New NSAIDs Shift Treatment Paradigm

Dr. Hariprasad: Before we move on to some important new treatment options, I would like to discuss how the retinal specialists on the panel diagnose pseudophakic CME.

Dr. Benz: I like to obtain information about the cataract procedure from the referring surgeon. Was this a complex surgery? Did a small pupil cause problems? Was vitreous lost or not? The details play a role in how aggressively I might treat the patient. I also like to get a good history from the patient. How was your vision before surgery? How was your vision the first day and week afterward? How has it evolved?

I examine the eye from the front to the back with attention to the ocular surface, the IOL, whether vitreous strands are coming into the anterior chamber. Are the IOL haptics rubbing on the posterior surface of the iris? Many mechanical factors could cause subtle, chronic inflammation. In the back of the eye, I check for an attached or detached hyaloid and epiretinal membrane, which might be causing traction.

I look for concomitant diseases, such as age-related macular degeneration and diabetic retinopathy. If I am seeing the patient for the first time, I use OCT and FA.

Dr. Hariprasad: It is very important to rule out other diseases so they do not go untreated.

Dr. Warren: We really cannot overemphasize the importance of the patient history. Asking questions, particularly regarding the presence of concurrent systemic disease and when symptoms began, is crucial for leading us to the correct diagnosis. Sometimes, in particular with pseudophakic CME, the patient practically hands us the diagnosis.

EXPERIENCE WITH A NEW GENERATION OF NSAIDS

Dr. Hariprasad: Once CME is diagnosed, pseudophakic or otherwise, an NSAID may be used as treatment. What is the difference between old-generation (ibuprofen, aspirin, diclofenac, ketorolac) and new-generation (celecoxib, rofecoxib, nepafenac, bromfenac) NSAIDs?

We really cannot overemphasize the importance of the patient history. Asking questions, particularly regarding the presence of concurrent systemic disease and when symptoms began, is crucial for leading us to the correct diagnosis. — Keith A. Warren, MD

Dr. Lindstrom: What we are trying to do is prevent the synthesis of prostaglandins. The pharmacology of NSAIDs dictates that they need to be on board before the insult or injury, which is cataract surgery in our case. That does not mean they are not effective if used later, but ideally they are on board before the insult or injury.

In addition, we are trying to block the cyclooxygenase COX) side of the pathway that leads to production of prostaglandins and thromboxane and related compounds. That is why NSAIDs are particularly effective: The more specific they are, the potentially fewer side effects they cause. In my opinion, we have strong data to show the newer drugs are more effective because they are more specific. The newer options provide penetration and potency as well.

On the leukotriene side of the pathway, steroids are helpful and synergistic with NSAIDs. Early on, I was involved in several studies that explored whether or not older-generation NSAIDs could replace steroids. Those studies demonstrated that NSAIDs cannot replace steroids and that the two medications should be used synergistically. It turns out steroids also work best when given preoperatively. We also have learned that antibiotics should be given preoperatively. It would improve outcomes if ophthalmologists realized that they should pretreat with all three of these drugs.

Dr. Hariprasad: Another distinction is that COX-2 may be the inducible form of COX. We all have COX-1 constitutively expressed in the vitreous, but trauma to the eye can cause a rise in COX-2. Dr. Warren, would you say this might be a reason for some differences between the new and old NSAIDs?

Dr. Warren: Yes, that is possible. In addition to their ability to address the more COX-2-mediated prostaglandin synthesis, the penetration of the new NSAIDs makes them more effective.

Dr. Hariprasad: One of the new-generation topical NSAIDs is nepafenac, and it has a unique property. Its active molecule is really amfenac. Amfenac has poor penetration, so a drug delivery device, if you will, with excellent penetration, was created, which is nepafenac. Nepafenac is converted to amfenac in the eye. This unique "pro-drug" structure may explain the increased activity with nepafenac compared with other NSAIDs in treating macular edema.

CME DUE TO UVEITIS AND MECHANICAL TRACTION

Dr. Hariprasad: I have done some work with chronic, uveitic CME.¹ What has been your experience treating patients with uveitic CME?

Dr. Ober: I have a series of patients with uveitis and secondary recalcitrant CME. Like many uveitis patients, they also have glaucoma, which is a dilemma. I wanted to treat their CME with steroids, but did not want to worsen the glaucoma. The lowest risk alternative therapy was a topical NSAID. They didn't experience 100% improvement, but 2 of 4 patients had significant edema reduction and vision improvement after treatment with topical nepafenac alone. NSAIDs are an intermediate treatment step that has long been ignored.

Dr. Hariprasad: How do you approach a case with mechanical traction on the macula and secondary CME?

Dr. Benz: I may give a short course of treatment with a steroid or NSAID or both, but if true traction is involved, that is a surgical issue in my opinion.

Nepafenac … is really amfenac, [which] has poor penetration. So a drug delivery device, if you will, with excellent penetration, was created, which is nepafenac. Nepafenac is converted to amfenac in the eye. This unique "pro-drug" structure may explain the increased activity with nepafenac compared with other NSAIDs in treating macular edema. — Seenu M. Hariprasad, MD

Dr. Warren: In a study I performed involving patients who are steroid responders (n=15), nepafenac improved retinal thickness and vision in 3 of the 4 patients who had vitreoretinal interface disorders.² Ultimately, those patients went to surgery and had the mechanical traction relieved.

NEED FOR INTRAVITREAL INJECTIONS CAN BE REDUCED

Dr. Hariprasad: Dr. Ober and I wrote a paper that has been accepted for publication, which showed that 22 eyes with CME treated with nepafenac responded well.³ It appears the newer NSAIDs are strong enough in certain patients that we may not need a concomitant steroid. Perhaps we can obviate the need for intravitreal injections in some cases.

I propose that we are in the midst of a paradigm shift. Do you think the retinal specialist's approach to CME has changed compared with what we had been doing 3 years ago?

Dr. Ober: I definitely see a change. I have experienced treatment success with the new-generation NSAIDs, thereby preventing a need to administer injections. I say that with a caveat. In certain situations, I skip the intermediate medication step because I want resolution more quickly. The longer the edema lasts, the worse vision may be in the end, so I may inject right away. Some of the doctors who refer patients to me still use older-generation NSAIDs and I would like to see them change that.

Also, I use steroids with the NSAID. I believe in the studies that showed the combination was superior to NSAID monotherapy. However, those studies did not use the newer-generation drugs, so I am open to new approaches.

Dr. Benz: In most cases, I combine a topical steroid and an NSAID. For steroid responders, I may use an NSAID alone. For patients who have mild CME and have been on an older NSAID, I switch them to a newer-generation NSAID. I also use NSAID monotherapy in patients who have chronic CME from mechanical causes and are not good candidates for surgery. In chronic cases, feel more comfortable using an NSAID than a steroid.

Dr. Ober: I have had 2 cases of CME following vitrectomy in which the patients responded extraordinarily well to topical nepafenac alone. Both patients had a macular hole, went on to have cataract surgery and developed significant CME with retinal thickness of approximately 600 μm.

Dr. Warren: I have been using NSAIDs in almost all of my surgeries, either before, during or after the procedure, or all of the above, particularly in cases where I am peeling an epiretinal membrane. With small-incision surgery, the incidence of CME is increasing, likely because we are not doing as complete a vitrectomy and that can serve as a reservoir for inflammatory mediators. When I use an NSAID, nepafenac is my drug of choice for reducing inflammation and for patient comfort.

TAKING A PREVENTIVE APPROACH TO CYSTOID MACULAR EDEMA

Dr. Hariprasad: Dr. Warren, is there evidence in the literature that a cataract surgeon can modulate rates of pseudophakic CME with appropriate prophylaxis?

Dr. Warren: McColgin and Raizman⁴ reported that 12% of patients treated with steroids for 4 weeks before cataract surgery developed CME, while patients treated with the NSAID diclofenac for 2 days before and 4 weeks after surgery did not. Wolf and Braunstein⁵ reported that patients treated postoperatively with topical prednisolone alone had a significantly higher incidence of visually significant CME than those treated with topical prednisolone and nepafenac.

Dr. Lindstrom: NSAIDs have other benefits, too. They keep the pupil larger for a longer duration of time and many studies have shown they reduce postoperative discomfort. They also reduce photophobia.

Dr. Benz: With the trend toward small-gauge surgery, retinal specialists are also evaluating factors such as postoperative comfort. It seems we are learning some lessons from our anterior segment colleagues. RP