corneal epithelial cells in tissue culture. Vet Ophthalmol 2002;5:127 135.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract 2013;43:1039 1054.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lanuza R, Rankin AJ, KuKanich B, et al. Evaluation of systemic absorption and renal effects of topical ophthalmic flurbiprofen and diclofenac in healthy cats. Vet Ophthalmol 2016;19(suppl 1):24 29.

    • Crossref
    • Search Google Scholar
    • Export Citation

Supplementary Materials

  • Figure 1

    Photograph that depicts the use of a Cochet-Bonnet esthesiometer with a 12/100-mm nylon filament to measure the CS of the left eye of a domestic shorthair cat. Starting with a filament length of 60 mm, the filament was advanced perpendicularly toward the axial aspect of the cornea until a slight deflection of the filament was observed following corneal contact, after which the filament was withdrawn slightly, and the process repeated 4 more times. If a blink reflex was not elicited by the filament on at least 3 of the 5 attempts, the filament length was shortened in 5-mm decrements and the procedure was repeated. The recorded filament length was the shortest length that induced a blink response on 3 of the 5 attempts (ie, the shorter the filament length, the less sensitive the cornea). Filament length was then converted to CTT (reported in g/mm2) on the basis of information provided in a conversion table supplied by the manufacturer of the esthesiometer.

  • 1.

    Chan-Ling T. Sensitivity and neural organization of the cat cornea. Invest Ophthalmol Vis Sci 1989;30:1075 1082.

  • 2.

    Nasisse MP, Guy JS, Davidson MG, et al. Experimental ocular herpesvirus infection in the cat. Sites of virus replication, clinical features and effects of corticosteroid administration. Invest Ophthalmol Vis Sci 1989;30:1758 1768.

    • Search Google Scholar
    • Export Citation
  • 3.

    Maggs DJ. Update on pathogenesis, diagnosis, and treatment of feline herpesvirus type 1. Clin Tech Small Anim Pract 2005;20:94 101.

  • 4.

    Gould D. Feline herpesvirus-1: ocular manifestations, diagnosis and treatment options. J Feline Med Surg 2011;13:333 346.

  • 5.

    Haesaert SP. Drugs and recurrent ocular herpes. Am J Optom Physiol Opt 1986;63:223 228.

  • 6.

    Hendricks RL, Barfknecht CF, Schoenwald RD, et al. The effect of flurbiprofen on herpes simplex virus type 1 stromal keratitis in mice. Invest Ophthalmol Vis Sci 1990;31:1503 1511.

    • Search Google Scholar
    • Export Citation
  • 7.

    Barba KR, Samy A, Lai C, et al. Effect of topical anti-inflammatory drugs on corneal and limbal wound healing. J Cataract Refract Surg 2000;26:893 897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Chen X, Gallar J, Belmonte C. Reduction by antiinflammatory drugs of the response of corneal sensory nerve fibers to chemical irritation. Invest Ophthalmol Vis Sci 1997;38:1944 1953.

    • Search Google Scholar
    • Export Citation
  • 9.

    Aragona P, Stilo A, Ferreri F, et al. Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren's syndrome patients. Eye (Lond) 2005;19:535 539.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Szerenyi K, Sorken K, Garbus JJ, et al. Decrease in normal human corneal sensitivity with topical diclofenac sodium. Am J Ophthalmol 1994;118:312 315.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Giuliano EA. Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology. Vet Clin North Am Small Anim Pract 2004;34:707 723.

  • 12.

    Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf 2002;25:233 250.

  • 13.

    Gaynes BI, Onyekwuluje A. Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension. Clin Ophthalmol 2008;2:355 368.

  • 14.

    Sun R, Gimbel HV. Effects of topical ketorolac and diclofenac on normal corneal sensation. J Refract Surg 1997;13:158 161.

  • 15.

    Narváez J, Kroll P, Guzek JP. Effect of topical diclofenac and ketorolac on patient discomfort and corneal sensitivity. J Refract Surg 2002;18:145 148.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol 2010;55:108 133.

  • 17.

    Ahuja M, Dhake AS, Sharma SK, et al. Topical ocular delivery of NSAIDs. AAPS J 2008;10:229 241.

  • 18.

    Radi ZA, Render JA. The pathophysiologic role of cyclo-oxygenases in the eye. J Ocul Pharmacol Ther 2008;24:141 151.

  • 19.

    Sellers RS, Silverman L, Khan KN. Cyclooxygenase-2 expression in the cornea of dogs with keratitis. Vet Pathol 2004;41:116 121.

  • 20.

    Sim ZH, Pinard CL, Plattner BL, et al. Cyclooxygenase-2 expression in the eyes of cats with and without uveitis. Am J Vet Res 2018;79:90 97.

  • 21.

    Aragona P, Tripodi G, Spinella R, et al. The effects of the topical administration of non-steroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects. Eye (Lond) 2000;14:206 210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Acosta MC, Berenguer-Ruiz L, García-Galvez A, et al. Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci 2005;46:282 286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Hsu KK, Pinard CL, Johnson RJ, et al. Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats. Am J Vet Res 2015;76:253 265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Todd PA, Sorkin EM. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1988;35:244 285.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Tang-Liu DD, Liu SS, Weinkam RJ. Ocular and systemic bio-availability of ophthalmic flurbiprofen. J Pharmacokinet Biopharm 1984;12:611 626.

  • 26.

    Gillis JC, Brogden RN. Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997;53:139 188.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Blocker T, Van Der Woerdt A. A comparison of corneal sensitivity between brachycephalic and domestic short-haired cats. Vet Ophthalmol 2001;4:127 130.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Lum E, Murphy PJ. Effects of ambient humidity on the Cochet-Bonnet aesthesiometer. Eye (Lond) 2018;32:1644 1651.

  • 29.

    Cantarella RA, de Oliveira JK, Dorbandt DM, et al. Effects of topical flurbiprofen sodium, diclofenac sodium, ketorolac tromethamine and benzalkonium chloride on corneal sensitivity in normal dogs. Open Vet J 2017;7:254 260.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Seitz B, Sorken K, LaBree LD, et al. Corneal sensitivity and burning sensation. Comparing topical ketorolac and diclofenac. Arch Ophthalmol 1996;114:921 924.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Singer DD, Kennedy J, Wittpenn JR. Topical NSAIDs effect on corneal sensitivity. Cornea 2015;34:541 543.

  • 32.

    Binder DR, Herring IP. Duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in clinically normal cats. Am J Vet Res 2006;67:1780 1782.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Dorbandt DM, Labelle AL, Mitchell MA, et al. The effects of topical diclofenac, topical flurbiprofen, and humidity on corneal sensitivity in normal dogs. Vet Ophthalmol 2017;20:160 170.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Kulkarni PS, Fleisher L, Srinivasan BD. The synthesis of cyclooxygenase products in ocular tissues of various species. Curr Eye Res 1984;3:447 452.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin 2006;22:1133 1140.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Masferrer JL, Kulkarni PS. Cyclooxygenase-2 inhibitors: a new approach to the therapy of ocular inflammation. Surv Ophthalmol 1997;41(suppl 2):S35–S40.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Hendrix DV, Ward DA, Barnhill MA. Effects of anti-inflammatory drugs and preservatives on morphologic characteristics and migration of canine corneal epithelial cells in tissue culture. Vet Ophthalmol 2002;5:127 135.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract 2013;43:1039 1054.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lanuza R, Rankin AJ, KuKanich B, et al. Evaluation of systemic absorption and renal effects of topical ophthalmic flurbiprofen and diclofenac in healthy cats. Vet Ophthalmol 2016;19(suppl 1):24 29.

    • Crossref
    • Search Google Scholar
    • Export Citation

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