Steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) have been our main weapons against inflammationbut the battleground is changing. Specifically, there are new drugs, new ways of delivering them and new treatment paradigms.
This article introduces new developments within these classes of pharmaceuticals and reviews the similarities and differences between them.
Inflammation Basics
While NSAIDs and steroids both fight inflammation, there are many differences in their efficacy, mechanisms of action and side effects.
The bodys mediators of inflammation follow a common chemical cascade, which we now partially understand. The acute phase of inflammation begins with the degradation of cells that release chemical mediators into the surrounding area. Phospholipids, one of the main substances released, are quickly converted by the enzyme phospholipase A2 to arachidonic acid.
Next, arachidonic acid may enter two different arms of the inflammatory cascade. By following one pathway, it may be converted to prostaglandins by the enzyme cyclo-oxygenase.1 Prostaglandins mediate the pain response, increase vasopermeability (which leads to redness and swelling), cause miosis and increase uveoscleral outflow.2
Arachidonic acid may also follow another pathway and be converted to leukotrienes by the enzyme lipoxygenase. Leukotrienes are responsible for recruiting white blood cells (leukocytes) to the area of inflammation, where they attempt to eliminate the offending stimulus. While these white blood cells perform a needed function, they can damage the healthy surrounding tissue.
The Differences
NSAIDs stop the action of cyclo-oxygenase, thus preventing prostaglandin synthesis. However, topical ophthalmic NSAIDs do not block the lipoxygenase arm of the chemical cascade.
Steroids inhibit phospholipase A2 to block both arms of the inflammatory cascade. Steroids decrease vasopermeability, redness, edema and pain. An added advantage: They keep leukocytes sequestered from the site of inflammation by blocking the lipoxygenase arm. Although NSAIDs are effective mediators of pain and edema, they are unable to sequester white blood cells as steroids do.
Steroids have been used to treat all types of ocular inflammation. NSAIDs are formally approved for inhibiting intraoperative miosis, managing postoperative inflammation, treating ocular allergic conditions, and controlling pain after cataract and refractive surgery.3
Off-label uses of NSAIDs include prevention and treatment of cystoid macular edema (CME) and temporary management of ocular pain (due to abrasion, erosion, foreign body, etc.).4 They have effectively replaced the pressure patch and cycloplegia to control pain associated with corneal abrasions.5
Whats New with NSAIDs
Approximately 5 million prescriptions for topical NSAIDs are written annually in the United States, and that amount is expected to increase.6 Topical NSAIDs allow us to treat many symptoms of inflammation without the risks of increased intraocular pressure or cataract formation associated with steroids. NSAIDs have become the standard of care for treating pain from corneal injury and CME (in conjunction with steroids). However, NSAIDs have not been shown to be clearly effective in treating uveitis, and they play no role in preventing or treating corneal graft rejection.
Acular (ketorolac tromethamine 0.5%, Allergan) and Voltaren (diclofenac sodium 0.1%, Novartis) have been the standard bearers for NSAIDs in primary eye care.7 Voltaren is approved for management of postoperative inflammation, pain and photophobia following cataract or refractive surgery.4 Aculars approved indications are similar but also include treatment of allergic conjunctivitis symptoms.8 Both drugs should be used four times a day. Studies have shown subtle differences between these agents, but largely, they are considered clinical equivalents.7,9
Recent developments in NSAIDs include:
Acular PF. The active drug remains the same as Acular, but Acular PF is a unit dose preservative-free formulation of ketorolac 0.5%. It is intended mainly for treatment of pain associated with refractive surgery.10
Acular LS. In 2003, Allergan introduced Acular LS, which has a lower concentration of ketorolac (0.4%) vs. standard Acular (0.5%). This significantly lowers the stinging sensation (a reported side effect of many topical NSAIDs) without a decrease in efficacy. The stinging sensation of NSAIDs is reportedly worse with pre-existing allergies, so the use of Acular LS for these patients should improve comfort and compliance. The reduced strength remains effective at preventing CME secondary to cataract surgery.11 Acular LS retains the q.i.d. dosing schedule.
Xibrom. Xibrom (bromfenac 0.09%, ISTA Pharmaceuticals) is a potent new NSAID that received FDA approval in March 2005. It is the only topical ophthalmic NSAID that has b.i.d. dosing.12 The systemic form of bromfenac was implicated as a cause of liver failure and has been removed from the
Xibrom is FDA approved for treating ocular inflammation after cataract surgery. Besides its advantage of decreased dosing, it may provide earlier reduction of inflammatory cells in the anterior chamber compared with other NSAIDs.15 Clinical trials showed only a 1.4% incidence of burning and stinging. Side effects in clinical trials (reported in 2% to 7% of patients) included abnormal sensation in the eye, conjunctival hyperemia, burning, stinging, pruritis, headache and iritis. As with other topical NSAIDs, bromfenac has been reported as a rare cause of corneal melting.16
Nevanac. Nevanac (nepafenac 0.1%, Alcon) is the first pro-drug approved in the NSAID class.17 Upon instillation, the enzyme hydrolase, which exists in the eye, converts nepafenac to amfenac, a potent cyclo-oxygenase inhibitor. Bioactivation occurs mostly in the iris/ciliary body and retina/choroid, making this drug a potential treatment for posterior segment disease. Also, because nepafenac is a pro-drug, it may reduce the risk of surface complications because the active drug does not accumulate in the cornea and on the ocular surface.
Nevanac is currently approved for the treatment of inflammation and pain associated with cataract surgery. The recommended regimen is one drop three times a day starting one day before surgery and continuing the day of surgery and 14 days thereafter.18
Given its ability to penetrate deep into the eye and quickly attain therapeutic levels, look for Nevanac to play a larger role in treating retinal disease and as a therapeutic regimen for retinal procedures.17
Nevanac appears to be well tolerated with less burning and stinging than previous NSAIDs. In cataract surgery trials, Nevanacs most frequently reported adverse events (5% to 10%) following surgery were capsular opacity, decreased visual acuity, foreign-body sensation, increased intraocular pressure and sticky sensation. But, these events may stem from the procedure itself.
New Treatment With NSAIDs
For patients undergoing cataract surgery, NSAIDs used to be reserved only for cases of postoperative cystoid macular edema. CME is the leading cause of decreased vision after uncomplicated cataract surgery and can occur in as many as 12% of patients.6
Newer research has shown that routine use of an NSAID postoperatively can reduce the onset of CME. Initiation of the NSAID before cataract surgery is also beneficial, as it allows the drug to reach therapeutic levels prior to the surgery. The peer-reviewed literature suggests that in uncomplicated cases, NSAID therapy should start at least one day preoperatively and continue for at least three to four weeks postoperatively.19
With patients rising expectations of outcomes for modern cataract surgery, preventing the most common cause of decreased vision becomes critical. It is even more paramount with refractive IOLs because even a slight degradation in acuity makes for a less-than-optimal outcome.
NSAID Precautions
NSAIDs have been used for years with rare side effects. But when side effects do occur, they can be quite serious.
In 1999, NSAIDs were first reported to cause corneal melting.20 Investigations showed that many cases were related to the generic form of diclofenac manufactured by Falcon Pharmaceuticals, which voluntarily removed the drug from the market.
Subsequent investigations tried to elucidate who might be at risk of corneal melt from a topical NSAID. Patients with confirmed cases had received a significantly higher dose of NSAID than recommended. They also were more likely to have a pre-existing ocular comorbidity and to use the NSAID for a non-surgical vs. surgical therapeutic regimen.21 One theory: Ocular disease or trauma may allow more penetration of the NSAID into the cornea, resulting in higher concentrations within tissues and greater risk of complication.
Systemic disease has also been studied as a predisposition to corneal melting. Perhaps NSAIDs act as a trigger in an eye already predisposed to melting. Rheumatoid arthritis and diabetes mellitus are most often implicated, but studies have been conflicting about their association with corneal melting.19,21
The exact chemical etiology of the melt remains questionable as well. NSAIDs may suppress keratocyte proliferation, a necessary component in corneal remodeling.21
Another hypothesis: NSAIDs selective blockade of the cyclo-oxygenase pathway may allow all unused arachidonic acid to enter the lipoxygenase pathway, resulting in a large concentration of leukotrienes that subsequently recruit neutrophils. Neutrophils release collagenase and other enzymes that may potentiate corneal melting.21
Less serious side effects of topical NSAIDs include temporary decreased corneal sensation, superficial punctate keratitis and subepithelial infiltrates.19
Topical NSAIDs allow us to treat some characteristics of inflammation without the complications of steroids. They may also work synergistically with steroids, providing a better treatment than either drug alone. Much remains to be understood with NSAIDs, but expect their use in eye care to continue to increase.
Steroids
Nothing beats a steroid when we need to quell all aspects of inflammation. While no new steroids have been recently released, the hot topic in this class is new drug delivery systems. These new systems release a steady supply of medication over an extended period of time.
There are two approaches to the new drug delivery systems: a reservoir-style implant that releases a steady supply of drug over a long period of time and a biodegradable implant that releases a drug over a much shorter time frame. Both have their inherent advantages and disadvantages.22
Reservoir implants can last well more than two years, providing a fixed concentration of the drug. These implants may be more difficult to insert initially, but they require less replacement. Because the steroid is used over a longer time, however, patients are more prone to side effects.
The biodegradable implant provides a more pulsed drug delivery. The drug is typically delivered for one to three months before the implant dissolves. Many of these newer systems can be injected into the eye without surgery. Also, the shorter time frame of treatment should mean fewer side effects from the steroids.
Current and forthcoming implants include:
Retisert (fluocinolone acetonide, Bausch & Lomb). This is the first steroidal intravitreal implant approved for use in the United States.23 Retisert is an offspring of Vitrasert, the ganciclovir implant originally designed to treat cytomegalovirus retinitis.
Retisert consists of a tiny reservoir (0.59mg) designed to deliver sustained levels of fluocinolone acetonide over 30 months. The 2.5mm-by-1.5mm implant consists of a tablet of drug encased in a silicone cup with a polyvinyl alcohol membrane at the orifice. The reservoir is attached to a strut that can be sutured in the posterior segment.
Retisert was initially approved in 2005 for use in chronic noninfectious uveitis. In clinical trials, Retisert decreased the recurrence rate of uveitis from 40-54% to 7-14%, decreased the need for adjunctive systemic therapy from 47-63% to 5-10% and decreased the need for periocular steroid injections from 50-65% to 3-6%.24 It increased visual acuity by three or more lines in 19-21% of patients.24
On the downside, side effects often occurred. Within an average post-implantation period of two years, nearly all phakic eyes are expected to develop cataracts. Approximately 60% of patients will require medications to control intraocular pressure, and some 32% of these patients will likely require filtering procedures.25
Although frequent, these complications can be successfully managed and can be less deleterious than the alternative: uncontrolled inflammation. Look for new uses of Retisert in treating diabetic macular edema and wet age-related macular degeneration.
Medidur (fluocinolone acetonide, Alimera Sciences and pSivida Ltd.) This implant contains the same drug as Retisert but delivers it differently. Medidur is a non-erodable, narrow, 3mm cylinder that is implanted in the vitreous with a 25-gauge injector. Two versions are available: one that lasts 18 months and another that lasts three years. When depleted, the implant can be left in the vitreous base unless it causes a problem.22
Medidur is currently in Phase III clinical trials as a treatment for diabetic macular edema. In the future, it could be used to deliver different agents, such as vascular endothelial growth factor (VEGF) inhibitors for treating AMD, thus eliminating the need for the frequent intravitreal injections currently required.22
Posurdex (dexamethasone, Allergan.) Dexamethasone is about seven times more potent than fluocinolone, but for a much shorter time frame. With Posurdex, a biodegradable polymer is impregnated with an extruded form of the drug and delivered to the vitreous by a 23-gauge pen-like injector.23 Dexamethasone is constantly released for 37 days. The polymer of the implant breaks down to water and carbon dioxide, so removal is not required.
Posurdex is currently undergoing Phase III trials for treating macular edema persisting longer than 90 days. In Phase II trials, 36% of patients who received the 700g implant had at least a two-line improvement in best-corrected acuity compared to 19% of observation patients.22
With its shorter duration, Posurdex is expected to have fewer side effects. In the Phase II trials, only 17% of patients experienced an increase in IOP.
NSAIDs and steroids continue to evolve. Newer drugs and newer delivery systems are making this class of pharmaceuticals more effective and safer than before. Although these drugs and their newer delivery systems will be initially approved to fight inflammation, look for these advances to be adapted to innovative treatment for diabetic retinopathy, macular degeneration, and many other conditions.
Dr. Cakanac is in private practice in
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