Download ANTI-INFLAMMATORIES Alison Clode, DVM, DACVO Port City

ANTI-INFLAMMATORIES
Alison Clode, DVM, DACVO
Port City Veterinary Referral Hospital
Portsmouth, NH 03801
New England Equine Medical and Surgical Center
Dover, NH 03820
CORTICOSTEROIDS
Corticosteroids consist of glucocorticoids and mineralocorticoids. Glucocorticoids (GC) influence
metabolic and immune functions, while mineralocorticoids (MC) are responsible for electrolyte and water
balance, primarily through influencing sodium retention/excretion in the kidney. Glucocorticoids are extremely
effective anti-inflammatory agents, with multiple synthetic agents available based on the endogenous form,
cortisol (hydrocortisone is the pharmacologic equivalent of cortisol). The physiologic effects of GC are
widespread and non-specific, and include anti-inflammatory functions (i.e., decreased cellular and fibrinous
exudation and tissue infiltration, decreased neovascularization, decreased capillary permeability) and effects on
tissue regeneration and repair (i.e., decreased fibroblastic and collagen formation reactions, decreased epithelial
and endothelial regeneration). These effects are produced via plasma protein-mediated transport of the GC to
the cell, following by entry into and subsequent binding of the GC to the cytosolic GC receptor protein, the
nature of which determines the sensitivity of an individual cell to GC. Glucocorticoids bind to this receptor and
form a receptor-ligand dimer, which translocates to the nucleus to bind hormone responsive elements (HREs),
or glucocorticoid response elements (GREs), located within the genomic DNA. Binding to the genomic DNA
either increases (transactivation) or decreases (transrepression) gene expression, ultimately leading to the
cellular effects of GC.
In general, anti-inflammatory genes (i.e., lipocortin) and genes modulating gluconeogenesis (i.e.,
glucose-6-phosphatase) are upregulated, while pro-inflammatory genes (i.e., interleukins, chemokines,
cytokines) are downregulated in response to GC. Increased expression of lipocortin results in inhibition of
phospholipase A 2 , ultimately preventing biosynthesis of arachidonic acid, prostacyclin, thromboxane A,
prostaglandins, and leukotrienes, all of which are mediators of inflammation. In addition to these genomic
effects, GC reduce leukocyte migration to sites of inflammation, as well as stabilize lysosomal membranes,
possibly via a cAMP-mediated effect. This stabilization effectively blocks white blood cell (neutrophil, mast
cell, basophil) degranulation, decreasing the release of additional proinflammatory components such as
proteases, histamine, and bradykinin. Vascular effects of GC include inhibition of angiogenesis and reduction
of capillary permeability. Effects of GC on tissue regeneration and repair include decreased fibroblastic and
keratocytic activity, increased collagenolytic activity, and inhibition of wound healing (including epithelial and
endothelial regeneration).
The cellular effects of GC are exerted in response to virtually any type of inflammation, whether
allergic, infectious, or traumatic, stimulating all aspects of their physiologic actions equally and resulting in
situations in which the beneficial effects may be overcome by negative effects (i.e., reduced migration and
activation of leukocytes in the presence of infection may limit the harmful effects of inflammation, however
reduced host defenses in turn may potentiate infection in the absence of appropriate antimicrobial therapy).
The potency of a GC is determined by its base chemical structure, concentration, and dosage, all of
which determine the strength of the binding to the transport protein, receptor, and DNA. The goal with therapy
for inflammatory diseases is to utilize a corticosteroid with maximal anti-inflammatory (GC) effect and minimal
MC effect, thus avoiding the electrolyte and water imbalances that occur with MC therapy. The MC effect is
related to the relative sodium-retaining activity, compared to a value designation of 1 for
cortisol/hydrocortisone (Table 1). Agents with lower sodium retention thus have less effect on water balance
than do those with greater sodium retention.
Table 1. Relative Potencies of Commonly Encountered Corticosteroids (Adapted from Sendrowski DP et al.,
in Clinical Ocular Pharmacology1).
Corticosteroid
Hydrocortisone (cortisol)
Cortisone acetate
Prednisone
Prednisolone
Triamcinolone
Methylprednisone
Fludrocortisone
Dexamethasone
Betamethasone
Anti-inflammatory Potency
1.0
0.8
4.0
4.0
5.0
5.0
20.0
25.0
25.0
Sodium Retention
1.0
0.8
0.8
0.8
0.0
0.0
125.0
0.0
0.0
Ocular Bioavailability of Topical Steroid Preparations
The efficacy of a topically applied ophthalmic corticosteroid depends upon multiple drug- and patientrelated factors, which influence transcorneal and intraocular penetration and anti-inflammatory activity. Of the
drug-related factors, the base steroid and its relative potency, concentration, and formulation are critical, while
patient-related factors include frequency and route of administration and presence of surface ocular disease.
As with all topical ophthalmic drugs, biphasic (lipid-soluble and water-soluble) preparations best
penetrate the alternating hydrophobic-hydrophilic-hydrophobic corneal layers, and therefore are expected to
achieve the greatest corneal tissue and intraocular levels. The solubility of individual steroids is manipulated by
altering their chemical structures, with acetate derivatives the most lipophilic, alcohol derivates of intermediate
solubility, and salts (sodium phosphate or hydrochloride) the most hydrophilic.2-4 The derivative frequently
dictates the ideal formulation, with hydrophilic derivatives more likely formulated as solutions and lipophilic
derivatives more likely formulated as suspensions or ointments. While increasing the concentration of a topical
ophthalmic medication frequently increases its clinical efficacy, prednisolone acetate 1.5% and 3.0% are no
more efficacious at reducing inflammation than is prednisolone acetate 1.0%, even in the presence of greater
intraocular penetration, in a rabbit model of corneal disease.5 If greater clinical efficacy is desired, the frequency
of administration may be increased or the route of administration altered to achieve this goal.
A few interesting points regarding topical ophthalmic corticosteroids should be considered. The first is
that, while dexamethasone and betamethasone are significantly more potent than prednisolone (Table 1),
prednisolone acetate preparations have superior intraocular penetration and are thus better at controlling anterior
uveitis (versus superficial inflammatory disease with dexamethasone or betamethasone).3 Additionally, while
prednisolone acetate penetrates the intact corneal epithelium better than prednisolone phosphate, the phosphate
derivative has superior penetration in the presence of corneal ulceration.3 This variation in penetration, while
significant, should be considered in light of the relative anti-inflammatory efficacy, which indicates that
prednisolone acetate is superior both in the presence and absence of the corneal epithelium, based on
comparisons using a rabbit model of corneal inflammation (Table 2). This is highlighted by the greater
bioavailability of dexamethasone phosphate preparations relative to alcohol or acetates, in contrast to the
consistently superior anti-inflammatory activity of the acetate derivative (Table 2).
Table 2. Comparison of the Derivative of Ophthalmic Corticosteroids with Corneal Concentration (Adapted
from Sendrowski DP et al., in Clinical Ocular Pharmacology1)
Corticosteroid
Prednisolone acetate 1%
Prednisolone acetate 1%
Prednisolone phosphate 1%
Prednisolone phosphate 1%
Dexamethasone acetate 0.1%
Dexamethasone acetate 0.1%
Dexamethasone alcohol 0.1%
Dexamethasone alcohol 0.1%
Dexamethasone phosphate 0.1%
Dexamethasone phosphate 0.1%
Epithelium
Intact
Epithelium
Absent
X
X
X
X
X
X
X
X
X
X
Bioavailability
(mcg/min/g corneal
tissue)
2, 395
4,574
1,075
16,338
111
118
543
1,316
1,068
4,642
Anti-Inflammatory
Efficacy (%)
51
53
28
47
55
60
40
42
19
22
Dexamethasone
Dexamethasone is a long-acting synthetic corticosteroid, available as 0.1% alcohol or phosphate
derivative suspensions or solutions, or as a 0.05% phosphate derivative ointment. The anti-inflammatory
efficacy of the alcohol is superior to that of the phosphate derivative. Within 30 minutes of topical
administration of either the alcohol or phosphate form, dexamethasone is detectable within the human aqueous
humor, with peak drug levels occurring between 90 and 120 minutes. The persistence of detectable levels for
up to 12 hours suggests that metabolism of dexamethasone in the human aqueous humor is minimal.
Betamethasone
Betamethasone is a long-acting synthetic corticosteroid, available as a 0.1% phosphate solution.
Prednisolone
Prednisolone is an intermediate-acting synthetic corticosteroid, available as 1% or 0.125% acetate
suspension and 1% or 0.125% phosphate solution (Ak-Pred, Inflamase®). The acetate derivative has superior
anti-inflammatory activity to the phosphate derivative, and is considered the most effective drug for anterior
uveitis.
Evaluation in dogs
Two pre-operative medication protocols in dogs undergoing cataract surgery were evaluated in a recent
study, comparing administration of 1 drop of 1% prednisolone acetate q8h for seven days prior to surgery with
administration of 1 drop three times the evening prior to surgery and four times the morning of surgery.6
Assessment of blood-aqueous barrier breakdown by anterior chamber fluorophotometry performed preoperatively and 2 and 9 days post-operatively, along with subjective clinical assessments, found no significant
difference in control of post-operative inflammation between the two treatment groups. A significantly greater
incidence of postoperative ocular hypertension was found in dogs receiving prednisolone acetate for one week
prior to surgery, when IOP was measured 4 and 8 hours post-operatively.
Evaluation in cats
Anterior chamber paracentesis was used to induce blood-aqueous barrier disruption in both eyes of
normal cats, and was followed by unilateral application of a single dose of either 1% prednisolone acetate, 0.1%
dexamethasone, 0.03% flurbiprofen, of 0.1% diclofenac immediately and at 6, 10 and 24 hours postparacentesis (the contralateral eye served as an untreated control).7 Flare was measurement using a laser-flare
meter at 4, 8, and 26 hours post-paracentesis, and the relative ability of each anti-inflammatory was assessed. A
significant reduction in flare at all three time points was associated only with 1% prednisolone acetate;
diclofenac 0.1% significantly reduced flare at the 8- and 26-hour timepoints; 0.1% dexamethasone significantly
reduced flare at the 4-hour timepoint; and flurbiprofen 0.03% did not significantly reduce flare at any timepoint.
Triamcinolone
Triamcinolone acetonide is an intermediate-acting synthetic corticosteroid, with the primary uses in
ophthalmology being subconjunctival injection for anterior segment inflammatory diseases or intravitreal
injection for posterior segment inflammatory disease. As a very hydrophobic molecule, it has a long residence
time following injection, thereby conferring a long duration of action (up to 5-6 months in humans following
intravitreal injection).8
Evaluation in dogs
Intravitreal injection of triamcinolone acetonide (8 mg once) in the normal eyes of research dogs under
sedation documented an increase in IOP in all eyes immediately following injection (also occurred in eyes
receiving intravitreal saline control), as well as visible drug crystals within the vitreous.9 In the 3 months
following injection, no increase in IOP was documented, and the crystals remained in 5/11 eyes. Conjunctival
hyperemia was the most significant side effect of injection.
Evaluation in horses
Intravitreal injection of 10 mg, 20 mg, or 40 mg of triamcinolone acetonide in normal horses resulted
in sustained drug ocular concentrations for a minimum of 3 weeks following injection.10 All eyes had transient
corneal edema, and 33% (4 eyes, 1 treated and 3 control) developed bacterial endophthalmitis. Additionally, no
significant differences in IOPs or ERG parameters of treated or control (BSS) eyes were documented.10
Fluorometholone
Fluorometholone is a structural analogue of progesterone (rather than cortisol), available as a 0.1%
alcohol ointment or suspension, a 0.25% alcohol suspension, or a 0.1% acetate suspension (FML Forte
Liquifilm®, FML Liquifilm®, FML S.O.P®). The anti-inflammatory efficacy of fluorometholone alcohol is
slightly lower than that of prednisolone acetate or dexamethasone alcohol, while that of the acetate derivative is
comparable to prednisolone acetate.1 Its tendency to raise IOP is lower at 0.1% concentration, but increases
with the 0.25% concentration.
Medrysone
Medrysone is also a synthetic derivative of progesterone available as a 1.0% suspension (HMS®), and
has lower corneal penetration and clinical efficacy, demonstrating minimal effect on intraocular (versus surface
ocular) inflammation.
Loteprednol etabonate
Loteprednol etabonate is a soft drug, meant to decrease drug-related side effects, available as a 0.5%
suspension (Lotemax®) and 0.2% suspension (Alrex®). A soft drug is one that is synthesized from an inactive,
nontoxic metabolite of an active drug. Modification of the inactive metabolite creates a metabolically unstable
active compound that is transformed in vivo to the inactive metabolite, after its pharmacologic effects have been
expressed at the desired site of action. In placebo-controlled clinical trials, loteprednol etabonate demonstrated
good clinical effect in patients with conjunctivitis, while its effect in the treatment of acute anterior uveitis,
while evident, was less than that of prednisolone acetate.1 A benefit of loteprednol etabonate is its reduced risk
of inducing an IOP elevation.11-13
Rimexolone
Rimexolone is available as a 1% suspension (Vexol®) that has comparable efficacy to prednisolone
acetate for the treatment of uveitis only when administered in aggressive pulsed doses to patients with mild to
moderate inflammation.1
Side Effects
Ocular side effects of ophthalmic corticosteroids can be numerous, including the development of
cataracts, increased IOP, infection, decreased would healing, mydriasis, and calcific keratopathy. While these
side effects may be frequent in humans, some are less common in animals. With the exceptions of mydriasis
and calcific keratopathy, these side effects may occur in association with systemically administered
corticosteroids as well.
Systemic side effects of topical ophthalmic corticosteroids include glucocorticoid-induced
hepatopathy, suppression of endogenous glucocorticoid production, or local alopecia.14-18 It is important to note
that such side effects occur more readily with systemic administration of corticosteroids, but occur in a doseand duration-dependent manner following topical ophthalmic administration. Following administration of
topical 0.1% dexamethasone ointment to normal horses every 5 to 9 hours for 8 days, dexamethasone was
detectable in the serum and urine for up to 1 day following cessation of therapy.19 In calves, dexamethasone
administered parenterally in an experimental situation resulted in bilateral exophthalmos due to aberrant orbital
adipose deposition, in the absence of such deposition elsewhere in the body.20
Cataracts
Posterior subcapsular cataracts may develop in humans following all routes of administration (topical,
systemic, cutaneous, inhalation), with generally minimal effect on vision. Correlations with dosage and
duration exists, with patients receiving oral prednisone at < 10 mg/day demonstrating an 11% incidence of
cataract development, a 30% incidence with 10 – 15 mg/day doses, and 80% incidence with > 15 mg/day over 1
to 4 years.1 Additionally, children receiving corticosteroids will develop cataracts on lower doses for shorter
durations. It is apparent that other factors (i.e., genetics, environment, age) also play a role. Discontinuation of
therapy frequently stops progression of the cataract, and in children has been reported to result in resolution or
partial resolution of the cataract. Development of such cataracts in small animals has not been reported.
The pathophysiology of cataract development is not fully known. Postulated mechanisms include
metabolic disturbances involving glucose or its metabolism, lenticular enzyme systems, or lenticular protein
synthesis; altered osmotic and/or ionic balances due to steroid-induced Na+/K+-ATPase modulation; loss of
protection from oxidative injury leading to conformational changes in proteins and formation of disulfide bonds
and creating protein aggregates; direct addition of steroids to lens proteins to form protein adducts; or aberrant
lens epithelial cell behavior due to altered growth factor production induced by corticosteroids.21
Ocular Hypertension or Glaucoma
Significant but frequently reversible increases in IOP occur in humans following systemic or topical
corticosteroid therapy. The elevations generally occur within 2 to 8 weeks following initiation of therapy, and
resolve within 1 to 3 weeks following discontinuation. Elevations are generally more severe in glaucomatous
(open-angle) eyes versus normal eyes, ranging from a few mmHg to greater than 15 mmHg increase. Factors
involved that increase the susceptibility of an individual to steroid-induced IOP elevations include a genetic
predisposition (greater increase in IOP in eyes of relatives of patient with open-angle glaucoma), age, the
presence of myopia of 5D or greater, and duration of therapy (long-term systemic therapy induces greater
increase). Certain steroids (dexamethasone, betamethasone, and prednisolone, versus fluorometholone alcohol
or medrysone) are associated with a greater chance of IOP elevation as well, possibly due to varied intraocular
bioavailability, receptor specificity, pharmacokinetic half-life, or metabolism.
The pathophysiology of glaucomatous reactions to corticosteroids is thought to involve activation of
glucocorticoid receptors in the trabecular meshwork. The resulting alterations in gene expression affect the
extracellular matrix, cytoskeletal elements, and cell adhesion molecules, altering the morphology of the
trabecular meshwork to increase the resistance to AH outflow.22
Ocular hypertension has been reported in Beagles with primary open-angle glaucoma following topical
administration of 0.1% dexamethasone,23 however a similar increase did not result in healthy dogs following
oral administration of hydrocortisone for 5 weeks.24 It has also been induced experimentally in cats and cattle
following administration of topical dexamethasone or prednisolone acetate.25-27
Infection
Due to their mechanism of action on the immune system, steroids increase susceptibility to infection.
In humans with bacterial infections of the cornea, topical corticosteroids may be administered with the goal of
minimizing subsequent corneal scarring, however it is imperative that an appropriate, specific, therapeutic
antibiotic be administered at the same time. Use of corticosteroids in the presence of fungal infections is
generally not advised, regardless of the degree of anticipated scarring. Use of corticosteroids in the presence of
viral infections prolongs the course of disease, and is generally reserved only for those cases with a significant
stromal inflammatory component, which is likely indicative of an immune-response to viral infection, as
opposed to active viral replication. In veterinary ophthalmology, use of corticosteroids in the presence of
bacterial or fungal corneal infections is contraindicated. Although decreased corneal scarring would be ideal,
the risks of such therapy are far too great in our patients to justify such a therapeutic protocol.
Aside from potentiating existing infections, an additional concern with prophylactic topical antibiotic
and corticosteroid therapy is the potential to alter the normal ocular surface microflora to potentially more
deleterious pathogens. A study utilizing normal horses evaluated this potential by treating eyes three times
daily for 2 weeks with either neomycin/polymyxin B/bacitracin, prednisolone gentamicin, neomycin/polymyxin
B/dexamethasone, or artifical tears, and taking serial ocular surface bacterial and fungal cultures.28 In that study,
although number of positive cultures and population of organisms did change slightly at various time points, no
overall significant detrimental effects of treatment on normal ocular flora were found.
Decreased Wound Healing
Separate from potentiating ocular surface infections and thereby inhibiting wound healing, the
increased collagenolytic activity induced by the topical corticosteroids likely directly decreases wound healing
as well. While more pronounced with topical administration, systemic administration has also be reported to
adversely affect epithelial regeneration. Fibroblast activity and collagen deposition necessary to heal deeper
corneal wounds is also inhibited by corticosteroid administration, manifesting as reduced tensile strength. This
may have significant implications post-operatively, as intraocular surgical procedures requiring corneal
incisions are often treated with topical corticosteroids post-operatively. Not surprisingly, different base steroids
and derivatives have variable effect on wound healing, with dexamethasone phosphate appearing to be least
deleterious of the commonly used topical corticosteroids.29,30 A study comparing the in vitro effects of
dexamethasone, prednisolone, and hydrocortisone on cultured canine corneal epithelial found dexamethasone to
have fewer effects on cell morphology and migration than the other corticosteroids,31 however negative effects
have been reported on human keratocytes,32 emphasizing the consideration that topical administration of
corticosteroids with a corneal wound, even when necessary, should be initiated with awareness.
Mydriasis
Mydriasis has been induced in healthy human volunteers within 1 week following initiation of topical
dexamethasone application, as well as in monkey eyes.1 It may occur in conjunction with ptosis, and the
supposition is that a component of the drug vehicle induces the effects.
Calcific Band Keratopathy
Calcium deposition in the cornea in conjunction with topical application of corticosteroids has been
reported in people. Patients with persistent epithelial defects, as occur post-operatively, in association with
herpesvirus infection, or dry eye, are potentially predisposed.1
Contraindications
Contraindications to the use of topical ophthalmic corticosteroids in veterinary medicine include
corneal ulceration, known or suspected corneal infection, or a known hypersensitivity to any particular
formation. Corticosteroids (topical or systemic) should be administered with caution and regular in patients
with diabetes mellitus or other endocrine diseases, infectious diseases, chronic renal failure, congestive heart
failure, systemic hypertension, or gastric ulceration. When necessary to administer (i.e., postphacoemulsification in a diabetic dog), the minimal dose required should be administered for the shortest period
of time required.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Inflammation is mediated by prostaglandins (PGs), specifically the pro-inflammatory series 2 PGs
(PGE 2 , PGD 2 , PGF 2α , PGI 2; series 1 and series 3 PGs are anti-inflammatory), and leukotrienes. Series 2 PGs
and thromboxane A 2 , which is critical for platelet production and aggregation, are produced from arachidonic
acid (derived from cell membrane phospholipids under the influence of phospholipase A 2 ) by the
cyclooxygenase (COX) enzyme system. COX exists in two prominent isoforms, COX-1 (constitutive) and
COX-2 (inducible). COX-1 is present in most tissues under normal circumstances and produces PGs
responsible for homeostatic functions, while COX-2 is present primarily in response to cellular insult or injury.
Leukotrienes, which produce lesser inflammatory responses than PGs, are produced from eicosapentanoic acid
(also a precursor to anti-inflammatory series 3 PGs) by the enzyme lipoxygenase. Ocular effects of PGs
(particularly PGE 2 ) include miosis, increased IOP, reduced blood-aqueous barrier stability, conjunctival and
iridal vasodilation and vascular permeability, and corneal vascularization.33 It is important to note however, that
COX enzyme localization and expression, subsequent PG expression, and PG receptor sensitivities vary
significantly among species, thus modulating effects of tissue injury and response to pharmacologic
intervention.33
Nonsteroidal anti-inflammatory drugs (NSAIDs) target the COX pathway, with individual NSAIDs
exhibiting variable selectivity for either the COX-1 or COX-2 isoform. The molecular action of the drug is
based upon competitively blocking the enzyme active site in a reversible or irreversible manner. Selective
inhibition of the inducible COX-2 isoform is believed to lead to fewer deleterious side effects, as protective
functions mediated primarily by COX-1 are spared. It is also believed however, that COX-2 is expressed by
vascular endothelial cells and, when downregulated by COX-2 selective NSAIDs, the relative increase in
thromboxane levels associated with normal COX-1 activity may in turn negatively impact the cardiovascular
system. Additional anti-inflammatory effects of NSAIDs, independent of COX inhibition, include decreased
neutrophil chemotaxis and migration, decreased expression of inflammatory cytokines, decreased mast cell
degranulation, and free-radical scavenging.34 Due to the fact that they are organic acids, NSAIDs accumulate at
sites of inflammation, increasing their overall anti-inflammatory effect.
Ophthalmic NSAID Usage
NSAIDs, administered topically or systemically, are used in ophthalmology to control inflammation
and provide analgesia. Preoperative administration of NSAIDs prior to cataract removal is utilized to attain
maximal mydriasis and minimize breakdown of the blood-aqueous barrier associated with surgical manipulation
and subsequent release of PGs. Postoperative administration is helpful to decrease inflammation and minimize
negative effects on corneal wound healing, however corticosteroids remain the gold standard topical ocular antiinflammatory medication. Administration of topical NSAIDs in humans following surgical refractive
procedures is highly effective as pain control, and also as treatment for postoperative cystoid macular edema.1
Many topical ophthalmic NSAIDs are also approved for use in allergic conjunctivitis.34
NSAIDs safe for topical ophthalmic use include indole acetic acid, aryl acetic acid, and aryl propionic
acid derivatives, which are readily formulated as solutions due to their water-soluble nature (Table 3).
Salicylates, fenamates, and pyrazolones are too toxic for topical ocular use. As most NSAIDs are weakly
acidic, they exist in their ionized form in the tear film pH and thus only weakly penetrate the cornea. Reducing
the pH of topical formulations increases the unionized fractions and intraocular penetration, however it also
increases the local irritant effects following administration. Additionally, the anionic nature of NSAIDs favors
formation of insoluble complexes with cationic quaternary ammonium preservatives such as benzalkonium
chloride.35,36
Table 3. Derivative Classes of Common NSAIDs (Adapted from Ahuja et al., Am Assoc Pharm Sci J, 200836)
Derivative Class
Salicylic acid
Indole acetic acid
Aryl acetic acid
Aryl propionic acid
Examples
Aspirin
Indomethacin
Diclofenac
Ketorolac
Nepafenac
Bromfenac
Ibuprofen
Flurbiprofen
Ketoprofen
Suprofen
Naproxen
Enolic acid
Piroxicam
Side Effects and Contraindications
Local side effects occurring with topical administration of NSAIDs are most commonly related to
direct ocular surface irritation (hyperemia, contact dermatitis). Superficial punctate keratitis has also been
reported with chronic NSAID use, possibly in relation to decreased corneal sensitivity (diclofenac has been
implicated as having the greatest impact.37 Significant keratomalacia has also been reported with topical
NSAIDs, particularly diclofenac (brand name and generic) and ketorolac, primarily when administered
following cataract removal or photorefractive surgeries.38,39
Investigation of NSAID-induced corneal toxicity has elucidated multiple possible mechanisms. In
terms of the direct pathways of inflammation, NSAID administration may exacerbate disease processes.
Corneal epithelial arachidonic acid metabolism involves COX, lipoxygenase, and cytochrome P450 enzymes,
each of which result in production of various inflammatory mediators (PGs, leukotrienes, and eicosatetranoic
acid derivatives, respectively). In cases of trauma, infection, or autoimmunity, each pathway is stimulated,
while in cases of hypoxia, stimulation of the COX enzyme system is decreased and activation of the leukotriene
and cytochrome P450 systems is increased.40 Administration of a topical NSAID is therefore less efficacious, as
the contribution of the COX pathway is reduced, and topical NSAIDs may also exacerbate the cytochrome P450
system, thus increasing (rather than decreasing) the inflammatory response.41 Additionally, PGE 2 may play a
role in decreasing production of matrix metalloproteinases (MMP), which are in part responsible for
keratomalacia.42 Inhibition of PGE 2 therefore may serve to promote MMP production. Finally, NSAIDs may
induce direct cellular damage that inhibits wound healing.34 An in vitro study utilizing cultured canine epithelial
cells noted dose-dependent adverse alterations in cell morphology and wound healing following treatment with
suprofen.31 The same study also evaluated thimerosal, a preservative commonly used in ophthalmic preparations
(including NSAIDs), and found a significant deleterious effect on epithelial cell morphology and wound
closure.
As with any topical ophthalmic medication, systemic side effects may occur. Nonselective COX
inhibitors are classically associated with an increased risk of gastrointestinal side effects (primarily gastric
ulceration) related to inhibition of COX-1 and subsequent decreased production of protective PGs. Altered
platelet function also occurs due to decreased production of thromboxane A 2 , which stimulates production and
aggregation of platelets (this effect is most pronounced with aspirin, as its inhibition of COX is irreversible).
Renal side effects may also be noted due to reduced production of vasodilatory PGs, which increase renal blood
flow. In humans, bronchial asthmatic attacks have been reported, likely in association with shunting of
arachidonate to the lipoxygenase pathway due to decrease COX activity. This results in increased production of
leukotrienes, which are potent nonvascular smooth muscle spasmogens.34 In veterinary medicine,
gastrointestinal disease is the most notable complication, while cats also experience bone marrow suppression.43
Systemic Agents
Multiple agents are available for systemic administration in veterinary medicine, including aspirin,
flunixin meglumine, phenylbutazone, etogesic, carprofen, meloxicam, deracoxib, firocoxib, and tolfenamic
acid. Evaluation of flunixin meglumine, carprofen, and tolfenamic acid in experimentally-induced bloodaqueous barrier breakdown in dogs indicated that all three are effective at limiting ensuing intraocular
inflammation.44-47 In dogs with blood-aqueous barrier breakdown associated with topical administration of
pilocarpine, flare production was inhibited by 68% in dogs receiving pre-treatment with oral carprofen relative
to untreated controls.46 Dogs undergoing repeat AH paracentesis demonstrated statistically significantly lower
elevations in intraocular PGE 2 levels following pretreatment with oral carprofen, compared with placebotreated controls.48 Also in dogs with experimentally-induced blood-aqueous barrier breakdown associated with
repeated AH paracentesis, pre-treatment with oral tepoxalin significantly inhibited the intraocular production of
PGE 2 , relative to dogs pre-treated with oral meloxicam or carprofen, or untreated controls.49 Clinical
evaluation of the efficacy of carprofen as an analgesic in dogs undergoing enucleation was evident in
comparison with tramadol, with fewer dogs receiving pre-operative carprofen requiring post-operative rescue
analgesia (1/22) than those receiving pre-operative tramadol (6/21) (Delgado JAVMA 2014). Evaluation of the
intraocular penetration of firocoxib versus flunixin in horses demonstrated significantly greater intraocular
firocoxib levels, however no significant difference in intraocular PGE2 levels were present between horses
receiving firocoxib orally or flunixin orally (Hilton JVIM 2011)
.
Topical Agents
Topical agents include preparations of ketorolac, diclofenac, indomethacin, flurbiprofen, suprofen,
bromfenac, and nepafenac, available as solutions or suspensions, with most containing preservatives.
Ketorolac
Ketorolac, available as 0.4%, 0.45%, and 0.5% solutions, is approved for use in reducing ocular pain
and inflammation after corneal refractive surgery and cataract surgery, and is also effective as treatment for
post-operative cystoid macular edema (due to PGE 2 ) and ocular surface inflammatory conditions. The 0.45%
solution of ketorolac was developed in part to reduce potential deleterious effects of topical NSAIDs on the
corneal epithelium, as it is formulated without the preservative present in the 0.4% and 0.5% concentrations, as
well as present in other topical NSAIDs, and it is formulated with carboxymethylcellulose as a carbomer that
may increase epithelial wound healing.50,51 In support of this possibility, a comparison of the effect of different
formulations of ketorolac, bromfenac 0.09%, and nepafenac 0.1% on epithelial wound healing in an ex vivo
porcine wound model identified increased rate of healing with the 0.45% ketorolac formulation relative to the
other topically applied NSAIDs.50
Multiple studies comparing the relative efficacy of ketorolac with that of other topical NSAIDs in
humans undergoing cataract surgery or vitrectomy exist, which generally indicate superior penetration and
superior PGE 2 inhibition by ketorolac.52,53 Compared to bromfenac and nepafenac, ketorolac 0.45% reached
significantly greater AH levels following one day of pre-operative dosing to human patients undergoing cataract
surgery.54 Additionally, inhibition of AH PGE 2 activity in patients receiving drug for one day prior to
phacoemulsification was significantly greater in patients receiving ketorolac 0.45% versus nepafenac 0.1%,
with a trend toward greater inhibition with ketorolac versus bromfenac 0.09%.55 Treatment with ketorolac 0.4%,
bromfenac 0.09%, or nepafenac 0.1% (versus untreated controls) prior to vitrectomy identified greater
intravitreal concentrations of ketorolac than bromfenac, nepafenac, and amfenac (the active metabolite of
nepafenac), as well as significantly reduced intravitreal PGE 2 levels in patients treated with ketorolac versus
nepafenac or control (untreated) patients.56
While ketorolac demonstrates stronger pharmacodynamics and potential clinical effect in patients
undergoing phacoemulsification or vitrectomy, nepafenac has been demonstrated to have a few advantages over
both bromfenac and ketorolac in patients underoing photorefractive keratectomy (PRK). Comparison of the
effects of ketorolac 0.4% (with preservative) versus nepafenac 0.1% on corneal epithelial wound healing and
pain control following PRK revealed no difference in reepithelialization rates nor in overall pain assessment
between the two treatment groups, however ketorolac was associated with significantly greater discomfort upon
instillation.57 A similar study compared the effects of three different drug combinations on corneal epithelial
wound healing and pain control following PRK: ketorolac 0.4% with gatifloxacin 0.3%; bromfenac 0.09% with
gatifloxacin 0.3%; and nepafenac 0.1% with moxifloxacin 0.5%.58 Time to reepithelialization was significantly
shorter in the nepafenac group (mean 5.5 days versus 7.2 days for bromfenac group), while the ketorolac group
demonstrated intermediate healing time. Postoperative pain scores were significantly reduced in patients
receiving nepafenac on postoperative days 1 and 3, while statistically significant pain score reductions were not
present until day 3 in patients receiving bromfenac and nepafenac.
Diclofenac
Diclofenac (0.1% solution) is approved for use in achieving mydriasis for cataract surgery, and is also
used to reduce ocular pain following corneal refractive surgery. Following topical administration, it reaches
high corneal tissue levels in normal and inflamed corneas, however it poorly penetrates into the aqueous humor
in the presence of corneal inflammation.59 Its ability to control blood aqueous barrier breakdown in dogs
following anterior chamber paracentesis was greater than that of flurbiprofen and suprofen in one study,60 while
in a study utilizing pilocarpine to induce blood-aqueous barrier breakdown, diclofenac was inferior to
flurbiprofen.61
Evaluation in cats
Anterior chamber paracentesis was used to induce blood-aqueous barrier disruption in both eyes of
normal cats, and was followed by unilateral application of a single dose of either 1% prednisolone acetate, 0.1%
dexamethasone, 0.03% flurbiprofen, of 0.1% diclofenac immediately and at 6, 10 and 24 hours post-
paracentesis (the contralateral eye served as an untreated control).7 Flare was measured using a laser-flare meter
at 4, 8, and 26 hours post-paracentesis, and the relative ability of each anti-inflammatory was assessed. A
significant reduction in flare at all three time points was associated only with 1% prednisolone acetate;
diclofenac 0.1% significantly reduced flare at the 8- and 26-hour timepoints; 0.1% dexamethasone significantly
reduced flare at the 4-hour timepoint; and flurbiprofen 0.03% did not significantly reduce flare at any timepoint.
Evaluation of systemic absorption of diclofenac following four-times daily bilateral administration for 7 days
revealed measurable plasma diclofenac concentrations, with a reduction in glomerular filtration rate presumed
to be associated with study-induced volume contraction (Hsu AJVR 2015).
Indomethacin
Indomethacin (0.5% solution) is available in some countries as either a solution or a suspension, with
the solution demonstrating equivalent efficacy to the suspension in preventing miosis and blood-aqueous barrier
breakdown in dogs in associated with aqueous paracentesis.62 It has good intraocular penetration.63,64
Flurbiprofen
Flurbiprofen, available as a 0.03% solution, is approved for maintaining mydriasis in association with
cataract surgery, and also is used in the treatment of cystoid macular edema. Following topical administration,
intraocular levels are comparable to those achieved with diclofenac, however diclofenac has a longer intraocular
residence time than does flurbiprofen (~7 hours versus ~4 hours, respectively).65 It is effective at reducing
intraocular inflammation following laser anterior capsulotomy,66,67 however its efficacy relative to that of
diclofenac is variable.60,61
Bromfenac
Bromfenac is available as a 0.09% solution. Its chemical structure is identical to that of amfenac (see
below), however it has a bromine atom that imparts favorable pharmacological properties. The first benefit of
the bromine addition is enhanced lipophilicity, which increases transcorneal penetration and potential efficacy.
The second benefit is increased duration of analgesic and anti-inflammatory activity, and the third benefit is
increased COX-2 inhibition.68 Although difficult to truly mimic in vitro, the COX-2 inhibitory activity of
bromfenac measured as an IC 50 (inhibitory concentration 50%, or concentration of drug required to inhibit COX
activity by 50%) is greater than that of diclofenac, amfenac, and ketorolac, based on in vitro studies.68
Bromfenac also has excellent intraocular penetration following topical administration, achieving measurable
corneal, aqueous humor, and intraocular tissue levels following application of a single dose in normal rabbits.69
Administration of a single drop in human patients prior to cataract removal demonstrated clinically effective
aqueous humor bromfenac concentrations up to 12 hours post-administration.70 Comparison of PGE 2 inhibitory
activity demonstrated greater inhibition with ketorolac,52 while bromfenac more effectively inhibited COX-2
than did ketorolac.71 Bromfenac also demonstrated superior clinical anti-inflammatory effect to that of
diclofenac following cataract removal, with a lower incidence of corneal epitheliopathy.68 A comparison of
post-surgical clinical efficacy of bromfenac and 0.1% betamethasone, alone or in combination, demonstrated no
significant difference in visual acuity, IOP, flare, or corneal swelling among the individual drugs or
combination.72 Comparison of bromfenac with celecoxib-impregnated IOL and prednisolone acetate therapy in
dogs undergoing phacoemulsification identified increased aqueous flare in bromfenac-treated eyes at 24 hours
post-operatively, as well as increased IOP in bromfenac-treated eyes at 4 and 12 weeks post-operative,
decreased PCO in bromfenac-treated eyes at 54 weeks post-operatively (Brookshire VO 2015). Evaluation of
prevalence of post-operative ocular hypertension (POH) in dogs following phacoemulsification and receiving
either fluribprofen or bromfenac pre- and post-operatively identified an increased tendency toward elevated IOP
at 2-hours post-operatively, as well as a slower decrease in IOP in the 6 weeks following surgery, in dogs
treated with bromfenac (Lu VO 2016).
Nepafenac
Nepafenac is available as a 0.1% suspension, and is the only NSAID prodrug formulation currently
available. As an amide prodrug, nepafenac is not a free acid, and being less polar with less ionic influence, the
corneal epithelium less effectively limits its intraocular penetration.73 While nepafenac itself is only weakly
inhibitory of COX enzymes relative to other NSAIDs, it has excellent intraocular penetration, allowing it to
reach the presumable sites of hydrolytic conversion (iris, ciliary body, retina, choroid – not the cornea) to the
active form amfenac.74 Patients receiving either nepafenac, bromfenac, or ketorolac prior to cataract removal
had significantly greater aqueous humor nepafenac concentrations (205.3 ng/ml) than either bromfenac or
ketorolac (25.9 ng/ml and 57.5 ng/ml, respectively), and those levels were reached within 30 minutes
(bromfenac and ketorolac maximum concentrations were reached at 240 and 60 minutes, respectively).75
Comparison of the in vitro COX-1 and COX-2 inhibitory activity of nepafenac, bromfenac, ketorolac, and
amfenac found ketorolac had the greatest COX-1 inhibitory activity while amfenac and bromfenac then
ketorolac had the greatest COX-2 inhibitory activity (nepafenac had least COX-1 and COX-2 activity),
supporting the ability of nepafenac to penetrate the cornea and the likely clinical efficacy of its active
metabolite amfenac to control intraocular inflammation.75 Clinical evaluation of the ability of nepafenac to
control pain and inflammation associated with cataract surgery is supportive of nepafenac’s overall efficacy,
however comparison relative to ketorolac largely indicates comparable effects.76,77 Following corneal refractive
surgery however, one study showed marked corneal haze and delayed epithelialization associated with
nepafenac,78 while other studies have not documented the same deleterious effects in the short-term.79,80
References
1.
Sendrowski D, Jaanus S, Semes L, et al. Anti-Inflammatory Drugs In: Bartlett J,Jaanus S,
eds. Clinical Ocular Pharmacology. 5th ed. St. Louis: Butterworth Heinemann, 2008;221-244.
2.
McGhee C, Watson D, Midgley J, et al. Penetration of synthetic corticosteroids into human
aqueous humor. Eye 1990;4:526-530.
3.
McGhee C. Pharmacokinetics of ophthalmic corticosteroids. British Journal of
Ophthalmology 1992;76:681-684.
4.
Musson D, Bidgood A, Olejnik O. An in vitro comparison of the permeability of
prednisolone, prednisolone sodium phosphate, and prednisolone acetate across the NZW rabbit
cornea. Journal of Ocular Pharmacology 1992;8:139-150.
5.
Leibowitz H, Kupferman A. Kinetics of topically administered prednisolone acetate. Archives
of Ophthalmology 1976;94:1387-1389.
6.
McLean N, Ward D, Hendrix D, et al. Effects of one-week versus one-day preoperative
treatment with topical 1% prednisolone acetate in dogs undergoing phacoemulsification. Journal of
the American Veterinary Medical Association 2012;240:563-569.
7.
Rankin A, Khrone S, Stiles J. Evaluation of four drugs for inhibition of paracentesis-induced
blood-aqueous humor barrier breakdown in cats. American Journal of Veterinary Research
2011;72:826-832.
8.
Jonas J. Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Research
2006;38:218-245.
9.
Molleda J, Tardon R, Gallardo J, et al. The ocular effects of intravitreal triamcinolone
acetonide in dogs. The Veterinary Journal 2008;176:326-332.
10.
Yi N, Davis J, Salmon J, et al. Ocular distribution and toxicity of intravitreal injection of
triamcinolone acetonide in normal equine eyes. Veterinary Ophthalmology 2008;11:15-19.
11.
Novack G, Howes J, Crockett R, et al. Change in intraocular pressure during long-term use of
loteprednol etabonate. Journal of Glaucoma 1998;7:266-269.
12.
Whitcup S, III FF. New corticosteroids for the treatment of ocular inflammation. American
Journal of Ophthalmology 1999;127:597-599.
13.
Stewart R, Horwitz B, Howes J, et al. Loteprednol Etabonate Postoperative Inflammation
Study Group 1. Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for
postoperative inflammation. Journal of Cataract and Refractive Surgery 1998;24:1480-1489.
14.
Regnier A, Toutain P, Alvinerie M, et al. Adrenocortical function and plasma biochemical
values in dogs after subconjunctival treatment with methylprednisolone acetate. Research in
Veterinary Science 1982;32:306-310.
15.
Roberts S, Lavach J, Macy D, et al. Effect of ophthalmic prednisolone acetate on the canine
adrenal gland and hepatic function. American Journal of Veterinary Research 1984;45:1711-1714.
16.
Eichenbaum J, Macy D, Severin G, et al. Effect in large dogs of ophthalmic prednisolone
acetate on adrenal gland and hepatic function. Journal of the American Animal Hospital Association
1988;24:705-709.
17.
Glaze M, Crawford M, Nachreiner F, et al. Ophthalmic corticosteroid therapy: Systemic
effects in the dog. Journal of the American Veterinary Medical Association 1988;192:73-75.
18.
Murphy C, Feldman E, Bellhorn R. Iatrogenic Cushing's syndrome in a dog caused by topical
ophthalmic medications. Journal of the American Animal Hospital Association 1990;26:640-642.
19.
Spiess B, Nyikos S, Stummer E, et al. Systemic dexamethasone concentration in horses after
continued topical treatment with an ophthalmic preparation of dexamethasone. American Journal of
Veterinary Research 1999;60:571-576.
20.
Townsend W, Renninger M, Stiles J, et al. Dexamethasone-induced exophthalmos in a group
of Holstein calves. Veterinary Ophthalmology 2003;7:381-384.
21.
Jobling A, Augusteyn R. What causes steroid cataracts? A review of steroid-induced
posterior subcapsular cataracts. Clinical and Experimental Optometry 2002;85:61-75.
22.
Wordinger R, Clark A. Effects of glucocorticoids on the trabecular meshwork: towards a
better understanding of glaucoma. Progress in Retinal and Eye Research 1999;18:629-667.
23.
Gelatt K, Mackay E. The ocular hypertensive effects of topical 0.1% dexamethasone in
beagles with inherited glaucoma. Journal of Ocular Pharmacology and Therapeutics 1998;14:57-66.
24.
Herring I, Herring E, Ward D. Effect of orally administered hydrocortisone on intraocular
pressure in nonglaucomatous dogs. Veterinary Ophthalmology 2004;7.
25.
Zhan G, Miranda O, Bito L. Steroid glaucoma: Corticosteroid-induced ocular hypertension in
cats. Experimental Eye Research 1992;54:211-218.
26.
Bhattacherjee P, Paterson C, Spellman J, et al. Pharmacological validation of a feline model
of steroid-induced ocular hypertension. Archives of Ophthalmology 1999;117:361-364.
27.
Gerometta R, Podos S, Candia O. Steroid-induced ocular hypertension in normal cattle.
Archives of Ophthalmology 2004;122:1492-1497.
28.
Gemensky-Metzler A, Wilkie D, Kowalski J, et al. Changes in bacterial and fungal ocular
flora of clinically normal horses following experimental application of topical antimicrobial or
antimicrobial-corticosteroid ophthalmic preparations. American Journal of Veterinary Research
2005;66:800-811.
29.
Regnier A. Clinical Pharmacology and Therapeutics Part II In: Gelatt K, ed. Veterinary
Ophthalmology. 4th ed. Ames, Iowa: Blackwell, 2007;288-331.
30.
Pappa K. Corticosteroid Drugs In: Mauger T,Craig E, eds. Havener's Ocular Pharmacology.
6th ed. St Louis: Mosby, 1994;364-428.
31.
Hendrix D, Ward D, Barnhill M. Effects of anti-inflammatory drugs and preservatives on
morphologic characteristics and migration of canine corneal epithelial cells in tissue culture.
Veterinary Ophthalmology 2002;5:127-135.
32.
Bourcier T, Borderie V, Forgez P, et al. In vitro effects of dexamethasone on human corneal
keratocytes. INvestigative Ophthalmology and Visual Science 1999;40:1061-1070.
33.
Radi Z, Render J. The Pathophysiologic Role of Cyclo-Oxygenases in the Eye. Journal of
Ocular Pharmacology and Therapeutics 2008;24:141-151.
34.
Gaynes B, Fiscella R. Topical Nonsteroidal Anti-Inflammatory Drugs for Ophthalmic Use: A
Safety Review. Drug Safety 2002;25:233-250.
35.
Gupta M, Majumdar D. Effect of concentration, pH and preservatives on in vitro transcorneal
permeation of ibuprofen and flurbiprofen from non-buffered aqueous drops. Indian Journal of
Experimental biology 1997;35:844-849.
36.
Ahuja M, Dhake A, Sharma S, et al. Topical Ocular Delivery of NSAIDs. American
Association of Pharmaceutical Scientists Journal 2008;10:229-241.
37.
Aragona P, Tripodi G, Spinella R, et al. The effects of the topical administration of nonsteroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects.
Eye 2000;14:206-210.
38.
Congdon N, Schein O, Kulajita P, et al. Corneal complications associated with topical
ophthalmic use of nonsteroidal antiinflammatory drugs. Journal of Cataract and Refractive Surgery
2001;27:622-631.
39.
Hsu J, Johnston W, Read R, et al. Histopathology of corneal melting associated with
diclofenac use after refractive surgery. Journal of Cataract and Refractive Surgery 2003;29:250-256.
40.
Gaynes B, Fiscella R. Biotransformation in review: applications in ocular disease and drug
design. Journal of Ocular Pharmacology and Therapeutics 1996;12:527-539.
41.
Srinivasan B, Kulkarni P. Inhibitors of arachidonic acid cascade in the management of ocular
inflammation In: Bito L,Stjernschantz J, eds. The ocular effect of prostaglandins and other
eicosanoids. New York: Alan R. Liss, 1989;229-249.
42.
Ito A, Nose T, Takahashi S, et al. Cyclooxygenase inhibitors augment the production of promatrix metalloproteinase 9 (progelatinase B) in rabbit articular chondrocytes. FEBS Lett
1995;360:75-79.
43.
Giuliano E. Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology. Veterinary
Clinics of North America: Small Animal Practice 2004;34:707-723.
44.
Ward D, Ferguson D, Ward S, et al. Comparison of the blood-aqueous barrier stabilizing
effects of steroidal and nonsteroidal anti-inflammatory agents in the dog. Progress in Veterinary
Comparative Ophthalmology 1992;2:117-124.
45.
Millichamp N, Dziezyc J, Rohde B, et al. Acute effects of anti-inflammatory drugs on
neodymium:yttrium aluminum garnet laser-induced uveitis in dogs. American Journal of Veterinary
Research 1991;52:165-170.
46.
Krohne S, Blair M, Bingaman D, et al. Carprofen inhibition of flare in the dog measured by
laser flare photometry. Veterinary Ophthalmology 1998;1:81-84.
47.
Roze M, Thomas E, Davot J. Tolfenamic acid in the control of ocular inflammation in the
dog: pharmacokinetics and clinical results obtained in an experimental model. Journal of Small
Animal Practice 1996;37:371-375.
48.
Pinard C, Gauvin D, Moreau M, et al. Measurements of canine aqueous humor inflammatory
mediators and the effect of carprofen following anterior chamber paracentesis. Veterinary
Ophthalmology 2011;14:296-303.
49.
Gilmour M, Lehenbauer T. Comparison of tepoxalin, carprofen, and meloxicam for reducing
intraocular inflammation in dogs. American Journal of Veterinary Research 2009;70:902-907.
50.
Xu K, McDermott M, Villanueva L, et al. Ex vivo corneal epithelial wound healing following
exposure to ophthalmic nonsteroidal anti-inflammatory drugs. Clinical Ophthalmology 2011;5:269274.
51.
Garrett Q, Simmons P, Xu S, et al. Carboxymethylcellulose binds to human corneal epithelial
cells and is a modulator of corneal epithelial wound healing. Investigative Ophthalmology and Visual
Science 2007;48:1559-1567.
52.
Bucci F, Waterbury L. Comparison of ketorolac 0.4% and bromfenac 0.09% at trough dosing:
Aqueous drug absorption and prostaglandin E2 levels. Journal of Cataract and Refractive Surgery
2008;34:1509-1512.
53.
Bucci F, Waterbury L, Amico L. Prostaglandin E2 Inhibition and Aqueous Concentration of
Ketorolac 0.4% (Acular LS) and Nepafenac 0.1% (Nevanac) in Patients Undergoing
Phacoemulsification. American Journal of Ophthalmology 2007;144:146-147.
54.
Bucci F, Waterbury L. A randomized comparison of to-aqueous penetration of ketorolac
0.45%, bromfenac 0.09%, and nepafenac 0.1% in cataract patients undergoing phacoemulsification.
Current Medical Research and Opinion 2011;27:2235-2239.
55.
Bucci F, Waterbury L. Prostaglandin E2 Inhibition of Ketorolac 0.45%, Bromfenac 0.09%,
and Nepafenac 0.1% in Patients Undergoing Phacoemulsification. Advances in Therapy
2011;28:1089-1095.
56.
Heier J, Awh C, Busbee B, et al. Vitreous nonsteroidal antiinflammatory drug concentrations
and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and
nepafenac 0.1%. Retina 2009;29:1310-1313.
57.
Donnenfeld E, Holland E, Durrie D, et al. Double-Masked Study of the Effects of Nepafenac
0.1% and Ketorolac 0.4% on Corneal Epithelial Wound Healing and Pain After Photorefractive
Keratectomy. Advances in Therapy 2007;24:852-862.
58.
Durrie D, Kennard M, Boghossian A. Effects of Nonsteroidal Ophthalmic Drops on
Epithelial Healing and Pain in Patients Undergoing Bilateral Photorefractive Keratectomy (PRK).
Advances in Therapy 2007;24:1278-1285.
59.
Palmero M, Bellot J, Alcoriza N, et al. The ocular pharmacokinetics of topical diclofenac is
affected by ocular inflammation. Ophthalmic Research 1999;31:309-316.
60.
Ward D. Comparative efficacy of topically applied flurbiprofen, diclofenac, tolmetin, and
suprofen for the treatment of experimentally induced blood-aqueous barrier disruption in dogs.
American Journal of Veterinary Research 1996;57:875-878.
61.
Krohne S, Gionfriddo J, Morrison E. Inhibition of pilocarpine-induced aqueous humor flare,
hypotony, and miosis by topical administration of anti-inflammatory and anesthetic drugs to dogs.
American Journal of Veterinary Research 1998;59:482-488.
62.
Regnier A, Dossin O, Cutzach E, et al. Comparative effects of two formulations of
indomethacin eyedrops on the paracentesis-induced inflammatory response in the canine eye.
Veterinary Comparative Ophthalmology 1995;5:242-246.
63.
Sanders D, Goldstick B, Kraff C, et al. Aqueous penetration of oral and topical indomethacin
in humans. Archives of Ophthalmology 1983;101:1614-1616.
64.
Spiess B, Mathis G, Franson K, et al. Kinetics of uptake and effects of topical indomethacin
application on protein concentration in the aqueous humor of dogs. American Journal of Veterinary
Research 1991;52:1159-1163.
65.
Ellis P, Pfoff D, Bloedow D, et al. Intraocular diclofenac and flurbiprofen concentrations in
human aqueous humor following topical application. Journal of Ocular Pharmacology 1994;10:677682.
66.
Dziezyc J, Millichamp N, Smith W. Effect of flurbiprofen and corticosteroids on the ocular
irritative response in dogs. Veterinary Comparative Ophthalmology 1995;5:42-45.
67.
Millichamp N, Dziezyc J. Comparison of flunixin meglumine and flurbiprofen for control of
ocular irritative response in dogs. American Journal of Veterinary Research 1991;52:1452-1455.
68.
Cho H, Wolf K, Wolf E. Management of ocular inflammation and pain following cataract
surgery: focus on bromfenac ophthalmic solution. Clinical Ophthalmology 2009;3:199-210.
69.
Baklayan G, Patterson H, Song C, et al. 24-Hour Evaluation of the Ocular Distribution of
14C-Labeled Bromfenac Following Topical Instillation into the Eyes of New Zealand White Rabbits.
Journal of Ocular Pharmacology and Therapeutics 2008;24:392-398.
70.
Miyake K, Ogawa T, Tajika T, et al. Ocular Pharmacokinetics of a Single Dose of Bromfenac
Sodium Ophthalmic Solution 0.1% in Human Aqueous Humor. Journal of Ocular Pharmacology and
Therapeutics 2008;24:573-578.
71.
Waterubry L, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and
ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Current Medical
Research Opinion 2006;22:1133-1140.
72.
Miyanaga M, Miyai T, Nejima R, et al. Effect of bromfenac ophthalmic solution on ocular
inflammation following cataract surgery. Acta Ophthalmologica 2009;87:300-305.
73.
Gaynes B, Onyekwuluje A. Topical ophthalmic NSAIDs: a discussion with focus on
nepafenac ophthalmic suspension. Clinical Ophthalmology 2008;2:355-368.
74.
Ke T, Graff G, Spellmann J. Nepafenac a unique nonsteroidal prodrug with utility in the
treatment of trauma-induced ocular inflammation. II in vitro bioactivation and permeation of external
ocular barriers. Inflammation 2000;24:371-384.
75.
Walters T, Raizman M, Ernest P, et al. In vivo pharmacokinetics and in vitro
pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. Journal of Cataract and
Refractive Surgery 2007;33:1539-1545.
76.
Nardi M, Lobo C, Bereczki A. Analgesic anti-inflammatory effectiveness of nepafenac 0.1%
for cataract surgery. Clinical Ophthalmology 2007;1:527-533.
77.
Lane S, Modi S, Lehmann R. Nepafenac ophthalmic suspension 0.1% for prevention of
ocular inflammation associated with cataract surgery. Journal of Cataract and Refractive Surgery
2007;33:53-57.
78.
Trattler W, McDonald M. Double-Masked Comparison of Ketorolac Tromethamine 0.4%
Versus Nepafenac Sodium 0.1% for Postoperative Healing Rates and Pain Control in Eyes
Undergoing Surface Ablation. Cornea 2007;26:665-669.
79.
Caldwell M, Reilly C. Effects of topical nepfenac on corneal epithelial healing time and
postoperative pain after PRK: A bilateral, prospective, randomized masked trial. Journal of Refractive
Surgery 2008;24:377-382.
80.
Colin J, Paquette B. Comparison of the analgesic efficacy and safety of nepafenac ophthalmic
compared with diclofenac solution for pain and photophobia after excimer laser surgery. A phase II
double masked trial. Clinical Therapeutics 2006;28:527-536.
Brookshire H, English RV, Nadelstein B, Weight AK, Gift BW, and Gilger BC. Efficacy of COX-2
inhibitors in controlling inflammation and capsular opacification after phacoemulsification cataract
removal. Vet Ophthalmol 2015;18:175-185.
Hilton HG, Magdesian KG, Groth AD, Knych H, Stanley SD, Hollingsworth SR. Distribution of
flunixin meglumine and firocoxib into aqueous humor of horses. J Vet Intern Med 2011;25:11271133.
Hsu KK, Pinard CL, Johnson RJ, Allen DG, KuKanich BK, Nykamp SG. Systemic absorption and
adverse ocular and systemic effects after topical ophthalmic administratio of 0.1% diclofenac to
healthy cats. Am J Vet Res 2015;76:253-265.
Lu J, English R, Nadelstein B, Weigt A, Berdoulay A, Binder D, Ngan E. Comparison of topically
applied flurbiprofen or bromfenac ophthalmic solution on post-operative ocular hypertension in
canine patients following cataract surgery. Vet Ophthalmol 2016; doi: 10.1111/vop.12372
.