Insights on Anti-Inflammatories

A look at what we know about the efficacy and safety of steriods and NSAIDs.

Mark B. Abelson, MD and Anna Sleeper

SINCE THE1940s, TOPICAL STEROIDS HAVE BEEN THE standard, first-line therapy for treating ophthalmic inflammation as well as for pre- and postoperative treatments.1 More recently, the development of topical anti-inflammatory agents devoid of the detrimental effects of corticosteroid therapy has come to represent a significant advance in the development of ocular pharmacotherapy. Nonsteroidal anti-inflammatory drugs have been used in the management and prevention of ocular inflammation related to cataract surgery as well as the maintenance of mydriasis during surgery.2 Since the arrival and growing success of NSAIDs, there has been a vigorous debate over the best pre- and postoperative treatment for the everyday surgical patient.

This month, we will focus on the benefits and drawbacks of both pre- and postop treatment choices that are currently available, while also examining the most recent drugs that have been approved by the U.S. Food and Drug Administration, and those in the pipeline.

Steroidal Treatment

Steroids have been used extensively pre- and post-surgery as a result of their broad effects. They are generally considered stronger than other options, and superior at dealing with the inflammation associated with cataract surgery because they inhibit phospholipase A2 and subsequently inhibit both the cyclo-oxygenase and lipoxgenase pathways.3 In addition, steroids can enter the nucleus to interact with specific DNA sequences, altering production of inhibitory proteins, and thus inhibiting additional inflammatory mediator production. This mechanism contributes to steroids' broad activity: Corticosteroids suppress the inflammatory response to a variety of inciting agents of a mechanical, chemical or immunological nature. They exert additional anti-inflammatory actions, including a reduction in migration of macrophages and neutrophils, decreasing vascular permeability and suppressing the action of various lymphokines.4 They inhibit edema, cellular infiltration, capillary dilatation, fibroblastic proliferation and deposition of collagen.

As with any treatment, ophthalmic steroids come with their own set of risks, some of them very serious. These side effects typically require clinicians to reserve steroids for short-term use, which helps minimize risk while still reaping significant benefits.  Some of the more serious side effects noted with prolonged topical steroid use include ocular hypertension and glaucoma.5 Steroid-induced elevated intraocular pressure rarely occurs within the first two weeks of treatment, and after this, IOP increase can occur anytime from weeks to years.6 Some patients, however, are "steroid responders," so they will experience increased postoperative IOP as a result of their medications. Withdrawal of the steroid usually results in IOP returning to baseline within two to four weeks.7 In the case of an elevated IOP, conventional glaucoma medications can also be prescribed to manage this. Certain more recent-generation corticosteroids, the "soft steroids," include  loteprednol etabonate 0.2% (Alrex, Bausch & Lomb) and 0.5% (Lotemax, Bausch & Lomb). Though some suggest these agents may have a slightly lesser efficacy than dexamethasone or prednisolone acetate, they certainly do not exert as great an effect on IOP.

Cataract development is a rare possible side effect of topical corticosteroid use.

Other steroid side effects may include: mydriasis; ptosis; inhibition of corneal epithelial or stromal healing; formation of cataracts; punctate staining; corneal-scleral melting; damage to the optic nerve; and defects in visual acuity and visual fields.5

These serious side effects are rare, and most often the healing ability of these steroids outweighs the possible negative reactions.

Steroids offer the most potent efficacy in treating inflammation, and the stronger the steroid, the greater this efficacy. However, there is evidence that NSAIDs offer significant levels of efficacy in this scenario, as well.

The most commonly used anti-inflammatory topical steroidal agents are the prednisolones, specifically prednisolone acetate and prednisolone sodium phosphate (1% or 0.125%).8 Cystoid macular edema, in particular, is best treated by frequent, high-dose administration of a topical steroid, for example, prednisolone acetate eight times per day. Topical dexamethasone preparations are also potent agents, TobraDex (Alcon) being the current gold standard. This medication provides additional benefits as it also contains the aminoglycoside antibiotic tobramycin.

Fluorometholones are considered superior for their avoidance of increased IOPs and most side effects, but are effective primarily for mild surface inflammation, making them a more frequent choice for long-term care. As mentioned earlier, the soft steroids such as Lotemax have been developed to lower toxicity as well as increase more specific actions at a target organ.9 The recently approved Zylet (loteprednol etabonate 0.5%, tobaramycin 0.3%, Bausch & Lomb) incorporates a soft steroid with an antibiotic. Choosing a soft steroid in this combination medication confers a lower likelihood of this drug to increase IOP postop.1

NSAID Treatment

NSAID treatment is a more recent development in ophthalmic pre- and postop regimens, and is a gradual shift away from the potentially serious adverse effects of steroids.

NSAIDs are useful in controlling pain and inflammation without reducing the immune system. These drugs block only cyclo-oxygenase pathways and act non-selectively against both the COX-1 and COX-2 enzymes.10 The action of NSAIDs therefore inhibits the formation of prostaglandins and the subsequent products in this metabolic pathway.11,10

NSAIDs are most commonly used in the management and prevention of inflammation, mydriasis and cystoid macular edema related to cataract surgery and reduction of discomfort after refractive surgery,12,13 particularly in at-risk patients, such as those with diabetes. If the inflammation isn't adequately treated postoperatively in these patients, loss of vision due to increased IOP or capsule opacification may occur.11,14,15 NSAIDs have been so successful that they've limited cases of poor visual outcomes to a greater degree than any other treatment after cataract extraction.16

Topical ocular NSAIDs result in excellent absorption and penetration of the drug, but still present adverse effects. Pre-clinical trials using a rabbit model have shown that 74 percent of the administered topical dose reaches the systemic circulation by nasolacrimal drainage,17 leaving open the possibility that systemic toxicity may be possible with topical ophthalmic administration of NSAIDs, particularly if dosed long-term.

For example, research has shown that systemic absorption of topical ophthalmic NSAIDs exacerbates bronchial asthma, most likely as a result of their potency as COX-inhibitors.18 Although extremely rare, other potential systemic effects related to topical ophthalmic NSAID therapy include inhibition of platelet function, renal disease, and gastrointestinal irritation and ulceration.4 While these effects have the possibility of occurring, increased risk is found most often in geriatric patients, users of tobacco, alcohol, antacid or proton-pump inhibitors; and those with a history of systemic corticosteroid or anticoagulant therapy.19

While systemic effects should be considered, NSAIDs may also produce some local adverse events, the most common being stinging and conjunctival hyperemia.10 As a result of pre-cataract surgery treatment to prevent intraoperative miosis, topical NSAIDs are also known to cause post-cataract atonic mydriasis in 0.2% of patients.20,21 Other effects that can result from topical NSAID use are contact dermatitis, and, less commonly, corneal complications. Most of the reported cases of corneal complications occur in patients whose tear production is insufficient and who are concurrently using corticosteroids.22 There also was a time when excessive use of NSAIDs and steroids was associated with corneal melts in immune compromised individuals with autoimmune disease, though this was rare.

It has now become a more popular standard of care to use NSAIDs both preoperatively and postoperatively to provide better anti-inflammatory control and help to discourage undesired miosis during the procedures. Water-soluble NSAIDs including Flurbiprofen 0.03% (Ocufen, Allergan) and Suprofen 1% (Profenal, Alcon) were the first treatments approved by the FDA for intraoperative use to inhibit excessive miosis during cataract surgery. Ketorolac tromethamine 0.5% (Acular, Allergan) shortly followed these other medications. Acular PF is also the only topically effective NSAID that is available in a preservative-free formulation.8

Diclofenac (Voltaren Ophthalmic, Novartis) is another NSAID indicated for treatment of inflammation after cataract surgery. The diclofenac indication also includes the temporary relief of photophobia and pain in refractive-surgery patients.

Several NSAIDs have been recently approved or are in development. Of particular interest is the recent approval of bromfenac ophthalmic solution 0.09% (Xibrom, ISTA Pharmaceuticals) for treating ocular inflammation after cataract surgery. This solution is the first b.i.d. ophthalmic NSAID to be approved in the United States. Clinical study results presented at the most recent meeting of the Association for Research in Vision and Ophthalmology showed that ocular pain resolved significantly more quickly with bromfenac than placebo (mean: 1.9 days compared to 5.9 days with placebo), and the agent effectively reduced post-cataract surgery inflammation as early as three days post-surgery (Donnenfeld E. ARVO Abstract #791, 2005).

Allergan has followed up their Acular series with a new formation, ketorolac tromethamine 0.4% (Acular LS). This lower-dose drug is more comfortable than the original Acular and is indicated for the reduction of eye pain and burning/stinging specifically after corneal refractive surgery.

Another upcoming NSAID is nepafenac (Nevanac 0.1%, Alcon). This treatment, pending approval, will be the first pro-drug topical NSAID. Studies have shown that it inhibits retinal inflammation and exhibits superior corneal penetration compared to other NSAIDs.23,24

Farther back in the pipeline is the agent rEV131 from Evolutec. rEV131 is the recombinant form of a native protein secreted in the saliva of the Rhipicephalus appendiculatus tick. In preclinical models of inflammation it has shown comparable anti-inflammatory activity to corticosteroids and will be entering phase-II trials in ocular indications later this year.25

Joining Forces

In addition to all the recent approvals and upcoming agents, efforts to combine steroids and NSAIDs are also in progress. Multiple studies have shown comparable results between steroids and NSAIDs in reducing inflammation and increasing healing. For example, Ketorolac has shown similar effectiveness as loteprednol etabonate 0.5% suspension in the reduction of inflammation after routine phaco.26 A recent study of NSAID effects on postop inflammation includes the concurrent administration of steroids, and some evidence suggests that NSAIDs and steroids have the potential for synergistic activity.27 Some researchers also think that this activity with concurrent dosing may aid in more rapid resolution of symptomatic CME.

One study in particular supported combination therapy, finding that it improved Snellen visual acuity by an average of 3.8 lines for 28 patients.28 These initial combinations have revealed interesting results, although more studies must be performed to determine whether the effects are related to NSAID treatment alone or to a synergistic effect resulting from the combined agents' activities.

Use of ophthalmic steroids, NSAIDs and antibiotics with surgery is clearly the standard of care. However, it's extremely difficult to calculate the exact degree of their benefit, since they're used to prevent adverse events before they start, but the question remains an important one. There's also a question as to exactly which postop regimen(s) yields the best chance for a complication-free post-surgery recovery. Though these answers remain to be found, it's clear that with the many and varied options available now and in the near future, our ability to ensure the safest and most favorable outcomes from cataract surgery is certainly growing. 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Sleeper is a research associate at ophthalmic research associates in North Andover.

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