Topically applied nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the management of postoperative ocular inflammation and for the prevention and treatment of cystoid macular edema (CME) after cataract surgery. In addition, they are useful for the prevention of intraoperative miosis during cataract surgery, for the relief of symptoms of seasonal allergic conjunctivitis, and for the reduction of ocular discomfort after refractive surgery. 1,2 In this chapter, the current status of topically applied NSAIDs and their potential therapeutic benefit for ophthalmic disorders are summarized.
Chemical Classification and Commercial Preparations
Commercially available 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. The classification of this group of drugs as NSAIDs serves to underscore that their chemical structures lack a steroid nucleus that is biosynthetically derived from cholesterol. This ophthalmic clinical pharmacology review will emphasize the indoles, the phenylacetic acids, and the phenylalkanoic acids, because they are commercially available throughout the world as topically applied ophthalmic preparations. The salicylates, fenamates, and pyrazolone derivatives are either too toxic or too unstable in solution for commercial formulation as eye drops.
Indomethacin, an indole derivative, was initially formulated as a sesame seed oil solution. However, this preparation was locally irritating and unsuitable for widespread clinical use. Today topical indomethacin is commercially available outside of the United States as a 1% aqueous suspension (Indocid Ophthalmic Suspension, Merck, Sharp & Dohme). Although a 0.1% indomethacin ophthalmic solution has been formulated, it is not commercially available. 3
The phenylalkanoic acids are water-soluble. This pharmacological group includes flurbiprofen, suprofen, and ketorolac. Because of their favorable solubility characteristics, these acids are formulated as ophthalmic solutions. Flurbiprofen 0.03% (Ocufen Ophthalmic Solution, Allergan) and suprofen 1% (Profenal Ophthalmic Solution, Alcon) are approved by the US Food and Drug Administration (FDA) for intraoperative use to inhibit excessive miosis during cataract surgery. Ketorolac tromethamine 0.5% (Acular Ophthalmic Solution, Allergan) is approved in the United States for the treatment of seasonal allergic conjunctivitis and postoperative inflammation after cataract surgery and for use after refractive surgery. It is the only topically effective NSAID that is available in a preservative-free formulation (Acular PF Ophthalmic Solution, Allergan).
Diclofenac 1% (Voltaren, Novartis Ophthalmics) is a phenylacetic acid derivative that is readily soluble in water and is, therefore, available as an ophthalmic solution. Its use is approved by the FDA for minimizing postoperative inflammation after cataract surgery and for minimizing pain and photophobia after refractive surgery.
Diclofenac 1% formerly was available also in a generic form (Falcon, Alcon) approved for treatment of postoperative inflammation after cataract surgery. This generic form of diclofenac was preserved with polyquad polyquaternium-1 and included tocophersolan and mannitol as emollients. These excipients differ from those present in Voltaren 1%, which is preserved with sorbic acid and edetate sodium and includes polyoxyl-35 as an emollient. The potential significance of these differences in formulation is not clear.
Pharmacokinetics can be defined as the action of one's body on a drug after the drug's administration. Although all NSAIDs are well absorbed after oral ingestion, with peak serum levels achieved in 1 to 3 hours, ocular instillation of topical NSAIDs provides ocular tissue and aqueous humor levels adequate to inhibit prostaglandin (PG) synthesis. In fact, commercially available, topically applied NSAIDs appear to penetrate the eye better after topical application than after oral administration. This observation makes it unreasonable for ophthalmologists to prescribe systemic NSAIDs to achieve most ocular therapeutic effects. This is particularly true in light of the enhanced likelihood for undesirable systemic side effects that can accompany the oral administration of these agents. NSAIDs are metabolized 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 after topical or systemic administration. Topically applied NSAIDs can gain access to the systemic circulation after mucosal absorption from the nasolacrimal outflow system. Therefore, even local administration of NSAIDs can be accompanied by systemic toxicity, particularly if nasolacrimal occlusion and eyelid closure are not employed after eye drop instillation.
Pharmacodynamics is defined as the action of a drug on one's body. Many investigators cite the pharmacodynamic relationship of NSAIDs and cyclooxygenase inhibitors. More specifically, aspirin and other NSAIDs decrease the synthesis of PGs within our tissues by inhibiting cyclooxygenase. This enzyme facilitates the formation of endoperoxides from arachidonic acid by participating in the cascade of reactions that ultimately generate PGs within our bodies. The resultant endogenous PGs can produce many 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 response and allergic reactions.
Although NSAIDs do not inhibit lipoxygenase and, therefore, have no direct ability to inhibit the generation of endogenous leukotrienes, diclofenac appears capable of reducing the level of leukotriene formation in vitro by an indirect means. 4 There is evidence that NSAIDs have a free radical scavenger activity that may be beneficial during inflammation. Therefore, inhibition of COI activity is clearly not the only potential mechanism of activity for this group of drugs. 1
Maintenance of Mydriasis During Cataract Surgery
Flurbiprofen 0.03% and suprofen 1% were the first NSAIDs approved by the FDA for use as intraoperative inhibitors of miosis during cataract surgery. This pharmacological activity is of clinical benefit because decreasing pupil size is a recognized risk factor for vitreous loss and zonular breaks during cataract surgery involving implantation of an intraocular lens. 1 Many clinical studies report that preoperative NSAID application provides a significant pharmacological effect to prevent excessive miosis during cataract surgery. All the commercially available topical NSAIDs appear to share this therapeutic benefit. 5–7 However, 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 suggests 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.
Although most ophthalmologists prefer using topical NSAIDs prior to performing cataract surgery, it is probably unreasonable to require the routine use of these agents for all ophthalmic practices, because adequate intraoperative mydriasis can frequently be achieved and maintained by the use of good surgical technique, a combination of preoperative parasympatholytic and sympathomimetic eye drop therapy, and a sympathomimetic in the intraocular irrigation solution used for irrigation and aspiration of cortical remnants.
Postoperative Inflammation After Cataract Surgery
Double-masked, prospective, randomized, active and placebo-controlled clinical studies provide good evidence that topical NSAIDs are potentially useful in limitating excessive postoperative inflammation after cataract surgery. 1,2 However, it is of historical interest that during the 1970s, several studies evaluated the effect of topically applied indomethacin on the inflammatory response in the early postoperative period after ocular surgeries, with inconsistent results. Once studies were designed to evaluate the effects of indomethacin given prior to and immediately after the surgical procedures, the results were more impressive. It is interesting that, at present, topically applied NSAIDs are officially approved by the FDA for only postoperative use. However, it has become the standard of care to use these agents both preoperatively and postoperatively to provide better antiinflammatory control and help to discourage undesired miosis during the surgical procedure. Well-designed studies support this preoperative dosage regimen. 6,7
Many studies of NSAID effects on postoperative inflammation include the concurrent administration of corticosteroids. There is good evidence that NSAIDs and corticosteroids have a potential for synergistic activity. 8,9 Therefore, it is difficult to conclude from these studies whether the observed effects on postoperative inflammation are related to NSAID treatment alone or to a synergistic effect resulting from the combined pharmacological activities of the NSAID and corticosteroid. It is also possible that the concurrent corticosteroid treatment may mask the tendency for any given NSAID to cause ocular irritiation.
Double-masked, randomized, active and placebo-controlled studies including patients undergoing cataract surgery have reported antiinflammatory effects from topically applied 1% indomethacin, 0.03% flurbiprofen, 0.5% ketorolac, and 0.1% diclofenac ophthalmic preparations. 1,2 These investigations report a measurable antiinflammatory effect from topical NSAID treatments as compared to placebo after intracapsular and extracapsular cataract extractions, with and without implantation of an intraocular lens. The correlation between slit-lamp observations and anterior ocular fluorophotometry appears consistent. In addition, studies using laser cell flare meter methodology provide further support for this potentially beneficial therapeutic benefit. 10–12 Studies comparing NSAIDs to corticosteroids have demonstrated no significant difference in the results of these treatments as judged by slit-lamp examinations for cells, flare, and chemosis, but NSAID treatment appears to be more effective than topical steroids in reestablishing the blood-aqueous barrier, as quantitatively measured with anterior ocular fluorophotometry. 1,2,10 A double-masked, prospective, randomized study of 120 patients after cataract surgery and implantation of an intraocular lens showed no statistical difference between the antiinflammatory effects of postoperatively administered ketorolac 0.5% and diclofenac 0.1% ophthalmic solutions, as evaluated with slit-lamp examinations and laser cell flare measurements. 12
In summary, many well-designed clinical studies provide evidence that topically applied NSAID ophthalmic preparations are potentially useful in the management of postoperative inflammation after cataract surgery. Furthermore, there is good evidence that this treatment is potentially beneficial even with the application of current surgical technology. 13 Although the various topical NSAID preparations previously mentioned are available and used throughout the world for avoiding excessive inflammation after cataract surgery, at the time of this writing diclofenac 0.1% (Voltaren) and ketorolac 0.5% (Acular) ophthalmic solutions are the only topically applied NSAIDs specifically approved by the FDA for this indication in the United States.
Prevention and Treatment of CME After Cataract Surgery
Excellent reviews have summarized potential approaches to the prevention and treatment of CME after cataract surgery. 14,15 These reviews stress the importance of placebo-controlled, double-masked, randomized trials in influencing decisions about the efficacy of potential treatments for CME after cataract surgery, because this syndrome's natural history includes spontaneous resolution. In addition, evaluating prophylactic therapy separately from the treatment of chronic CME is emphasized, as is the importance of differentiating between asymptomatic angiographic CME and clinically significant CME, which is associated with a reduction in vision.
There is no FDA-approved therapy for the prevention and treatment of CME after cataract surgery. However, a recently completed metaanalysis concludes that application of a topical NSAID for this indication is potentially beneficial. 16 This metaanalysis is in agreement with a recent review article on this subject. 17
Although NSAIDs are effective in the prophylaxis of angiographic CME, a significant and sustained effect on visual acuity has not been demonstrated. 1,2,14,15,17 In addition, 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, the possibility exists for a synergistic effect when these drugs are used together.
A large, randomized, double-masked clinical trial has compared 0.03% flurbiprofen, 1% indomethacin, and placebo for their ability to prevent CME during a 6-month period after cataract surgery, as assessed by Snellen and contrast sensitivity measurements. 18 The incidence of clinical CME as determined by contrast sensitivity scores was significantly lower for the drug-treated groups, but the effects were not sustained. In addition, this study involved concurrent use of corticosteroids. To date, there is only one randomized, double-masked study of prophylaxis of CME using NSAIDs without concurrent corticosteroids: It reports less postoperative angiographic CME in the group treated with ketorolac 0.5% as compared to the placebo group. 19
Although there are fewer studies of the treatment of chronic CME (defined as reduced vision associated with CME that has been present for at least 6 months), two double-masked, placebo-controlled, randomized studies in which corticosteroids were not used demonstrate that ketorolac 0.5% ophthalmic solution, administered as a single drop four times daily for up to 3 months, improves vision in some patients with chronic CME after cataract surgery. 20,21
These studies provide evidence that this topical NSAID treatment offers benefit to some patients for the prevention and treatment of CME after cataract surgery. In addition, it has recently been demonstrated that the concurrent administration of corticosteroids and NSAIDs may provide a synergistic activity resulting in more rapid resolution of symptomatic CME. 8 The potential application of topical NSAIDs for the treatment and prevention of CME is discussed in greater detail and compared to other potential treatments (including corticosteroids, carbonic anhydrase inhibitors, and hyperbaric oxygen) in a recent publication. 17
On the basis of evidence that ketorolac 0.5% ophthalmic solution administered as one drop four times daily is effective in reducing the ocular pruritis that often accompanies seasonal allergic conjunctivitis, 22 the FDA has approved this preparation (Acular) for use in the United States. In addition, some studies suggest that diclofenac (Voltaren) also is effective in treating seasonal allergic conjunctivitis, 23 and there are reports of potentially useful effects after suprofen (Profenal) treatment of giant papillary conjunctivitis and vernal conjunctivitis. 24,25 Topical corticosteroids are commonly 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 glaucoma, cataracts, superinfections with viruses or fungi, and impaired wound healing. Therefore, topically applied NSAIDs offer a potentially safer alternative to minimizing the signs and symptoms of allergic eye disease.
Reduction of Discomfort After Refractive Surgery
Ketorolac and diclofenac are approved for use within the United States to reduce pain and photophobia after refractive surgery. 26–28 In addition, some practitioners use topically applied NSAIDs to reduce pain after corneal abrasions. One randomized, double-masked, placebo-controlled study of 100 patients has shown that the healing time was not significantly different for patients who were patched after noninfected, non–contact lens–related, traumatic, or foreign-body removal–related corneal abrasions measuring less than 10 mm as compared to patients who received topical ketorolac 0.5% four times daily without patching. All patients also received topical antibiotics. 29
Miscellaneous Potential Uses of Topical NSAIDs
Clinical studies have suggested a potential application for topical NSAIDs for the treatment of inflamed pinguecula and pterygia, argon laser trabeculoplasty, glaucoma, strabismus, refractive errors, and the management of pain and inflammation associated with corneal abrasions. 30–35 Laboratory studies have suggested that diclofenac might have a unique effect in preventing posterior capsule opacification after cataract surgery. 36 However, a randomized, double-masked, prospective clinical comparison of diclofenac 0.1% and ketorolac 0.5% given as one drop four times daily after cataract surgery and implantation of an intraocular lens did not demonstrate a difference in these drugs abilities to prevent posterior capsule opacification, as determined 3 years postoperatively. 37
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. For example, indomethacin solution in sesame seed oil was abandoned in favor of an aqueous suspension. Suprofen is prepared with 1% caffeine, because it is less irritating. 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 discomfort after instillation of these preparations. In addition, allergies and hypersensitivity reactions have been reported with all the NSAIDs.
Corneal complications after topical NSAID use are uncommon. However, superficial punctate keratitis, corneal infiltrates, and epithelial defects have been reported after use of these agents. 38–41 This is not surprising, because most preserved eye-drops can cause minor, transient corneal changes. 42,43
The recent reports of corneal melting is surprising and of great interest. 44 Although we await a complete and careful analysis of these cases of severe toxicity, thus far any potentially severe corneal toxicity appears to be more likely associated with generic diclofenac (Falcon, Alcon). However, even in these cases, the inconsistent and variable dose-toxicity relationships do not suggest a simple drug toxicity. Furthermore, the lack of a definitive diagnosis and indication for treatment, the concurrent presence of ocular disease, and use of additional medications in many of these cases complicates the analysis. 45–48 For example, many of the reported cases occur in patients with insufficient tear production who are concurrently using corticosteroids. These are important considerations, because corneal perforations have been reported in symptomatic and asymptomatic patients with dry eyes and in patients using only corticosteroids. 49–52 Practitioners can minimize the occurrence of corneal toxicity by attempting to make a definitive diagnosis before initiating antiinflammatory treatment and by conducting careful postoperative follow-up examinations.
Systemic administration of NSAIDs can be accompanied by serious side effects, such as gastrointestinal, central nervous system, hematological, renal, liver, dermatological, and metabolic changes. However, such effects appear to be largely avoided by topical NSAID administration. The possibility of systemic absorption exists after topical application, but whether this represents a clinically significant problem is not clear. 1 Although the literature describes less toxicity associated with the topical use of NSAIDs than with topically applied corticosteroids, NSAIDs have been used far less extensively. Furthermore, there are some theoretical objections to the inhibition of only the cyclooxygenase inhibitor 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.
This work was supported by a Department of Veterans Affairs merit review grant; a That Man May See, Inc., grant; and a department core grant from the National Institutes of Health and the University of California at San Francisco Department of Ophthalmology.
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