Accusations against NSAIDs Should Remain Unsaid

Claims of serious adverse effects are not borne out by the scientific literature.

BY SALIM BUTRUS, M.D., LAUREN LILYESTROM AND STEPHANIE LEUNG

When searching for new pharmaceutical agents, researchers often begin by investigating folk remedies. Willow bark, for example, was known in Hippocrates' time for its pain- and fever-reducing capabilities. With the isolation of salicin, the active component of willow bark, in the early 19th century, the nonsteroidal anti-inflammatory drug class was born. Systemic NSAIDs have since been safely and effectively used in both prescription and over-the-counter form to treat mild-to-moderate pain and inflammation.

During the last two decades, topical ophthalmic NSAIDs (e.g., bromfenac, nepafenac, and ketorolac) have been used to control post-surgical pain and inflammation, as well as intraoperative miosis during cataract surgery. As with any drug, these agents' efficacy and safety profile is linked to their mechanism of action, but the complexity of this mechanism can result in side effects, usually mild ones. Unfortunately, several more serious adverse events have been attributed to NSAID use rather than to concomitant conditions and medications, which are more likely at fault.

These adverse events, such as "melting" ulcers, are rare and typically occur in patients who have undergone previous ophthalmic surgeries, have autoimmune diseases, or are taking steroids concurrently. An in-depth look at their usage, mechanism, and adverse events reveals that when used appropriately, they are still a safe and effective treatment option for the control of mild to moderate ocular inflammation.

Anti-inflammatories Aren't Created Equal

Although NSAIDs and steroids can both be used to alleviate ocular inflammation through interactions with the arachidonic acid cascade, their precise interactions are different, and they therefore provide different therapeutic effects and can cause drastically different side effects. The pain and inflammation-reducing capabilities of NSAIDs are rooted in their ability to prevent cyclooxygenase (COX) enzymes from metabolizing arachidonic acid. Arachidonic acid is a polyunsaturated fatty acid found in the phospholipids of cell membranes. When cleaved by phospholipase A2, arachidonic acid is released from the cell membrane. Arachidonic acid can then be metabolized by lipoxygenases or COX enzymes to ultimately produce leukotrienes or prostaglandins, respectively. These end products interact with each other to increase vascular permeability and swelling, as well as to induce neutrophil chemotaxis.¹

NSAID-mediated COX inhibition includes the blocking of COX-2, an inducible enzyme that increases prostaglandin levels in response to injury^2,3 and plays a major role in ocular inflammation. NSAIDs have no direct effect on lipoxygenase, allowing that arachidonic acid pathway to continue unhindered.

This is in contrast to corticosteroids, which work at both the molecular and cellular levels to bring on anti-inflammatory effects. Primarily, these drugs block the action of phospholipase A2, thereby hindering the entire arachidonic cascade — both the lipoxygenase and the COX pathways. On the molecular level, steroids traverse plasma membranes and bind to steroid receptors on the cytoplasm to form a steroid-receptor complex. This complex then enters the nucleus, binds to chromatin, and stimulates mRNA to increase the production of proteins that regulate the antiinflammatory reaction.

Essentially, steroids work to alter genetics, including the expression of housekeeping genes, which are constitutively expressed in all cells and encode proteins that ensure the basic functioning and livelihood of the cell. The level of housekeeping gene expression can vary among different tissue types, but underexpression can lead to dysregulation of cell maintenance.⁴ One housekeeping gene dictates phospholipase A2 synthesis, so the steroid-mediated inhibition of this enzyme reduces levels of COX-1, which is responsible for prostaglandin synthesis throughout the body.^2,3 This broader mechanism of action can cause many side effects, including delayed wound healing, which are sometimes inadvertently attributed to concurrently-used NSAIDs.

Corneal Melts: The Phantom Menace?

The most common local side effects of ophthalmic NSAIDs are stinging and conjunctival hyperemia.⁵ Nevertheless, stinging is only temporary, occurs upon instillation, and lasts at most 10 minutes – not unlike other prescription products. Post-cataract surgery atonic mydriasis can also occur, but it might not be entirely due to NSAID use, as it's also associated with surgical trauma.⁶ A notable mark on the reputation of NSAIDs is the flare up of corneal ulcerations, primarily associated with generic diclofenac sodium ophthalmic solution (Falcon).

After a sudden burst of corneal melts was attributed to generic diclofenac, the product was withdrawn from the market in September 1999. Corneal melting has not been replicated in preclinical trials or controlled clinical trials of other ophthalmic NSAIDs, including brand name solutions of diclofenac. It's believed that the incidents of corneal complications associated with DSOS might have actually been due to its vehicle, solubiliser and/or preservative, and not the molecule itself.⁷ Therefore, a non-preserved agent might not exert such side effects and could be a more preferable treatment option.

A corneal ulceration, or "melt," is initiated when defects in the corneal epithelium fail to heal rapidly and properly. When the corneal epithelium breaks down, the wound spreads to the stroma and renders the cornea vulnerable to infection. This results in the accumulation of immune cells, ultimately leading to inflammation and ulceration. The intensely painful corneal destruction is progressive, and left untreated, does not end until the entire cornea has been affected and sight destroyed. Surgery to remove the ulcerative tissue is often required, along with the use of systemic or topical anti-inflammatory agents, to preserve the eye.⁸

These melts sometimes occur as complications of refractive surgery, especially if any of various autoimmune, inflammatory, or metabolic conditions is also present. These problematic conditions include rheumatoid arthritis, Wegner's Granulomatosis, Stevens-Johnson Syndrome, Lyell's Syndrome, diabetes, and even asthma.

Although topical ophthalmic NSAIDs operate locally, they can interact with systemic ailments. Pre-existing systemic diseases, ocular conditions, a history of anterior segment surgery, and concomitant corneal treatments have been reported to occur with many instances of NSAID-associated corneal trauma (Table 1). Topically applied NSAIDs can drain down the nasal-lacrimal duct; however, this only threatens the 10% to 30% of asthmatics who are NSAID or aspirin-intolerant.

Ocular manifestations of autoimmune diseases may be mistaken as drug effects in individuals taking NSAIDs while also suffering from autoimmune diseases. For example, individuals with rheumatoid arthritis experience the immune-mediated destruction of salivary and lacrimal glands and inflammation of the joints, and Sjögren's syndrome patients likewise suffer from lacrimal, salivary, and endocrine gland dysfunction, which can leave the ocular surface vulnerable to ulceration.¹⁰ Corneal complications can also occur among diabetics, as the excessive absorption of glucose interferes with neuronal functioning in the eye. In light of the possible corneal complications that can occur with pre-existing systemic disorders, clinicians need to be aware of the condition of a person's entire body — not just the eye — when treating ocular diseases. It's also important to recognize that perceived side effects may be the result of a systemic or pre-existing ocular condition, rather than the drug.

Clinical Analysis of Corneal Complications

An epidemiological study examined the frequency and severity of corneal complications in 129 patients who had used NSAIDs. A total of 140 eyes had experienced corneal complications, and 118 cases occurred no more than 60 days after ocular surgery. Thirty-nine eyes belonged to individuals with a pre-existing systemic condition, 60 to those with a history of ocular disease, and 24 to those with a history of surgery in the affected eye. Of the severe cases, 22 perforations were reported. The severity of the corneal insult significantly correlated to the presence of a systemic disease, and patients of severe cases had a significantly higher prevalence of diabetes than did patients of mild or moderate insults.¹¹ These data implicate many of corneal and surgery-related complications factors as contributors; therefore, it has not been definitively concluded that NSAIDs are an independent cause of corneal adverse events.

Several case reports further confirm that there is insufficient evidence for the isolated culpability of NSAIDs in corneal trauma cases. In a report of 11 NSAID-related corneal complications, all patients had a history of ocular surgery; 3 suffered from either dry eye or cystoid macular edema, and the remaining 8 had been concomitantly using corticosteroids.⁷ Ocular surgery and other corneal diseases compromise the corneal epithelium, increasing the risk of infection and subsequent melting to take place. With the adjunctive use of steroids to NSAID therapy, excessive suppression of prostaglandins can occur, and housekeeping genes and other growth factors become over-inhibited. This can also lead to corneal melts, thereby transforming NSAIDs from a beneficial treatment into a hazardous one. It is imperative that ophthalmologists administer NSAIDs with caution and keep pre-existing systemic diseases and concurrent corneal medications in consideration.

Finally, excessive or inappropriate NSAID dosing can be another factor that leads to corneal melts. In one report, a patient with a history of infection was treated with twice the recommended dose regimen of bromfenac. Not only was the usage of NSAID inappropriate because of the patient's past infection, but the dose regimen was also higher than what was recommended.¹² Other incidents of topical NSAID (ketorolac and diclofenac) abuse also provide support for the role of inappropriate dosing in corneal melts.^5,7

Conclusion

More than 100 million NSAID prescriptions were written in 2003, and several studies have indicated the safety and tolerability of various topical ophthalmic NSAIDs when they were used in accordance to directions.^13-16 Despite some unfavorable associations made with NSAIDs, these drugs have proven their efficacy and safety over the past quarter century, and they have been used in large doses systematically. Pre-existing conditions and factors, such as systemic diseases, high and/or excessive dosing, severe epithelial defects in the cornea, and concomitant medications — especially steroids — can decrease the efficacy and safety of NSAIDs. Ophthalmologists must take these considerations into account to ensure that any NSAID prescription is indeed necessary and appropriate. As clinicians appropriately tailor treatment to the specificities of each patient, the safe and effective use of NSAIDs will continue. OM

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