Topical Nonsteroidal
`
`Antiinflammatory Drugs for
`
`Ophthalmic Use
`
`T Allan J. Flach, M.D.
`
`Nonsteroidal antiinflammatory drugs (NSAIDs) formulated as oph-
`thalmic eye drops are commercially available throughout the world [1, 2].
`They have been used widely in the management of postoperative ocular
`inflammation and for the prevention and treatment of cystoid macular
`edema (CME) after cataract surgery. In addition, they have proved useful
`for the prevention of intraoperative miosis during cataract surgery, for
`the relief of symptoms of seasonal allergic conjunctivitis, and for the reduc-
`tion of ocular discomfort following refractive surgery. This chapter sum-
`marizes the current status of topically applied NSAIDS and their potential
`therapeutic benefit for ophthalmic disorders.
`
`I Chemical Classification
`
`NSAIDs consist of a chemically heterogeneous group of compounds
`that can be grouped into six major classes: salicylates, fenamates, indoles,
`phenylalkanoic acids, phenylacetic acids, and pyrazolones. Classification of
`these drugs as NSAIDs underscores that their chemical structures lack a
`steroid nucleus that is biosynthetically derived from cholesterol. In this
`chapter, the indoles, the phenylacetic acids, and the phenylalkanoic acids
`will be emphasized because they are commercially available as topical oph-
`thalmic preparations. The salicylates, fenamates, and pyrazolone deriva-
`tives are either too toxic or too unstable in solution for commercial formu-
`lation.
`
`Indomethacin is an indole derivative that was formulated initially as a
`sesame seed oil solution. However, this preparation proved to be locally
`irritating and unsuitable for widespread clinical use. Topical indomethacin
`is commercially available outside of the United States as a 1% aqueous
`suspension (Indocid Ophthalmic Suspension, Merck Sharp 8: Dohme). A
`0.1% indomethacin ophthalmic solution has recently been formulated, but
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`78 • Flach
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`it is not yet commercially available [3]. The phenylalkanoic acids are water(cid:173)
`soluble and are formulated as ophthalmic solutions. Flurbiprofen 0.03%
`(Ocufen Ophthalmic Solution, Allergan) and suprofen 1% (Profenal Oph(cid:173)
`thalmic Solution, Alcon) are approved by the Food and Drug Administra(cid:173)
`tion (FDA) for intraoperative use to inhibit miosis during cataract surgery.
`Ketorolac tromethamine 0.5% (Acular Ophthalmic Solution, Allergan) is
`approved in the United States for the treatment of seasonal allergic con(cid:173)
`junctivitis. Diclofenac 1% (Voltaren, Ciba Vision Ophthalmics) is a phenyl(cid:173)
`acetic acid derivative that is approved by the FDA for use to minimize
`postoperative inflammation after cataract surgery.
`
`• Pharmacokinetics
`
`Pharmacokinetics is defined most easily as the action of one's body on
`an administered drug. NSAIDs are well absorbed after oral administration,
`with peak serum levels achieved in 1 to 3 hours. These agents are metabo(cid:173)
`lized by the liver and excreted in the urine and the bile. All these drugs
`are 90 to 99% protein-bound and, therefore, are easily recovered from
`ocular tissues. Ocular instillation of topical NSAIDs provides ocular tissue
`and aqueous humor levels adequate to inhibit prostaglandin (PG) synthesis.
`In fact, these NSAIDs appear to penetrate the eye better after topical
`iiPPlication than after oral administration. This observation, coupled with
`a greater potential for undesirable systemic side effects with oral adminis(cid:173)
`tration, makes it unreasonable for ophthalmologists to prescribe systemic
`NSAIDs to achieve most ocular therapeutic effects. However, topically ap(cid:173)
`plied NSAIDs can gain access to the systemic circulation via mucosal ab(cid:173)
`sorption. Therefore, even local administration of NSAIDs can be accompa(cid:173)
`nied by systemic toxicity if nasolacrimal occlusion and eyelid closure are
`not employed following eye drop instillation.
`
`• Pharmacodynamics
`
`Pharmacodynamics is the action of a drug on one's body. Aspirin and
`other NSAIDs decrease the synthesis of PGs within human tissues by inhib(cid:173)
`iting cyclooxygenase. This enzyme facilitates the formation of endoperox(cid:173)
`ides from arachidonic acid within the cascade of reactions that ultimately
`generate PGs within the human body. The resultant endogenous PGs can
`produce many ocular pharmacological effects including miosis, increased
`permeability of the blood-ocular barriers, conjunctival hyperemia, and
`changes in intraocular pressure. In addition, PGs are known to possess
`chemokinetic activity, can serve as mediators of humoral and cellular
`phases of inflammatory responses and are associated with the pain re(cid:173)
`sponse and allergic reactions.
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`

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`Ophthalmic NSAIDS I 79
`
`Although NSAIDs do not inhibit lipoxygenase and, therefore, have
`no ability to inhibit directly the generation of ‘endogenous leukotrienes,
`diclofenac appears capable of reducing the level of leukotriene formation
`in vitro by indirect means [4]. There is evidence that NSAIDs have a free
`radical scavenger activity that may be beneficial during inflammation.
`Therefore, inhibition of cyclooxygenase activity clearly is not the only po-
`tential mechanism of activity for this group of drugs [1].
`
`I NSAIDs and Cataract Surgery
`
`Maintenance of intraoperative Mydriasis
`
`Clinical studies reporting NSAID efficacy describe a small pharmaco-
`logical effect on the intraoperative change in pupil size. Flurbiprofen
`0.03% and suprofen 1% were first approved by the FDA for use as intraop-
`erative inhibitors of miosis. Topical NSAIDs appear to share this therapeu-
`tic benefit [5]. This pharmacological activity is of potential clinical benefit
`because decreasing pupil size is a well-recognized risk factor for vitreous
`loss and zonular breaks during extracapsular cataract extractions with im-
`plantation of an intraocular lens [1]. The FDA’s summary bases of approval
`for flurbiprofen and suprofen suggest that the pharmacological effect of
`these NSAIDs on pupil size varies from one surgical practice to another,
`as previously discussed [2]. This fact implies that endogenous factors other
`than PG-induced miosis and surgical technique are playing important, and
`as yet undefined, roles in the etiology of surgically induced miosis.
`In summary, there is evidence that topically applied NSAIDs have a
`statistically significant inhibitory effect on intraoperative miosis. However,
`it is not clear that this effect is clinically significant for all surgeries. Ade-
`quate intraoperative mydriasis frequently is achieved and maintained by
`using good surgical technique, a combination of preoperative parasympa-
`tholytic and sympathomimetic eye drops, and the use of a sympathomi-
`metic in the intraocular irrigation solution during irrigation and aspiration
`of cortical remnants. Therefore, it probably is unreasonable to suggest the
`routine use of preoperative NSAIDs for inhibiting intraoperative miosis
`during cataract surgery for all ophthalmic practices.
`
`Reduction of Postoperative Inflammation
`
`topical
`Many well—designed clinical studies provide evidence that
`NSAIDs are potentially useful in the management of inflammation after
`cataract surgery [1, 2]. During the 1970s, double-masked, randomized clin-
`ical studies evaluated the effect of topically applied indomethacin on the
`inflammatory response in the early postoperative period following ocular
`surgeries. Initially, the effects appeared variable. However, the results
`were more consistent once studies were designed to evaluate the effective-
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`80 I Flach
`
`ness of indomethacin given prior to and immediately after the surgical
`procedures. Unfortunately, many studies include concurrent administra-
`tion of corticosteroids. Therefore, it is difficult to conclude whether the
`observed effects on postoperative inflammation are related to NSAID
`treatment or a synergistic effect of indomethacin and corticosteroids. It
`also is possible that the concurrent steroid treatment masks indomethacin’s
`tendency to cause ocular irritation.
`Several double-masked, randomized placebo- and active-controlled
`studies including patients undergoing cataract surgery have reported anti-
`inflammatory effects from topically applied 1% indomethacin, 0.03%
`flurbiprofen, 0.5% ketorolac, and 0.1% diclofenac ophthalmic prepara-
`tions [1, 2]. These investigations report a measurable antiinflammatory
`effect from topical NSAID treatments as compared to placebo after intra-
`capsular and extracapsular cataract extractions, with and without implanta-
`tion of an intraocular lens. The correlation between slit-lamp observations
`and anterior ocular fluorophotometry appears reasonably consistent. Stud-
`ies using laser cell—and-flare meter methodology further support this po-
`tential therapeutic benefit [6, 7]. Studies comparing NSAIDs to corticoste-
`roids have demonstrated that the results of these treatments show no
`
`significant difference as judged by slit-lamp examinations for cells, flare,
`and chemosis, but NSAID treatment appears more effective than topical
`steroids in reestablishing the blood-aqueous barrier as quantitatively mea-
`sured with anterior ocular fluorophotometry [1].
`In summary, many clinical studies provide evidence that topically ap-
`plied NSAID ophthalmic preparations are potentially useful in managing
`inflammation after cataract surgery. These preparations are available and
`in use throughout the world for this indication. However, at the time this
`chapter was written, diclofenac 0.1% ophthalmic solution (Voltaren) was
`the only NSAID specifically approved by the FDA for use within the
`United States as a postoperative antiinflammatory agent following cataract
`surgery.
`
`Prevention and Treatment of CME
`
`Thoughtful reviews have summarized potential approaches to the pre-
`vention and treatment of CME after cataract surgery [8, 9]. These reviews
`stress the importance of placebo-controlled, double-masked, randomized
`trials in making decisions about the efficacy of potential treatments for
`CME after cataract surgery because this condition’s natural history includes
`spontaneous resolution. Most reports emphasize the need to evaluate pro-
`phylactic therapy separately from the treatment of chronic CME and the
`importance of differentiating between angiographic CME and clinically
`significant CME (that associated with a reduction in vision).
`Topical NSAIDs are effective in the prophylaxis of angiographic CME.
`However, a statistically significant, sustained effect on visual acuity has not
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`Ophthalmic NSA|Ds I 81
`
`been demonstrated [1]. Unfortunately, most of the studies of prophylactic
`NSAID therapy include the concurrent use of corticosteroids. Insofar as
`corticosteroids inhibit the generation of PGs by a different mechanism
`than do NSAIDS it appears possible that a synergistic effect occurs when
`these drugs are used together. A randomized, double-masked clinical trial,
`using Snellen and contrast-sensitivity measurements, compares 0.03%
`flurbiprofen, 1% indomethacin, and placebo regarding their ability to pre-
`vent CME during a 6-month period after cataract surgery [10]. The inci-
`dence of clinical CME as determined by contrast-sensitivity scores is sig-
`nificantly lower for the drug- treated groups. However, these effects were
`not sustained, and this study included concurrent corticosteroids.
`Only one randomized, double-masked study of prophylaxis of CME
`with NSAIDs without concurrent corticosteroid therapy is found in the
`literature [11]. It reports less postoperative angiographic CME in the
`group treated with ketorolac 0.5% compared to the placebo group [11].
`Though there are fewer studies of the treatment of chronic CME, two
`double-masked, placebo-controlled, randomized studies demonstrate that
`ketorolac 0.5% ophthalmic solution, one drop given four times daily for
`up to 3 months, improves vision in some patients with chronic CME (of 6
`or more months’ duration) after cataract surgery [12, 13]. Hence, there is
`evidence that topical NSAID treatment offers benefit to some patients for
`the prevention and treatment of CME following cataract surgery.
`
`I Allergic Conjunctivitis
`
`Topical corticosteroids commonly are used in an attempt to reduce
`the signs and symptoms of allergic conjunctivitis. Unfortunately, their use
`can be accompanied by local toxicity, including secondary open-angle glau-
`coma, cataracts, superinfections with viruses or fungi, and impaired wound
`healing. There is evidence that ketorolac 0.5% ophthalmic solution, admin-
`istered as one drop four times daily, is effective in reducing the ocular
`pruritus that often accompanies seasonal allergic conjunctivitis [14]. There-
`fore, the FDA has approved this preparation (Acular) for use in the United
`States. In addition, some studies suggest that diclofenac is effective in the
`treatment of seasonal allergic conjunctivitis [15], and there are reports of
`potentially useful effects following suprofen treatment of giant papillary
`conjunctivitis and vernal conjunctivitis [16, 17].
`
`I Reduction of Discomfort After
`
`Refractive Surgery
`
`The topical NSAIDS are not approved for use following radial kera-
`totomy or photorefractive keratectomy within the United States. However,
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`82 I Flach
`
`there are reports that pain following refractive surgeries is reduced with
`the use of topical ketorolac and diclofenac ophthalmic solutions [l8—20].
`
`I Local and Systemic Toxicity of Topical NSAIDS
`
`The most common adverse reactions after topical instillation of the
`NSAIDs are transient burning, stinging, and hyperemia of the conjunctiva.
`Manufacturers have used various formulation methods to minimize this
`
`potential discomfort. Indomethacin solution in sesame seed oil was aban-
`doned in favor of an aqueous suspension. Suprofen is prepared with 1%
`caffeine because it is less irritating in this form. Ketorolac is formulated
`as the tromethamine salt because the tromethamine moiety enhances the
`aqueous solubility and results in a solution that is less irritating to the eye.
`Despite these improvements, some patients will experience local discom-
`fort after instilling these preparations. In addition, allergies and hypersen-
`sitivity reactions have been reported with all the NSAIDs.
`Systemic administration of NSAIDs can be accompanied by serious
`side effects such as gastrointestinal, central nervous system, hematologic,
`renal, liver, dermatological, and metabolic changes. It appears, though,
`that these effects are largely avoided by topical administration. The pos-
`sibility of systemic absorption exists after topical application, but it is not
`clear whether this represents a clinically significant problem [1]. The litera-
`ture clearly describes less toxicity associated with the topical use of NSAIDs
`than with topically applied corticosteroids, but NSAIDS have been used
`"far less extensively. Furthermore, there are some theoretical objections
`to the inhibition of only the cyclooxygenase pathway for PG generation.
`Although an aggravation of ocular inflammation has not been observed in
`any of the clinical studies of NSAID use thus far reported, it is premature
`to assume that this treatment is completely safe. Therefore, NSAID use
`must be carefully monitored for adverse events, as is good practice with
`any new drug treatment.
`
`
`The efforts recorded in this chapter were supported by a Department of Veterans
`Affairs Merit Review grant, a That Man May See, Inc., grant, and a National Institutes
`of Health—University of California San Francisco, Department of Ophthalmology de-
`partmental core grant.
`
`I References
`
`1. Flach A]. Nonsteroidal anti-inflammatory drugs. In: Tasman W, ed. Duane’s foun-
`dations of clinical ophthalmology. Philadelphia: Lippincott, l994:l—32
`2. Flach A]. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol l992;36:
`259-284
`
`

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`Ophthalmic NSAlDs
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`I 83
`
`. Trinquand C, Richard C, Arnaud B. Three-arm, double-masked study of two oph-
`thalmic formulations of 0.1% indomethacin and 0.1% diclofenac in controlling in-
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`. Ku ED, Lee W, Kothari HV, et al. Effect of diclofenac sodium on the arachidonic
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`. Roberts CW. A comparison of diclofenac sodium to flurbiprofen for maintaining
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`. Roberts CW, Brennan KM. A comparison of topical diclofenac with prednisolone
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`8
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`. jampol LM. Pharmacologic therapy of aphakic cystoid macular edema: a review.
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`. ]ampol LM. Pharmacologic therapy of aphakic and pseudophakic cystoid macular
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`Tinkelman DG, Rupp G, Kaufman H, et al. Double-masked, paired-comparison
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`Laibovitz RA, Koester ], Schaich L, et al. Safety and efficacy of diclofenac sodium
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`Wood T, Steward R, Bowman R. Suprofen treatment of contact lens associated
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`Arshinoff EA. Use of topical nonsteroidal antiinflammatory drugs in excimer laser
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