Effect of topical administration of 0.1% diclofenac sodium ophthalmic solution at four frequencies on intraocular pressure in healthy Beagles

Brittany B. Martabano 1Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80525.

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Michala de Linde Henriksen 1Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80525.

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Jenny A. Colussi 1Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80525.

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Julia L. Sharp 2Department of Statistics, College of Natural Sciences, Colorado State University, Fort Collins, CO 80523.

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Zeke Wang 2Department of Statistics, College of Natural Sciences, Colorado State University, Fort Collins, CO 80523.

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Michael R. Lappin 1Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80525.

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Abstract

OBJECTIVE

To evaluate effects of topical ophthalmic administration of diclofenac on intraocular pressure (IOP) when applied at 4 frequencies to eyes of Beagles.

ANIMALS

8 ophthalmologically normal Beagles.

PROCEDURES

The study involved four 5-day experimental periods each separated by a 16-day washout period. During each period, 1 drop of 0.1% diclofenac sodium ophthalmic solution was administered to the right eye at 4 treatment frequencies (1, 2, 3, or 4 times/d); 1 drop of eyewash was administered to the left eye as a control treatment. A complete ophthalmic examination was performed on days 0 (day before first treatment) and 5 of each experimental period. Gonioscopy was performed on day 0 of the first period. The IOPs were measured at 7 am and 7 pm on days 1 through 5.

RESULTS

No abnormalities were detected during neuro-ophthalmic and ophthalmic examinations on day 0 of each experimental period. No adverse reactions to administration of diclofenac or eyewash were observed at any time point. No abnormalities were detected during ophthalmic examinations performed on day 5, and IOPs remained < 25 mm Hg in all 4 periods. No significant differences were identified between the treated and control eyes or among the 4 treatment frequencies.

CONCLUSIONS AND CLINICAL RELEVANCE

Topical ophthalmic administration of diclofenac up to 4 times/d in dogs with no ophthalmic abnormalities did not significantly increase the IOP. Additional research is needed to evaluate the effect of topical ophthalmic administration of diclofenac on IOP in dogs with anterior uveitis.

Abstract

OBJECTIVE

To evaluate effects of topical ophthalmic administration of diclofenac on intraocular pressure (IOP) when applied at 4 frequencies to eyes of Beagles.

ANIMALS

8 ophthalmologically normal Beagles.

PROCEDURES

The study involved four 5-day experimental periods each separated by a 16-day washout period. During each period, 1 drop of 0.1% diclofenac sodium ophthalmic solution was administered to the right eye at 4 treatment frequencies (1, 2, 3, or 4 times/d); 1 drop of eyewash was administered to the left eye as a control treatment. A complete ophthalmic examination was performed on days 0 (day before first treatment) and 5 of each experimental period. Gonioscopy was performed on day 0 of the first period. The IOPs were measured at 7 am and 7 pm on days 1 through 5.

RESULTS

No abnormalities were detected during neuro-ophthalmic and ophthalmic examinations on day 0 of each experimental period. No adverse reactions to administration of diclofenac or eyewash were observed at any time point. No abnormalities were detected during ophthalmic examinations performed on day 5, and IOPs remained < 25 mm Hg in all 4 periods. No significant differences were identified between the treated and control eyes or among the 4 treatment frequencies.

CONCLUSIONS AND CLINICAL RELEVANCE

Topical ophthalmic administration of diclofenac up to 4 times/d in dogs with no ophthalmic abnormalities did not significantly increase the IOP. Additional research is needed to evaluate the effect of topical ophthalmic administration of diclofenac on IOP in dogs with anterior uveitis.

Topical ophthalmic NSAID formulations are commonly used in veterinary medicine to control chronic low-grade intraocular infammation or after intraocular surgery (eg, phacoemulsification).1–4 These drugs decrease infammation through the inhibition of prostaglandin synthesis1,2 and inhibit COX enzymes that convert arachidonic acid to prostaglandins and thromboxane A2.5,6 Two COX isoenzymes have been identified. Constitutive COX-1, which is equally expressed on the endoplasmic reticulum of all cells, is responsible for production of prostaglandins that are required for tissue homeostasis, whereas COX-2 is responsible for production of prostaglandins primarily at sites of infammation.2,7 Topical ophthalmic NSAID formulations commonly used in veterinary medicine (eg, 0.1% diclofenac, 0.03% furbiprofen, and 0.5% ketorolac) are considered nonselective COX inhibitors, whereas 0.09% bromfenac is considered a COX-2–selective inhibitor.7

A paucity of reports exist on the effects of topical application of NSAIDs or the frequency of application of NSAIDs on IOP in ophthalmically normal animals. It is believed that topically applied NSAIDs have the potential to increase IOP.8–12 In human medicine, studies13–16 have yielded conflicting results regarding the effect of topically applied NSAIDs on IOPs. The purpose of the study reported here was to determine the effect of topical ophthalmic administration of diclofenac at 4 treatment frequencies on IOP of ophthalmically normal Beagles. We hypothesized that diclofenac topically administered at a frequency of 1, 2, 3, and 4 times/d would cause a significant increase in IOP in ophthalmically normal eyes of dogs and that the increase would be in a frequency-dependent manner.

Materials and Methods

Dogs

Eight sexually intact male Beagles were used in the study. All of the dogs were research Beagles that had been conditioned to routine handling and various diagnostic procedures. All dogs were housed alone or in pairs in cages of a research facility under controlled environmental conditions (12 hours of light and 12 hours of darkness; lights on at 7 am and lights off at 7 pm) throughout the duration of the study. The study was performed in compliance with Colorado State University guidelines for research and approved by an institutional animal care and use committee (protocol No. 17-7601A).

Ophthalmic examination

The study consisted of four 5-day experimental periods. The day before the start of each experimental period (day 0), all dogs were weighed and a full ophthalmic examination (including gonioscopy prior to experimental period 1) was performed by both a board-certified veterinary ophthalmologist (MdLH) and an intern in a veterinary ophthalmology training program (BBM). Ophthalmic examination included a neuro-ophthalmic examination (menace response, dazzle reflex, direct and indirect pupillary light responses, palpebral reflex, and oculocephalic reflex), evaluation of tear production with STT stripsa (reference range, > 15 mm/min),17 assessment after application of fluorescein stain,18,b rebound tonometryc to measure IOP (reference range, 12 to 25 mm Hg),18 slit-lamp biomicroscopy,d and binocular indirect ophthalmoscopye with a 2.2 panretinal lens.f Three IOP measurements with an SD ≤ 5% (indicated as a low or absent bar on the result screen) were recorded, and the mean of the 3 measurements was calculated. Gonioscopyg was performed during the ophthalmic examination of the initial experimental period to enable evaluation of the anterior face of the iridocorneal angle and ciliary cleft for signs of goniodysgenesis (cleft angle categorized as normal open, narrow, or closed).18 A normal open angle was defined as a normal width ciliary cleft and normal appearance of the pectinate ligament in all 4 quadrants (inferior, superior, nasal, and temporal).19,20 Dogs with abnormalities for the ophthalmic and neuro-ophthalmic examinations, including gonioscopy, were excluded from the study.

Ophthalmic treatments were administered on days 1 through 5. An ophthalmic examination, including neuro-ophthalmic examination, slit-lamp biomicroscopy, indirect ophthalmoscopy, evaluation of tear production with an STT, assessment after application of fluorescein stain, and rebound tonometry to measure IOP, was performed on day 5 at the end of each experimental period; gonioscopy was not repeated on day 5.

Experimental procedures

During the first experimental period, each dog received 1 drop (0.05 mL/drop) of 0.1% diclofenac sodium ophthalmic solutionh in the right eye (treated eye)21 and 1 drop (0.05 mL/drop) of purified water eyewashi in the left eye (control eye)21 1 time/d (7 am). During the second experimental period, each dog received 1 drop of diclofenac in the right eye and 1 drop of eyewash in the left eye 2 times/d (7 am and 7 pm). During the third experimental period, each dog received 1 drop of diclofenac in the right eye and 1 drop of eyewash in the left eye 3 times/d (7 am, 1 pm, and 7 pm). During the fourth experimental period, each dog received 1 drop of diclofenac in the right eye and 1 drop of eyewash in the left eye 4 times/d (7 am, 11 am, 4 pm, and 9 pm). Treatments were administered at times that would mimic the typical time for owner administration during waking hours at each frequency. The treatments were administered immediately after IOP was measured when the times coincided. A 16-day washout period was provided between successive experimental periods.

During each experimental period, IOP was measured by use of a rebound tonometer at 7 am and 7 pm on days 1 through 5. Twice-daily measurement of IOP was selected to provide measurements in the morning and evening but limit handling of the dogs and potential stress that could result if dogs were handled > 2 times/d. All IOP measurements were obtained by the same investigator (BBM), during which each dog was gently manually restrained. Dogs were allowed to remain in the position (standing, sitting, or sternal recumbency) in which they appeared to be most comfortable, with the head directed straight forward to ensure there was no jugular vein compression during recording of IOPs. For each time point, 3 IOP measurements (each with an SD ≤ 5%) were recorded; the mean for the 3 measurements was calculated. At all time points, the IOP of the right eye was recorded first and then that of the left eye.

Before each IOP measurement, the dog was grossly examined (without a slit-lamp biomicroscope) for evidence of potential adverse reactions to the treatment. Signs considered consistent with an adverse reaction included blepharospasm, conjunctival hyperemia, and ocular discharge.

Statistical analysis

Data analyses were performed with statistical analysis software.j A linear mixed-effects model was used to compare IOP measured on day 5 at 7 pm between the treated and control eye (fixed effect) and among treatment frequencies (fixed effect) and to assess potential interaction between treatment and treatment frequency. Dog was included as a random effect in the model to account for the fact that measurements were performed on both eyes. A linear mixed-effects model was used to compare treatment, treatment frequency, time (morning and evening; fixed effects), and all 2-way interactions; dog was included as a random effect in the model to account for the measurements on both eyes. The Akaike information criterion value was used to select the appropriate covariance structure necessary to account for covariation among measurements within individual dogs; the Toeplitz covariance structure was selected.22 The IOP obtained at 7 am on day 1 and 7 am on day 5 for each treatment frequency and for each eye were compared by use of the matched-pairs t test. Values of P ≤ 0.05 were considered significant.

Results

Mean ± SD age of the 8 Beagles was 1.8 ± 0.7 years (range, 1.3 to 2.7 years), and mean body weight was 10.9 ± 2.1 kg (range, 7.8 to 13.2 kg). No abnormalities were detected during the neuro-ophthalmic and ophthalmic examinations conducted on each dog at the start of each experimental period (day 0). No abnormalities were detected during the gonioscopic examinations; there were no signs of a narrow or closed ciliary cleft or an abnormal pectinate ligament that could have indicated goniodysplasia and predisposition for primary angle-closure glaucoma. Mean IOP of all dogs remained within the reference range throughout the study. No adverse reactions to the diclofenac administration were detected during the study. No abnormalities were detected during neuro-ophthalmic and ophthalmic examinations conducted at the completion of each experimental period (day 5).

Mean ± SD IOP for the treated eye across all treatment frequencies and IOP measurements (days 1 through 5) was 16.77 ± 2.55 mm Hg, whereas mean IOP for the control eye was 16.91 ± 2.47 mm Hg. Mean IOP for the treated eye on day 5 across all treatment frequencies was 17.27 ± 2.55 mm Hg; mean IOP for the control eye was 17.58 ± 2.68 mm Hg (Table 1). Mean IOP for the treated and control eyes across all study days and treatment frequencies was summarized (Figure 1). There were no significant differences in IOP between treated and control eyes (P = 0.208) or among treatment frequencies (P = 0.337), and there was no evidence of an interaction between treatment frequency and treatment (treated vs control) for IOPs measured at 7 pm on day 5. This indicated that there was no significant difference in IOP between the treated and control eyes among the 4 treatment frequencies on the last day of each experimental period.

Table 1—

Mean ± SD values of IOP for 8 ophthalmologically normal Beagles treated with 0.1% diclofenac sodium ophthalmic solution (treated eyes) or eyewash solution (control eyes) at each of 4 treatment frequencies.

Treatment frequency (No./d)Day 1Day 2Day 3Day 4Day 5Overall
TreatedControlTreatedControlTreatedControlTreatedControlTreatedControlTreatedControl 
118.3518.5617.0815.7117.2916.9017.50 17.9018.2317.6317.31
± 2.84± 2.42± 2.83± 2.46± 2.93± 2.71± 2.16± 2.55± 2.51± 2.92± 2.64± 2.75
217.6417.5616.5617.2917.2917.2716.1316.6317.1317.5016.9517.25
± 2.36± 2.45± 2.72± 2.05± 2.62± 2.62± 1.83± 1.91± 2.41± 2.49± 2.41± 2.29
316.8117.3316.2716.4816.1316.1516.6316.7517.2717.5816.6216.86
± 1.61± 1.93± 2.30± 1.95± 2.44± 1.89± 3.22± 2.53± 2.59± 2.64± 2.46± 2.22
415.6316.6515.1915.5615.7315.8316.1016.0016.7917.0015.8916.21
± 2.39± 2.37± 2.56± 2.51± 1.60± 2.08± 2.65± 2.64± 2.78± 2.75± 2.43± 2.47
Overall17.1117.5316.2816.2616.6116.5416.5916.6417.2717.5816.7716.91
± 2.51± 2.35± 2.64± 2.31± 2.49± 2.36± 2.53± 2.40± 2.55± 2.68± 2.55± 2.47

Diclofenac solution was administered to the right eye and eyewash solution to the left eye 1 time/d (7 am), 2 times/d (7 am and 7 pm), 3 times/d (7 am, 1 pm, and 7 pm), and 4 times/d (7 am, 11 am, 4 pm, and 9 pm) for 5 days. The IOP was measured twice daily at 7 am and 7 pm. A washout period of 16 days was provided between successive experimental periods.

Figure 1—
Figure 1—

Mean ± SD values of IOP for 8 ophthalmologically normal Beagles treated with 0.1% diclofenac sodium ophthalmic solution (solid line) or eyewash solution (control eyes; dotted line) at each of 4 treatment frequencies. Diclofenac solution was administered to the right eye and eyewash solution to the left eye 1 time/d (7 am; a), 2 times/d (7 am and 7 pm; B), 3 times/d (7 am, 1 pm, and 7 pm; C), and 4 times/d (7 am, 11 am, 4 pm, and 9 pm; D) for 5 days. The IOP was measured twice daily at 7 am and 7 pm. A washout period of 16 days was provided between successive experimental periods.

Citation: American Journal of Veterinary Research 81, 1; 10.2460/ajvr.81.1.41

Time of day (am and pm) was also included in the statistical model to account for variation in IOP within and between days. No significant interaction was identified between treatment frequency and treatment (P = 0.970) or between treatment and time of day (P = 0.660). This indicated that the mean IOP did not differ significantly between treatments among treatment frequencies and mean IOP over time did not differ significantly between treatments. A significant (P < 0.001) interaction was identified between treatment frequency and time of day, which indicated that changes in mean IOP over time were not the same for all treatment frequencies. For example, mean IOP for treatment with diclofenac 4 times/d was the lowest on all days and among all treatment frequencies, except for the morning of days 3 and 4 (Figure 1). Again, there were no significant differences in mean IOP between treated and control eyes (P = 0.769) or among treatment frequencies (P = 0.175). No significant (P value range, 0.437 to 0.858) differences were detected between mean IOP at 7 am on day 1 and 7 am on day 5 for any of the 4 treatment frequencies for the treated or control eyes. No diurnal effect on IOP was detected.

Discussion

The objective of the study reported here was to evaluate the effect of topical administration of 0.1% diclofenac sodium ophthalmic solution on IOP in ophthalmically normal eyes of dogs. Diclofenac often is topically applied after intraocular surgery to reduce postoperative inflammation or control low-grade anterior uveitis in veterinary1,23,24 and human25 patients. There was no effect at any time of topical administration of 0.1% diclofenac sodium on IOP in ophthalmically normal Beagles when the drug was administered at 4 frequencies (1 to 4 times/d) during the 5-day treatment period. Additionally, there was no effect of duration of treatment on IOP as determined by comparison of IOP of the treated eye on days 1 and 5.

To evaluate potential effects of diclofenac administration in the treated eye on IOP of the control eye, mean IOP of the control eye at 7 am on day 1, which was measured before any medication was administered, was compared with the mean IOP of the control eye at 7 am on day 5 of each experimental period. The lack of a significant difference in these values indicated that there was no contralateral effect on the control eye for any of the 4 treatment frequencies, nor was a diurnal effect on IOP detected. Although evaluation of potential diurnal effects was not our primary objective, a higher IOP was detected in the morning in another study.26

No relevant effect of topical administration of diclofenac on IOP was detected in the study reported here; however, clinical decisions regarding the topical administration of NSAIDs in eyes with inflammation and a high IOP should be considered carefully. Most of the published literature suggests that dogs with intraocular inflammation treated with topical NSAIDs frequently have a significant increase in IOP, compared with results for control treatments.8–10,27 However, administration of flurbiprofen and corticosteroid drugs in eyes of dogs with laser capsulotomy–induced inflammation did not cause a significant change in IOP in 1 study.28 It is important to mention that IOP was measured for only 1 hour after laser capsulotomy in that study,28 and this may not have been a sufficient amount of time to determine that treatment had no effect on IOP.

In a study8 conducted to evaluate the effect of diclofenac and other topically applied anti-inflammatory medications on the IOP of dogs with pilocarpine-induced aqueous flare, it was found that both diclofenac and flurbiprofen (administered topically 3 times/d during a 2-day treatment period) resulted in significant elevations in IOP at 31 hours after inflammatory insult. A conflicting result was obtained in a study25 of humans, which revealed that diclofenac does not affect the incidence or magnitude of IOP increases during the early postoperative period after cataract surgery. In another randomized, double-masked study29 that involved evaluation of the effects of ketorolac, diclofenac, and prednisolone acetate on treatment of flare induced by phacoemulsification in human patients, no significant effect on postoperative hypertension was detected among treatments.

Because it has not been consistently determined that there is elevation in IOP in the inflamed eyes of humans or dogs treated with topically administered NSAIDs, the mechanism underlying a high IOP is not fully understood. However, in situations where an increase in IOP is detected, this increase is thought to be related to a decrease in outflow at the iridocorneal angle.11 Several mechanisms have been proposed for the manner by which anti-inflammatory treatments (including corticosteroid drugs) may cause an increase in IOP in humans. Proposed mechanisms include alterations in extracellular matrix components within the aqueous humor outflow pathway,30 inhibition of proteases and phagocytosis within the trabecular meshwork,31 accumulation of mucopolysaccharides in the iridocorneal angle,32 and alterations in the morphology of trabecular meshwork cells,33 all of which lead to an increase in resistance of the outflow of aqueous humor.9,30

In 1 study,10 dogs received the COX-inhibitor flunixin meglumine administered IV or flurbiprofen administered topically, and acute inflammation was induced by disruption of the anterior lens capsule by use of a neodymium:yttrium-aluminum-garnet laser. Both drugs caused an increase in IOP in the inflamed eyes, compared with the IOP in untreated control eyes. It was postulated that the increase in IOP could have been attributable to an increase in ocular blood flow that led to an increase in the fluid volume of the ciliary processes and increased ultrafiltration of aqueous humor, thus resulting in influx of extravasate into the eye associated with disruption of the blood-aqueous barrier. Alternatively, the investigators in that study10 proposed that prostaglandin production as a part of the response to ocular irritation could have led to an increase in IOP. Therefore, topical use of anti-inflammatory agents may contribute to increases in IOP by decreasing prostaglandin release.10

Several studies have been performed to evaluate the effect of topical administration of flurbiprofen on inflamed eyes. However, it is unclear whether extrapolation of these results to diclofenac is appropriate. In a pharmacokinetic study34 of diclofenac and flurbiprofen in humans, diclofenac was detected in the aqueous humor at lower concentrations than was flurbiprofen but for a longer duration (up to 24 hours after instillation, whereas flurbiprofen could not be detected > 7.25 hours after instillation). Information about the specific effects of diclofenac on IOP in inflamed eyes is also important because flurbiprofen currently is not being manufactured.

One limitation of the study reported here was the small number of Beagles. In addition, the treatment duration of 5 days was substantially less than in clinical settings, but it was chosen in an effort to reduce the use of the Beagles for prolonged periods. Before the study was initiated, we made the decision to measure IOP twice daily during each experimental period to reduce stress on the Beagles and to limit the amount of handling. This was a limitation because a potential short-term effect of diclofenac during the 12-hour window between 7 am and 7 pm could have resulted in an increase in IOP that was missed.

In another study35 conducted to evaluate the effect of a systemically administered medication on IOP in Beagles, investigators found that an acclimation period of 5 days was necessary for accurate IOP results. Dogs of the present study were not provided an acclimation period, which could be considered a limitation. However, they were well accustomed to routine handling and restraint and displayed no evidence of distress during IOP measurements. In addition, the data did not indicate an increase in variability in measurements obtained during the first and fourth experimental periods.

Results of the present study suggested that there was minimal effect on the IOP of ophthalmically normal dogs with the topical administration of 0.1% diclofenac sodium ophthalmic solution. However, additional studies of the use of diclofenac in eyes with experimentally induced intraocular inflammation in a controlled setting are required to evaluate the effect of diclofenac used at various treatment frequencies on inflamed eyes. Topical use of diclofenac for dogs with ocular inflammation or a history of postoperative hypertension or glaucoma should be carefully considered until appropriate studies have been performed.

Acknowledgments

Supported in part by the Colorado State University College of Veterinary Medicine and Biomedical Sciences Center for Companion Animal Studies Young Investigator Grant program; supplies and equipment were provided by Anvision Inc and Jorgensen Labs. Sources of support or supplies and equipment did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

The authors declare that there were no conflicts of interest.

Presented as an abstract at the American College of Veterinary Ophthalmologists Annual Conference, Minneapolis, September 2018.

ABBREVIATIONS

COX

Cyclooxygenase

IOP

Intraocular pressure

STT

Schirmer tear test

Footnotes

a.

Mark Blu STT, OptiTech Eyecare, Allahabad, India.

b.

Fluorescein sodium ophthalmic strips, OptiTech Eyecare, Allahabad, India.

c.

TonoVet, Icare Finland Oy, Helsinki, Finland.

d.

Kowa SL–17 portable slit-lamp biomicroscope, Kowa Co, Tokyo, Japan.

e.

Welch Allyn binocular indirect ophthalmoscope, Welch Allyn Distributors, Skaneateles Falls, NY.

f.

Volk 2.2 pan retinal lens, Volk Optical Inc, Mentor, Ohio.

g.

Ocular Koeppe diagnostic gonio lens, Ocular Instruments, Bellevue, Wash.

h.

Alcon, Fort Worth, Tex.

i.

Major Pharmaceuticals, Livonia, Mich.

j.

SAS, version 9.4, SAS Institute Inc, Cary, NC.

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