Ocular pharmacology
NSAIDs make a comeback

Surgeons cite role in CME, reducing discomfort

Moderate cortical cataract; a number of surgeons are using NSAIDs during cataract surgery to prevent cystoid macular edema
Source: John D. Sheppard, M.D.


Clear lens and cataract cross section
Source: John D. Sheppard, M.D.


Hypermature cataract with phacolytic glaucoma
Source: John D. Sheppard, M.D.

Saddled with bad press for a number of years, nonsteroidal anti-inflammatory drugs (NSAIDs) have made a comeback in a number of U.S. ophthalmologists’ operating rooms. “NSAIDs are the most underutilized [class of] drug on the market,” said John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Medical School, Norfolk.
Their utility ranges from preventing post-op cataract surgery cystoid macular edema (CME) and reducing pain and inflammation, to preventing miosis and even treating allergic disease.
One need only look at some of the pharmaceutical companies’ earning reports to see how NSAIDs have returned to the market in full force. For instance, net revenue for the NSAID Xibrom (bromfenac ophthalmic solution 0.09%, Ista Pharmaceuticals, Irvine, Calif.) grew 108% in 2007 compared with 2008. And in fourth quarter 2007, sales of Alcon’s (Fort Worth, Texas) anti-infective and anti-inflammatory products, a group of three medications which includes the NSAID Nevanac (nepafenac ophthalmic suspension 0.1%) grew by more than 14%.
Other players in the field are Voltaren (diclofenac sodium 0.1%, Novartis, Basel, Switzerland) and Acular (ketorolac tromethamine, Allergan, Irvine, Calif.).
Surgeons estimate that 50% to 75% of their U.S colleagues now use NSAIDs routinely during surgery.
“The cynic could say it’s because of marketing of these drugs, but I also think with the growth of multifocal IOLs, accommodating IOLs, and clear lens extraction, the non-steroidals help with quality of vision and to prevent CME,” said Francis S. Mah, M.D., co-medical director, Charles T. Campbell Ophthalmic Microbiology Laboratory, University of Pittsburgh School of Medicine, Pittsburgh.
This class of medications got a bad reputation in 1999 when a number of corneal melting cases were associated with NSAID use. However, many of these cases were associated with a generic NSAID that is no longer on the market, and the patients were treated with NSAIDs for a longer than normal duration and at unusually high dosing frequencies, said Edward J. Holland, M.D., professor of ophthalmology, University of Cincinnati, Ohio.
Some surgeons also hesitate to use them because of their cost and concerns about patient compliance in following the dosing regimen.
Here’s how some ophthalmic surgeons put NSAIDs to use.

Preventing CME

Although NSAIDs are U.S. Food and Drug Administration (FDA)-approved to reduce post-op pain or inflammation, their heralded role in many surgeons’ hands is reduction of CME. “I think the number-one cause of less than perfect vision is a small amount of macular edema,” said Calvin W. Roberts, M.D., clinical professor of ophthalmology, Weill Medical College of Cornell University, New York. Previously, edema may have been marked by 20/30 or 20/40 vision post-op; nowadays, with patients’ desire for 20/20 vision at one day post-op, small amounts of CME as measured by changes in ocular coherence tomography (OCT) can be seen even in patients with 20/20 vision, Dr. Roberts said. “Their Snellen vision is OK, but the problem is contrast sensitivity. It’s measuring the quality versus the quantity of vision,” he said.
“We’re much more aggressive about diagnosing any visual loss associated with retinal thickening post-op,” Dr. Holland agreed.
In a previously published study presented at the 2006 ASCRS•ASOA Symposium & Congress in San Francisco, Dr. Roberts compared how NSAIDs could help reduce CME after cataract surgery by giving one group of patients NSAIDs pre- and post-op, while a second group received only steroids. The patients who had received NSAIDs had a mean post-op macular thickness of 4.2 microns, while the patients who had received only steroids had 10.4 microns of macular thickness. “We were able to correlate the change in thickness to contrast sensitivity,” he said.
NSAIDs have an even larger role in pre- and post-op care with the proliferation of premium IOLs and patients’ high expectations, surgeons said.
“I hope 100% of doctors who insert premium IOLs are using NSAIDs,” Dr. Sheppard said. “The NSAIDs are synergistic with steroids in preventing post-op inflammation. It’s not a standard-of-care issue, it’s quality of care. The last thing you want is a patient who’s 20/40 on week three.”
“The multifocal IOLs split light as it comes in, and it’s harder for the maculas to get a precise discrimination because they only get half as much light,” Dr. Roberts said. “That’s why non-steroids are absolutely critical for the preservation of macular function in these patients.”
It’s also important to use NSAIDs to prevent CME and not just administer them if the patient seems to be developing CME, Dr. Holland said. Using NSAIDs only once with signs of CME present could still lead to lessened quality of vision, he said. With a normal cataract patient, a typical dosing regimen is to start NSAIDs three days before surgery, Dr. Roberts said. Dosing frequency will depend on the NSAID used—this can range from two to four times a day. Dr. Roberts said his patients also begin their antibiotic three days before surgery and follow a similar dosing pattern, making compliance easier. On the day of surgery, patients will use their non-steroidal and dilating drops.
After surgery, Dr. Roberts will add steroids to help control post-op inflammation, but he will also continue the NSAID and antibiotic. Patients use all three medications for a week. At one week, they will stop the antibiotics and steroids but continue NSAIDs for about a month.

Other uses

In addition to preventing CME and miosis and reducing post-op discomfort and inflammation after cataract surgery, surgeons are finding other uses for NSAIDs.
Their use is common after refractive surgery, particularly in combination with oral steroids after PRK and other surface procedures, Dr. Sheppard said. “This combination has allowed surface procedures to have a second renaissance,” he said.
Dr. Sheppard also uses NSAIDs peri-operatively in patients undergoing the YAG laser. He will administer an NSAID along with a drop of proparacaine and a 4% lidocaine pledget any time he removes a suture, a small conjunctival cyst, or a corneal foreign body. “This markedly reduces discomfort,” he said.
Some NSAIDs, such as Acular, are also FDA-approved for allergic conjunctivitis; Dr. Sheppard finds NSAIDs particularly helpful in allergic patients with photophobia. Despite their role in allergic treatment, Dr. Roberts said NSAIDs’ role in allergy patients has been diminished as better ocular allergy medications have entered the market.
NSAIDs also play a role in the treatment of ocular surface disease, said Robert Latkany, M.D., founder and director, Dry Eye Clinic, New York Eye and Ear Infirmary, New York.
“I use them in patients with ocular rosacea, allergic conjunctivitis, and dry eye,” he said. “They don’t work 100% of the time, but there’s a subgroup of patients who benefit nicely from them. And I think they’re safer than steroids.” He finds that ocular rosacea patients with secondary dry eye benefit the most from their use, with some patients taking them for months at a time, while others just use them as needed to quiet their symptoms.
Dr. Latkany also has used NSAIDs in patients with Sjögren’s syndrome. “They’re a reasonable option,” he said.
Dr. Holland would rather shy away from NSAID use in patients with severe ocular surface problems such as Sjögren’s because of the risk of corneal melting, he said. However, Dr. Latkany has not experienced this problem.
Some other patient groups in whom to avoid NSAID use include those with neurotrophic keratitis, because of the risk of worsening the denervation effect and delayed healing, Dr. Sheppard said. Dr. Roberts also cautions against NSAID use in patients with rheumatoid arthritis.
Surgeons should also be careful to follow the dosing regimens given for each NSAID because increased dosing was a problem with the corneal melting cases, Dr. Mah said

Future directions

A study that determines the best dosing regimen for NSAIDs would add a powerful voice to the field, Dr. Holland said. “I think the NSAIDs are quite good, but we’ve arbitrarily picked how to use them,” he said. A prospective trial with patients who have diabetes and macular disease—who are at a higher risk for CME—may show that pre-treating these patients with NSAIDs for seven days may not be long enough, Dr. Holland said.
Dr. Mah also believes more surgeons would like to see head-to-head comparisons of the NSAIDs in treating CME, and whether there’s a class effect or if potency matters.

Editors’ note: Dr. Sheppard has financial interests with Alcon (Fort Worth, Texas), Allergan (Irvine, Calif.), and Bausch & Lomb (Rochester, N.Y.), among other companies. Dr. Mah has financial interests with Alcon, Allergan, and Inspire Pharmaceuticals (Durham, N.C.). Dr. Holland has financial interests with Advanced Medical Optics (Santa Ana, Calif.), Alcon (Fort Worth, Texas), Allergan (Irvine, Calif.), and Bausch & Lomb (Rochester, N.Y.), among other companies. Drs. Roberts and Latkany have no financial interests related to their comments.

Contact Information
Holland: 859-331-9000, eholland@fuse.net
Latkany: 212-689-2020, relief@dryeyedoctor.com
Mah: 412-647-2259, mahfs@upmc.edu
Roberts: 212-734-7788, robertsmd1@aol.com
Sheppard: 757-622-2200, docshep@hotmail.com