Comparison of the effects of IV administration of meloxicam, carprofen, and flunixin meglumine on prostaglandin E2 concentration in aqueous humor of dogs with aqueocentesis-induced anterior uveitis

Margi A. Gilmour Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078.

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Mark E. Payton Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078.

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Abstract

Objective—To compare the effects of meloxicam, carprofen, and flunixin meglumine administered IV on the concentration of prostaglandin E2 (PGE2) in the aqueous humor of dogs with aqueocentesis-induced anterior uveitis.

Animals—15 adult dogs with ophthalmically normal eyes.

Procedures—Each dog was assigned to 1 of 4 treatment groups. Treatment groups were saline (0.9% NaCl) solution (1 mL, IV), meloxicam (0.2 mg/kg, IV), carprofen (4.4 mg/kg, IV), and flunixin meglumine (0.5 mg/kg, IV). Each dog was anesthetized, treatment was administered, and aqueocentesis was performed on each eye at 30 and 60 minutes after treatment. Aqueous humor samples were frozen at −80°C until assayed for PGE2 concentration with an enzyme immunoassay kit.

Results—For all 4 treatment groups, PGE2 concentration was significantly higher in samples obtained 60 minutes after treatment, compared with that in samples obtained 30 minutes after treatment, which indicated aqueocentesis-induced PGE2 synthesis. For aqueous humor samples obtained 60 minutes after treatment, PGE2 concentration did not differ significantly among groups treated with saline solution, meloxicam, and carprofen; however, the PGE2 concentration for the group treated with flunixin meglumine was significantly lower than that for each of the other 3 treatment groups.

Conclusions and Clinical Relevance—Flunixin meglumine was more effective than meloxicam or carprofen for minimizing the PGE2 concentration in the aqueous humor of dogs with experimentally induced uveitis. Flunixin meglumine may be an appropriate pre-medication for use prior to intraocular surgery in dogs.

Abstract

Objective—To compare the effects of meloxicam, carprofen, and flunixin meglumine administered IV on the concentration of prostaglandin E2 (PGE2) in the aqueous humor of dogs with aqueocentesis-induced anterior uveitis.

Animals—15 adult dogs with ophthalmically normal eyes.

Procedures—Each dog was assigned to 1 of 4 treatment groups. Treatment groups were saline (0.9% NaCl) solution (1 mL, IV), meloxicam (0.2 mg/kg, IV), carprofen (4.4 mg/kg, IV), and flunixin meglumine (0.5 mg/kg, IV). Each dog was anesthetized, treatment was administered, and aqueocentesis was performed on each eye at 30 and 60 minutes after treatment. Aqueous humor samples were frozen at −80°C until assayed for PGE2 concentration with an enzyme immunoassay kit.

Results—For all 4 treatment groups, PGE2 concentration was significantly higher in samples obtained 60 minutes after treatment, compared with that in samples obtained 30 minutes after treatment, which indicated aqueocentesis-induced PGE2 synthesis. For aqueous humor samples obtained 60 minutes after treatment, PGE2 concentration did not differ significantly among groups treated with saline solution, meloxicam, and carprofen; however, the PGE2 concentration for the group treated with flunixin meglumine was significantly lower than that for each of the other 3 treatment groups.

Conclusions and Clinical Relevance—Flunixin meglumine was more effective than meloxicam or carprofen for minimizing the PGE2 concentration in the aqueous humor of dogs with experimentally induced uveitis. Flunixin meglumine may be an appropriate pre-medication for use prior to intraocular surgery in dogs.

Prostaglandins are lipids derived from fatty acids. They are synthesized locally within tissue cells and are released through the prostaglandin transporter on a cell's plasma membrane. Prostaglandins are mediators found in virtually all tissues and organs; they have a variety of strong physiologic effects and a short half-life. Prostaglandins have multiple actions, but most cause muscle constriction and mediate inflammation. This is particularly evident in the eyes, where prostaglandins (particularly PGE2) induce miosis and increase permeability of the anterior uveal vasculature, which causes an influx of cells, protein, and fibrin into the aqueous humor.1–4 Measurement of PGE2 concentration in the aqueous humor has been used experimentally as a method for assessing anterior uveitis in dogs.5–7,a–f

Corneal injury, particularly corneal perforation, results in the immediate release of prostaglandins from the cells of the anterior uvea.1,8,9 Intraocular surgery requires surgical perforation of the globe, generally through the cornea. In an effort to minimize the release of prostaglandins and subsequent uveitis, ophthalmic surgeons will usually pretreat a patient via parenteral administration of an NSAID. Nonsteroidal anti-inflammatory drugs inhibit COX, the enzyme required for prostaglandin synthesis. The NSAIDs are often classified on the basis of their preference or selectivity for inhibition of isoenzyme COX-1 or COX-2. In general, COX-1 synthesizes prostaglandins required for tissue homeostasis, such as gastric cytoprotection, renal blood flow regulation, and platelet function. In contrast, COX-2 synthesizes prostaglandins primarily at sites of inflammation, although it does have a small role in homeostasis of the CNS, kidneys, reproductive tract, and vascular endothelium, and it is required for the repair of gastric ulcers.10,11 Although many studies12–16 have been conducted to investigate the selective or preferential inhibition of COX isoenzymes, results have varied depending on the species and method of testing used. In dogs, the use of selective or preferential COX-2 inhibitors is thought to help prevent adverse effects on the kidneys and gastrointestinal tract that have been associated with COX-1 inhibitors. The NSAIDs currently approved for parenteral use in dogs are carprofen (selective COX-2 inhibitor) and meloxicam (preferential COX-2 inhibitor). Carprofen is approved for SC administration but is commonly administered IV in clinical practice. In the study reported here, carprofen was administered IV to maintain consistency in the treatment protocol and to mimic common presurgical use. Flunixin meglumine (preferential COX-1 inhibitor) is not approved for use in dogs but has been used in an extra-label manner for years for its anti-inflammatory and analgesic effects, including prior to intraocular surgery to minimize subsequent inflammation.7,8,17 The purpose of the study reported here was to compare the effects of 3 NSAIDs (carprofen, meloxicam, and flunixin meglumine) administered IV on the concentration of PGE2 in the aqueous humor of dogs with aqueocentesis-induced anterior uveitis.

Materials and Methods

Animals—Fifteen adult dogs that weighed between 8 and 31 kg were used in the present study. Eight were sexually intact male Beagles (university-owned research dogs). Seven were mixed-breed shelter-owned dogs (3 sexually intact females, 1 spayed female, and 3 sexually intact males); informed consent for each dog was obtained from authorized shelter personnel. All dogs underwent an ophthalmic examination that included biomicroscopy, indirect ophthalmoscopy, rebound tonometry, and fluorescein staining the day before inclusion in the study. The study protocol was approved by the Oklahoma State University Institutional Animal Care and Use Committee.

Procedures—The Beagles were sequentially assigned to each group in the order of their identification numbers, and the shelter dogs were sequentially assigned to each group in the order they were received at the shelter service for study enrollment. Dogs were allocated into 4 groups: control group (n = 3), meloxicamg-treated group (4), carprofenh-treated group (4), and flunixin megluminei–treated group (4). Each dog was premedicated with morphine (0.5 mg/kg, IM) and glycopyrrolate (0.01 mg/kg, IM). For each dog, anesthesia was induced with propofol (6 to 8 mg/kg, IV to effect) and maintained with isoflurane, and an isotonic, balanced electrolyte solutionj was administered (10 mL/kg/h, IV) for the duration of anesthesia. Dogs were positioned in sternal recumbency. Once anesthetized, each dog received saline (0.9% NaCl) solution (1 mL; control group), meloxicam (0.2 mg/kg), carprofen (4.4 mg/kg), or flunixin meglumine (0.5 mg/kg) IV in accordance with its treatment group allocation. Thirty minutes after treatment administration, controlled aqueocentesis was performed on each eye. A 27-gauge needle was inserted at the limbus and directed 1 mm through the corneal stroma into the anterior chamber to a depth of 1 mm. Aqueous humor (0.15 mL) was slowly aspirated into a 1-mL syringe over a period of 30 seconds. Anesthesia was maintained, and aqueocentesis was repeated on all eyes 60 minutes after treatment administration. Each controlled aqueocentesis was performed by the same investigator (MAG). Immediately following aqueocentesis at 60 minutes after treatment, all dogs were allowed to recover from anesthesia. Dogs in the control group were administered carprofen (4.4 mg/kg, SC) during the period between discontinuation of the isoflurane and extubation, and all dogs received 1% atropine sulfate solution and 1% prednisolone acetate solution topically in each eye. Administration of 1% prednisolone acetate was continued every 12 hours for 24 to 48 hours. All dogs were monitored for 48 hours for signs of pain (blepharospasm and epiphora) and signs of active uveitis (aqueous flare, miosis, and hypotony).

Measurement of PGE2 concentration—The aqueocentesis performed 30 minutes after treatment administration was used to obtain samples of aqueous humor for baseline measurement of PGE2 concentrations and to induce uveitis. The aqueocentesis performed 60 minutes after treatment administration was used to obtain samples of aqueous humor for determining changes in PGE2 concentrations. Samples of aqueous humor were frozen and stored at −80°C until assayed. Samples were thawed, and the PGE2 concentration was immediately measured with a commercial PGE2 monoclonal enzyme immunoassay kit.k All samples were measured in triplicate with no dilution. Because of the limited volume of each sample, it was not possible to assay samples at multiple dilutions. One assay plate containing samples from 3 dogs (1 each from the meloxicam-, carprofen-, and flunixin meglumine–treated groups) did not develop properly, which affected the absorbance values obtained from the plate reader for that plate. Data from these 3 dogs were discarded, which resulted in data from 3 dogs/treatment group (6 eyes) for analyses. The upper detection limit of the assay was 1,000 pg/mL; therefore, when necessary, the PGE2 concentration of the samples was truncated at 1,000 pg/mL during statistical analyses.

Data analysis—All data were analyzed with commercially available software.l Homogeneity of variance was determined with the Levene test. Significant heterogeneity of variance was detected between samples; therefore, a natural logarithmic transformation of PGE2 concentrations was used to alleviate heterogeneity during analyses. Comparisons of PGE2 concentrations by treatment group and eye (right vs left) were performed via an ANOVA, with time after treatment administration included as an independent variable in each model. No effect of eye (right vs left) was detected within time after treatment administration; therefore, the mean PGE2 concentration was calculated for each dog at each time after treatment administration and used for all subsequent analyses. Protected pairwise t tests were used to compare PGE2 concentrations between treatment groups. Nonparametric methods (Kruskal-Wallis tests) were used to compare PGE2 concentration in samples obtained 30 minutes after treatment with that in samples obtained 60 minutes after treatment. Non-transformed means and SEs were reported, and values of P < 0.05 were considered significant for all analyses.

Results

Animals—No clinically relevant abnormalities were found in any of the dogs during the ophthalmic examinations performed prior to study enrollment. One dog had multiple hyperreflective scars in the tapetal fundus of the right eye. After the aqueocenteses were performed, no signs of pain were observed in any dog. One dog had mild aqueous flare and miosis in the left eye that resolved within 48 hours. Six dogs had fibrin in the anterior chamber unilaterally (n = 4) or bilaterally (2), which was usually associated with the aqueocentesis site; this condition resolved in all eyes within 48 hours.

Concentrations of PGE2—The mean ± SE PGE2 concentration for each treatment group at each time after treatment administration was summarized (Table 1). There was no significant difference in the mean PGE2 concentration in the aqueous humor samples obtained 30 minutes after treatment among the 4 treatment groups. This finding indicated that there was no preexisting anterior uveitis in any of the study dogs. For all treatment groups, the mean PGE2 concentration was significantly higher in aqueous humor samples obtained 60 minutes after treatment, compared with the PGE2 concentration in samples obtained 30 minutes after treatment. This finding indicated that the aqueocentesis procedure effectively induced synthesis of PGE2. For aqueous humor samples obtained 60 minutes after treatment, the mean PGE2 concentration for the flunixin meglumine–treated group was significantly lower than the PGE2 concentrations for each of the other 3 treatment groups. The PGE2 concentration in aqueous humor samples from the other 3 treatment groups did not differ 60 minutes after treatment. The difference in the mean PGE2 concentration obtained 30 and 60 minutes after treatment revealed that the magnitude of PGE2 synthesis was significantly less in the flunixin meglumine–treated group, compared with that in the other 3 treatment groups (Figure 1).

Figure 1—
Figure 1—

Difference in the mean PGE2 concentration in aqueous humor samples obtained via aqueocentesis from the eyes of 12 anesthetized dogs 30 (baseline) and 60 minutes after administration of saline (0.9% NaCl) solution (1 mL, IV; [n = 3]; control), meloxicam (0.2 mg/kg, IV; [3]), carprofen (4.4 mg/kg, IV; [3]), or flunixin meglumine (0.5 mg/kg, IV; [3]; A). In panel B, notice that the y-axis scale was changed to better depict the magnitude of the flunixin meglumine treatment effect. For all treatments, PGE2 concentration was higher in samples obtained 60 minutes after treatment than that in samples obtained 30 minutes after treatment. *Value differs significantly (P < 0.05) from the value for each of the other 3 treatments.

Citation: American Journal of Veterinary Research 73, 5; 10.2460/ajvr.73.5.698

Table 1—

Mean ± SE (range) PGE2 concentration as determined with an enzyme immunoassay in samples of aqueous humor obtained via aqueocentesis from both eyes of 12 anesthetized dogs 30 (baseline) and 60 minutes after administration of saline (0.9% NaCl) solution (1 mL, IV; [n = 3]; control), meloxicam (0.2 mg/kg, IV; [3]), carprofen (4.4 mg/kg, IV; [3]), or flunixin meglumine (0.5 mg/kg, IV; [3]).

 PGE2 concentration (pg/mL)
Group30 minutes after treatment60 minutes after treatment
Control5.45 ± 0.30648.78 ± 165.75
 (4.42–6.35)(73.56 to > 1,000.00)
Meloxicam4.90± 0.47540.08 ± 154.71
 (3.57–6.11)(109.87 to > 1,000.00)
Carprofen4.46± 0.46576.78 ± 195.54
 (3.36–5.91)(23.70 to > 1,000.00)
Flunixin meglumine6.73± 1.2414.86 ± 1.54
 (3.69–10.50)(10.13 to 18.10)*

Within a column, value differs significantly (P < 0.05) from the value for each of the other 3 treatments.

Discussion

In the study reported here, IV administration of flunixin meglumine was more effective than IV administration of carprofen or meloxicam for minimizing the synthesis of PGE2 in dogs with experimentally induced anterior uveitis, and these results may have clinical relevance for dogs that require intraocular surgery. Aqueocentesis has been used to experimentally induce uveitis by the disruption of the blood-aqueous barrier in several species, including dogs.1,5,6,18–26 When the cornea is perforated, there is an acute decrease in intraocular pressure that initiates the release of prostaglandins from cells of the anterior uvea. This has been confirmed directly by the measurement of prostaglandin concentrations in the aqueous humor and indirectly by the measurement of protein concentrations in the aqueous humor, which increase as a result of PGE2-mediated breakdown of the blood-aqueous barrier.1,3,5,6,8,9,19 Therefore, the aqueocentesis-induction method of anterior uveitis is appropriate for assessing the effects of drugs administered prior to intraocular surgery on the synthesis of PGE2 by cells of the anterior uvea. In the present study, the increase in PGE2 concentration in samples of aqueous humor obtained 60 minutes after treatment, compared with that in samples of aqueous humor obtained 30 minutes after treatment, for the control (saline solution–treated) group indicated that aqueocentesis was an effective method for the induction of PGE2 in aqueous humor.

Concentrations of PGE2 varied substantially in the aqueous humor samples obtained 60 minutes after treatment for all treatment groups, except for the flunixin meglumine–treated group. For example, the mean PGE2 concentration in the aqueous humor for 1 dog in the carprofen-treated group was 44.43 pg/mL, whereas the PGE2 concentrations for the other 2 dogs in that group were 686 and > 1,000 pg/mL. This difference may have been caused by the variable effects of carprofen and meloxicam between dogs or a lack of precision in the measurement of higher concentrations of PGE2. The enzyme immunoassay used in the present study has the ability to accurately and precisely detect low PGE2 concentrations, but it becomes less precise as the PGE2 concentration increases. Although the flunixin meglumine–treated group had the highest baseline PGE2 concentration, the PGE2 concentrations detected in samples obtained 60 minutes after treatment were relatively low and consistent (range, 10 to 18 pg/mL) in all 6 eyes from the 3 dogs, which was in contrast to the much higher PGE2 concentrations and larger ranges detected in the other 3 treatment groups 60 minutes after treatment.

To our knowledge, few studiesa,c have been conducted to evaluate the effect of parenterally administered carprofen on the concentration of PGE2 in aqueous humor, and no studies have been conducted to evaluate the effect of IV administration of meloxicam on the concentration of PGE2 in aqueous humor. In 1 study,c following IV administration of a single dose of carprofen, investigators measured the PGE2 concentration in aqueous humor samples obtained before and after cataract surgery in dogs with and without uveitis and found no significant difference between carprofen-treated and untreated control dogs. Investigators in another studya evaluated the effect of SC administration of carprofen in dogs with aqueocentesis-induced uveitis and found no significant difference between the PGE2 concentrations in aqueous humor samples obtained from treated and control dogs.

In the present study, there was no significant difference in PGE2 concentrations among dogs treated with meloxicam, carprofen, or saline solution (control). These results are similar to results of another study6 in which investigators evaluated orally administered tepoxalin, carprofen, and meloxicam for the control of aqueocentesis-induced intraocular inflammation. In that study,6 orally administered tepoxalin inhibited PGE2 synthesis significantly more than did meloxicam or carprofen. Tepoxalin is a COX-1 preferential inhibitor and also inhibits 5-lipoxygenase, which is required for leukotriene synthesis but does not affect prostaglandin synthesis. In the present study, flunixin meglumine, which is also a COX-1 inhibitor, inhibited PGE2 synthesis significantly more than did meloxicam or carprofen. Results of these 2 studies indicate that COX-1 may have a more important role in anterior uveitis than has been assumed previously, and NSAIDs that inhibit COX-1 may be most appropriate for the premedication of patients prior to intraocular surgery.

In dogs, the use of a COX-1 inhibitor may raise concerns about renal function and the integrity of the gastrointestinal tract. Flunixin meglumine can cause gastroduodenal ulceration and perforation in dogs; however, these were associated with chronic oral administration27 or treatment with an inappropriately high dose, at a high frequency of administration, or for a long duration.17 Dogs of the latter study17 were additionally compromised by dehydration or concurrent use of dexamethasone sodium phosphate. Investigators in 2 studies5,7 detected a significant reduction in PGE2 synthesis in dogs treated with flunixin meglumine IV prior to experimental induction of uveitis. Both studies5,7 included the use of a higher dose of flunixin meglumine (1.1 and 2.2 mg/kg) than was used in the present study, and no significant difference in PGE2 concentration was found between dogs receiving 1.1 and 2.2 mg/kg doses.5 The 0.5 mg/kg dose of flunixin meglumine was selected for the present study because it is the dose most commonly used prior to intraocular surgery. On the basis of our clinical experience and long-term observations, flunixin meglumine administered IV at a dose of 0.5 mg/kg and appropriate IV administration of fluids during anesthesia result in minimal adverse effects on renal function and the gastrointestinal tract. However, it is still prudent to consider the use of an NSAID that is a COX-2 inhibitor for the treatment of geriatric patients, patients with renal or gastrointestinal compromise, and patients currently receiving a COX-2–inhibitor NSAID. Although NSAIDs that are COX-2 inhibitors are considered to have a wide margin of safety, clinicians should be cognizant that their use has the potential for adverse effects such as signs of nausea, diarrhea, gastrointestinal ulcers with or without hemorrhage, nephrotoxicosis, platelet dysfunction, and idiosyncratic hepatotoxicosis. The most common adverse effect associated with preoperative, parenteral administration of an NSAID is nephrotoxicosis, whereas adverse effects on the gastrointestinal tract are more common with long-term, oral administration of NSAIDs.27,28 The risk of nephrotoxicosis during anesthesia can be reduced by monitoring blood pressure and appropriate IV administration of fluids.28–33

The inability to accurately measure PGE2 concentrations > 1,000 pg/mL was a limitation of the present study. Determination of the actual PGE2 concentrations may have revealed even greater differences among treatment groups. For most of the samples, there was insufficient aqueous humor for serial dilutions to be performed in triplicate. In another study6 in which a few sample dilutions were performed for comparison, PGE2 concentrations determined for diluted samples differed substantially from PGE2 concentrations determined for undiluted samples. This may have been attributable to the loss of PGE2 in the samples as a result of repeated freezing and thawing. In the present study, the loss of data for 3 dogs (6 eyes) limited the number of samples, and a larger sample size would have strengthened the validity of the results. However, even with the reduced sample size in the study reported here, the lower concentration of PGE2 in aqueous humor samples obtained from dogs treated with flunixin meglumine, compared with the PGE2 concentration in aqueous humor samples obtained from dogs treated with carprofen or meloxicam, would appear to be clinically meaningful. Also, the lower PGE2 concentration in aqueous humor detected following administration of flunixin meglumine in the present study was similar to that detected following administration of tepoxalin, another preferential COX-1 inhibitor, in a previous study.6

Flunixin meglumine administered IV was more effective than IV administration of carprofen or meloxicam for minimizing the concentration of PGE2 in the aqueous humor of dogs with experimentally induced uveitis. The effects of carprofen and meloxicam on PGE2 concentration did not differ from that of saline solution. Therefore, flunixin meglumine may be an appropriate choice for the premedication of dogs prior to intraocular surgery.

ABBREVIATIONS

COX

Cyclooxygenase

PGE2

Prostaglandin E2

a.

Laus JL, Ribeiro AP, Escobar A, et al. Effects of carprofen administered by different routes to control experimental uveitis in dogs (abstr), in Proceedings. 38th Annu Meet Am Coll Vet Ophthalmol 2007;26.

b.

Pinard CL, Gauvin D, Moreau M, et al. Measurement of inflammatory mediators in aqueous humor following paracentesis of the anterior chamber in dogs (abstr), in Proceedings. 38th Annu Meet Am Coll Vet Ophthalmol 2007;81.

c.

Fischer A. Carprofen in the aqueous humor of dogs and cats with uveitis. Dissertation, Freie Universität Berlin, Berlin, Germany, 2000. Available at: library.vetmed.fu-berlin.de/diss-abstract/115881.html. Accessed Apr 10, 2009.

d.

Allgoewer I, Fischer A, Brunnberg L, et al. Concentration of carprofen in the aqueous humor of dogs with uveitis. Preliminary results (abstr), in Proceedings. 30th Annu Meet Am Coll Vet Ophthalmol 1999;16.

e.

Gilmour MA, Lehenbauer TW. Effects of tepoxalin in reducing intraocular inflammation in the dog (abstr), in Proceedings. 37th Annu Meet Am Coll Vet Ophthalmol 2006;17.

f.

Pinard CL, Moreau M, Martel-Pelletier J, et al. Effect of carprofen on aqueous humor levels of PGE2, NOx and TNF-α in an experimental canine uveitis model (abstr), in Proceedings. 37th Annu Meet Am Coll Vet Ophthalmol 2006;58.

g.

Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

h.

Rimadyl, Pfizer Animal Health, Exton, Pa.

i.

Banamine, Intervet/Schering-Plough Animal Health, Summit, NJ.

j.

Normosol-R, Abbott Laboratories Inc, North Chicago, Ill.

k.

Prostaglandin monoclonal E2 EIA kit, Cayman Chemical Co, Ann Arbor, Mich.

l.

SAS, version 9.2, SAS Institute Inc, Cary, NC.

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