Panel explores clinical considerations of NSAID use in surface ablation patients

Ocular Surgery News convened a round table discussion to examine the growing trend toward use of nonsteroidal agents in surface ablation. Part 1 of a two-part article.

Round Table Participants Moderator Richard L. Lindstrom Daniel S. Durrie Johnny L. Gayton Terrence P. O'Brien William B. Trattler

Richard L. Lindstrom, MD: Our primary agenda is to discuss the use of nonsteroidal anti-inflammatory drugs in surface ablation — not necessarily to position one NSAID over another, but to try to talk in general terms.

Let’s start by each of us giving a bit of background about the nature of our practices, and then, if you use NSAIDs, discuss how long you use them.

At my practice, Minnesota Eye Consultants, we are still 85% or so LASIK. When we do a surface ablation procedure, however, we use an NSAID. We started years ago with Voltaren (diclofenac sodium ophthalmic solution 0.1%, Novartis) and have had an opportunity to use all of the NSAIDs, and we have good results with them. The most commonly used NSAIDs in my practice, as a whole, are Acular LS (ketorolac tromethamine ophthalmic solution 0.4%, Allergan) and Nevanac (nepafenac ophthalmic suspension 0.1%, Alcon).

Daniel S. Durrie, MD: My practice is similar, and I am still predominantly doing LASIK with IntraLase (IntraLase Corp.), but the surface ablation has certainly grown. I am doing more surface ablation over old RKs, grafts, PRKs or enhancements. It is about 20% of the cases that we are doing now. I have been a strong believer in NSAIDs from the beginning. We did some studies on it in the early days and certainly found that it was helpful in pain relief.

I have evolved through the different NSAIDs and used them all. I recently did some studies comparing the most recently introduced NSAIDs — Acular LS, Nevanac and Xibrom (bromfenac ophthalmic solution 0.09%, Ista) — and we have found that they were all successful. We hear a lot from the companies about whose product is better than the others, but all of my patients did well. I have been using Nevanac the most, but I think it is because it has worked and I do not have many reasons to change. It has been something where, once I get it in my postoperative forms and start using it, until there is a reason to scientifically change, I usually do not. I did not find much difference between the different modern NSAIDs when I used them in a prospective randomized study.

So right now I use them. The important thing is that I just use them postop like I always have. I have always given people a prescription for it to take home and use it up to four times a day for 48 hours, and it seems to work well, as they all have for me over the years.

Johnny L. Gayton, MD: My practice is 100% surface ablation. I started out using Voltaren and then had success with Acular and later Acular LS. We just recently completed a randomized, masked study comparing Acular LS with Nevanac, in which 50 patients had one eye receive Acular LS and one eye receive Nevanac. Basically, we saw no difference as far as recovery and pain control. The difference that we actually saw was in the use of the drops. The Nevanac drop was more comfortable than Acular LS, but I would say both of them worked well, and I am using primarily Nevanac now. But I am doing 100% surface ablation, so I prescribe NSAIDs.

William B. Trattler, MD: I work at the Center for Excellence in Eye Care in Miami. We are a multi-specialty ophthalmology practice, and we have seven surgeons that perform refractive surgeries. I have been performing surface ablation on the vast majority of my patients for the past 5 years. However, I am on the verge of switching back toward lamellar procedures.

I have been excited about the studies that have come out on sub- Bowman’s keratomileusis, and we are in the process of acquiring an IntraLase. I am looking forward to being able to provide that for my patients. It is down the road, and even though I am all surface right now, I expect my practice profile to change. But I have been given the chance to spend a lot of time looking at how I can make my patients comfortable with surface ablation because that is key, especially in a practice where many of the other surgeons perform primarily LASIK. I had to make sure my patients had great results and were also comfortable.

I found that as part of a pain control regimen, topical NSAIDs are a really important part. They can help reduce discomfort and help keep your patients at a comfortable level during the postop period.

In our practice, we have had a chance to participate in a number of studies looking at the various medications, and at this point, we are mostly using Acular, although we definitely have had success with Xibrom. We are not using any Nevanac.

Dosing regimens

Dr. Lindstrom: Let us talk next about dosing regimen. One thing that is interesting to me is that while Xibrom is labeled at twice a day, Nevanac at three times a day and Voltaren and Acular at four times a day, you can use any of these drops basically every 4 to 6 hours effectively; it may not be, for example, that you have to wait 12 hours between doses when using Xibrom. I tell patients they can take them up to every 4 to 6 hours up to four times a day, and I tend not to allow them to use it past 3 days. What are your thoughts on this?

Dr. Trattler: We started off using Xibrom four times a day, but we have found that twice-a-day Xibrom works as well as four times a day. So my question is whether you noticed a difference between a twice-a-day or a four-times-a-day regimen?

Dr. Lindstrom: I allow my patients to use them as frequently as every 4 to 6 hours, regardless of which drop they are using if they feel like they need it for discomfort.

Dr. Trattler: We were doing that to start off with, too. But we actually participated in a head-to-head study with a couple of other sites looking at Xibrom as compared to Acular. We were impressed that twice-a-day Xibrom was effective at reducing discomfort. We did not have an arm of Xibrom four times a day, so I cannot comment specifically.

Dr. Lindstrom: You probably did not have Acular twice a day, either.

Dr. Trattler: We did not do that either. We tried to stay on label, and patients in both groups did well, so it was interesting.

Dr. Durrie: What is interesting here, and the reason I think we are going to see a difference in our discussion on how we use these, is that this is different than when we are using an antibiotic. With an antibiotic, we are trying to get coverage because we do not want bugs to grow. That is the reason we want to have patients use it three to four times a day depending on the duration of action of the antibiotic. But we are really using NSAIDs for pain control, and pain control varies tremendously from patient to patient, as does their willingness or their desire to use medications. So what I have done is said, “Do not use this more than four times a day, and do not use it for more than 48 hours.” That has worked out very well because they have gotten good pain control, and it gives them somewhat of a limit.

With the pain medication, I am trying to give them some guidance. I think that is the difference between the medications, and we make a big deal about it when we give the medicines on what they are for. We have the medications that you need to use, and then we have these other medications, such as artificial tears and the NSAIDs, that you can use if you want to or need them, and it usually works out pretty well.

Dr. Lindstrom: You said no more than four times a day for 48 hours?

Dr. Durrie: I said for 48 hours, and that is what I have always done. I guess that it really comes from the studies that were done years ago. I am glad to hear that you are using longer safely.

Dr. Lindstrom: I am at 72 hours, so I am not much longer, but many people do not need it on the third day.

Dr. Trattler: If you look at some of those pain studies, the patient on day 2 or 3 can actually report more discomfort than they experience on postoperative day 1. If you look at some of the data from these studies, you will note that day 1 sometimes is not the worse day. Often, of all the symptoms, patients report their worst symptoms on day 2 and 3. Although they will report that they experience pain, discomfort and foreign body sensation symptoms, it is interesting to note that photosensitivity can be one of the biggest complaints.

Dr. Gayton: I am using it for 72 hours because I have had a fair number of people experience more discomfort on day 2 and 3 than day 1. One of the things that I have done is told them to use the NSAID initially; if they are using Nevanac, it should be used every 8 hours, and with Acular LS, every 4 to 6 hours. I have told my patients to use it whether they need it or not because I have the philosophy that if you control the pain initially, it keeps it from getting too bad. It has also kept patients from using more of the escape pain medications and kept them comfortable without having to get into a severe pain state. I tell them to no longer use it after the third day, but if they feel like they need it, they can get in touch with me.

Terrence P. O’Brien, MD: Some of the analogy, as you have pointed out with the anti-infective, is that it is a different situation in terms of trying to achieve a certain level that will exceed by several factors the inhibitory concentration. Here, we are talking about inhibiting an enzyme, and there is an IC-50 for these compounds that may have diminishing returns dosing beyond maybe three times a day, especially with the newer ones. But I have been just twice a day for 48 hours, and I have not run into the other problems. I have not let patients use them ad lib because I worry about the total dose of preservatives and the surface situation.

Dr. Lindstrom: Who also allows the patients to use topical anesthetics if they have significant pain? I do. Does anyone else?

Dr. Trattler: I do, too, and that is why I instruct patients to use the NSAID on a specific regimen. I tell my patients that the escape medication is not the NSAID but the topical anesthetic. That is the purpose of a specific NSAID regimen in my practice. If they have experience breakthrough pain, I give them low-dose 0.05% tetracaine. I also give them the full strength tetracaine in a sealed container that they are supposed to open only if necessary, which is fortunately not often.

Dr. Durrie: We use topical anesthetics, but we use them a little differently. In fact, I do not give them to the patient at the time of surgery because the number of drops and everything else is confusing. At the 1-day postop visit, if the patient is hypersensitive — and we give them only to those patients — we then add it in at that point as needed. We are probably giving it to one out of 10 patients. These patients really benefit from it, but I do not find that the other nine need them. The NSAIDs usually take care of it.

Dr. Lindstrom: The main question I had, because I have heard this said anecdotally, is whether you can only use one or the other. I have heard people make the statement that if you use an NSAID, you cannot use a topical anesthetic or vice versa, and that has not been my experience.

Dr. O’Brien: They are complementary.

Dr. Trattler: For that one in 10 person who is more hypersensitive, do they commonly call during the night since you are waiting for the first postoperative visit before providing a topical anesthetic?

Dr. Durrie: As you said before, they are pretty much pain-free the first day. It is the patient who gradually builds over the next couple of days, and it is usually the patient who comes in and says, “I was fine until this morning when I woke up, and now I am really starting to feel them.” You can tell because they are wearing their sunglasses when they come in, and they are starting to go downhill.

The tetracaine comfort drops come in handy because the patients then feel like I am doing something for them, and it has given me a good idea of who needs them and who does not. The patients who come back for their 1-day postop and do not need anything always amaze me; their eyes are white and quiet, they are 20/20, and they are not tearing. It gives me a better understanding of who I need to watch more carefully because they are going to be a little more sensitive to discomfort, so I do not get calls that night. I do get those third-day calls, so I am glad that I have confirmation that I can extend the NSAIDs for another day because I agree that patients’ discomfort has a tendency to build by the third day.

Reasons for caution

Dr. Lindstrom: I agree that both NSAIDs and topical anesthetics can certainly be useful in controlling pain along with the appropriate bandage contact lens.

What should the surgeon be worried about? Most of the surgeons who do not use it are afraid of the side effects and complications more than they are concerned about the patient’s pain. If we really thought we could do this safely, we would have many more surgeons using these drops. So what should they be watching out for, and what should they do to stay out of trouble?

Dr. Gayton: I was intimately involved with the generic diclofenac and the corneal melting that occurred with that, and many of surgeons are still worried about the possibility. As I have lectured on cataract surgery and the use of NSAIDs, I find that a significant number of surgeons are still not using NSAIDs simply because they are worried about the possibility of delayed healing and corneal melting. In dealing with surface ablation and use of NSAIDs in cataract surgery, as well, I try to protect the corneal surface as much as possible. If a person has any dry eye at all, I will tend to use Restasis (cyclosporine ophthalmic emulsion, Allergan). I will also use frequent artificial tears and may even proceed with punctal occlusion. I think protecting the corneal surface is important in using NSAIDs. We will then watch people postoperatively, and if they are having any healing issues, we will get them off the NSAID as quickly as possible.

Dr. Trattler: I agree 100% that the key is to protect the corneal surface. For my routine surface ablation cases, I actually pre-treat every patient with punctal plugs and Restasis because so many of my patients who come in have pre-existing dry eye. They are often contact lens wearers, and they are coming in because they are not comfortable with their contacts. I would rather be proactive than have to deal with significant postoperative dry eye. Because dry eye typically worsens after surgery, I feel being proactive helps provide some additional safety when using NSAIDs.

But the key thing is when you see patients back for their postoperative visits, if they are not healing the way you expect, the next step is to work to optimize the ocular surface. This may include reducing or eliminating drops that have preservatives. As well, you may want to instruct your patient to stop their topical NSAID. Additionally, it is important to make sure the contact lens is fitting properly and that there is no rubbing from the contact lens. The main thing that we need to watch for early on is delays in epithelial healing. I think melting issues are extremely rare during the early postoperative period after surface ablation.

Dr. Lindstrom: When should the typical 8-mm to 9-mm epithelial defect be healed?

Dr. Trattler: An 8-mm to 9-mm defect, in my practice, typically closes up between days 4 and 5, but you can still observe the epithelial healing line for another couple of days. Most patients by day 5 will have closure of their epithelial defect, although occasionally it can take an additional day or 2.

Dr. Durrie: The problem patients that I am getting referred are when somebody has let a slow epithelial healing patient go too long. I want to emphasize that the epithelial defect should be closed by the fifth day. If not, you should change something. Whether that means changing the contact lens — either by taking it out or using a different brand — stopping the NSAID, looking at patching them or doing things that would get the epithelial defect to heal.

Aside from pain, the other thing we always worry about with surface ablation is the development of haze, and fortunately, we do not see it very often. But over the years, we have all seen a patient who is taking 10 to 14 days to heal. And guess where the haze is going to be — right smack in the center of where that epithelial defect was for that extra week. Those can be quite problematic for both the patient and the doctor down the road, so for anyone who is getting into day 5 and is not totally healed, I see them daily and treat them aggressively, even to the point where I have had to patch them to get them to heal.

Dr. Lindstrom: So no one here is using an NSAID longer than 3 days, which certainly is a good guideline.

Dr. Trattler: I did not mention how long I use my NSAIDs yet. I have been using Xibrom and Acular typically for 4 to 5 days, which is just until the patients come back. They probably could stop it at day 4, as on day 4 there is a lot less pain. But typically the patients use their NSAID throughout that entire 4- to 5-day healing process, and I instruct them to stop the NSAID on the day of bandage contact lens removal.

Dr. Lindstrom: Well, you treat a bit longer than the rest of us.

When to remove the contact lens

Dr. Durrie: One question that might be good at this point is when do you see patients back to remove their contact lens? We have been playing with this, and I am asking because I would like to know what everyone else is doing. It is always tough to bring patients back in 3 days, and 25% of them are not healed enough. If you wait 4 days, some could have been in 3 days. When does everyone bring their patients back to remove the contact lens?

Dr. O’Brien: That also segues into the discussion about the different methods of epithelial removal. That may change when you would see the person because with the epithelial separators, the re-epithelialization is longer than if you remove the epithelial sheet.

You have this sheet of epithelial that is staying there, and then there is the remodeling that takes place. So you are asking for trouble if the patient comes in at day 3 and you remove the lens. Invariably, there will still be some activity of re- epithelialization that is incomplete, so I would say at day 5 on those patients.

If things are not turning around by day 5, you have to revisit all of the issues that were pointed out earlier with the preservatives, even the steroid and maybe stopping the steroid temporarily. Most of the time, it is the bandage lens that may be interfering with re-epithelialization.

Dr. Lindstrom: So you take it out or change it for a different one?

Dr. O’Brien: I would take it out, and I will usually put a different one in because you have to watch out for the tight lens syndrome that may be worsening instead of healing. It is different in terms of how you do it. If you are doing a straight PRK in a young, healthy person, maybe at day 3 you can remove the bandage lens. But I think if you are doing epithelial separation and replacing the sheet, you probably need to keep the lens in at least through day 5.

Dr. Lindstrom: Does anyone else agree with this? Certainly, getting the epithelium to heal more rapidly is a plus. I have been impressed with the epithelial separator, or epikeratome as we call it, that the epithelium heals faster, not slower, if you take the epithelium off.

Dr. O’Brien: If you leave the sheet, though, it does heal a little longer. I agree with you that if you take it off, it will heal quicker. So I wanted to be clear that if you leave the epithelium, it might take another day or 2.

Dr. Lindstrom: It is like LASEK.

Dr. O’Brien: Yes, exactly.

Dr. Lindstrom: I think the epithelial separators tend to heal faster if you take the epithelium off.

Dr. O’Brien: Yes, I would agree.

Dr. Trattler: I would agree also. If you remove the epithelium, the epithelium heals faster after epi-LASIK.

Dr. Gayton: I leave the epithelium on virtually in 100% of my cases, and I would have to agree with Dr. O’Brien. Five days is when I almost always remove the contact lens.

Dr. O’Brien: Again, I think we are probably leaving the epithelium on to try to reduce the likelihood of haze. As Dr. Durrie pointed out, if there is haze, it is right in the center in these patients.

Dr. Lindstrom: Four to 6 days works pretty well logistically, too, because if you have a center that operates every day, the Monday patient is going to be seen at 4 days on a Friday and the Tuesday patient at 6 days on a Monday. All the others can be seen whenever it is more convenient for the patient at day 4 or day 5. That is a pretty good guideline. Does anybody see them on day 2 and 3 in between if it is a routine case?

Dr. Durrie: The only thing I do differently is that I have gone to doing a 7.5-mm epithelial defect as opposed to an 8.5 mm or 9 mm that I was doing before. I found that it covers the treatment zone and the optical zone well. I get a full 24-hour earlier healing.

It is a big deal to the patients to get back to work 1 day early. That is one of the things I have been trying to do; we talk about pain and haze, but you are trying to get the patients functional quicker, and that is something I have found to be helpful. I have been talking to the epikeratome manufacturers about making a smaller ring so I could do the epithelial defect, but do it smaller and take off the epithelium. I agree that the clean edges from the epikeratomes give you quicker epithelialization than scraping it off.

Dr. Lindstrom: The Navy group, Drs. Tanzer and Schallhorn, also showed that the newer generation silicone hydrogel contact lenses seemed to generate significantly faster healing. What contact lenses is everyone using?

Dr. Trattler: I have been impressed with the Acuvue Oasys (Vistakon) as a bandage contact lens. I think it definitely helps with postoperative comfort. When I switched to that lens, it really helped improve the patients’ comfort scores.

Dr. Durrie: I happen to be using Oasys most of the time, but I have used the Focus Night and Day (Ciba Vision) of them. It has been interesting, though, on patients who had one eye done with the Bausch & Lomb Soflens 66, which I was using before, and then when I came back for the second eye, I had switched them to the new lens. They think it is great. It is much more comfortable than the older lenses, so I think that these two new lenses, the Focus Night & Day and the Acuvue Oasys, have helped us out a lot.

Delayed epithelial healing

Dr. Lindstrom: Let us say that the patient has come back to you now. It is day 5, and they still have a 3-mm to 4-mm epithelial defect. They are still having some discomfort, and it is definitely an outlier. There is no infiltrate yet, there is no sign of an infection or any other issue; it is just a non-healing epithelial defect that is significantly delayed vs. your routine expectation. Tell us what you do for that patient.

Dr. O’Brien: First, I would question the patient as to some of the things they might be doing. They could be making things worse, and sometimes you will find out that the patients will be increasing their sleeping medications to high levels, which may have some anticholinergic drying effects. Or they may be taking antihistamines because their nose is running, which is from the tearing, but they might mistake it as being from allergies. You ask them some of these things to find out what they are doing.

The other thing that we often will find is that despite the fact that we will have given them a preservative-free sample of lubricating drops, the patient will have run out of those and bought the gallon-sized preservative-containing tears at Wal-Mart or Target, and they are putting those in every 15 minutes. So you are getting a preservative effect. Sometimes just reviewing what they are doing and stopping negative activity can be helpful.

But assuming they are following the guidelines and you still have a delayed healing, the contact lens may be playing a role in many of these cases with the tight lens syndrome. Therefore, usually we would remove the lens and change the base curve to a different one. I will usually at that time make certain that they have stopped the nonsteroidal and then even temporarily suspend the topical corticosteroid therapy for several days to try to promote re-epithelialization.

Dr. Lindstrom: Let’s say you are wearing an Acuvue Oasys. Will you go to a different base curve contact lens? Will you go to a higher water content? What will you change?

Dr. O’Brien: Usually there I would then switch to the Focus Night & Day and go to a flatter base curve.

Dr. Trattler: One of the things in South Florida is that many patients like to leave their fan on at nighttime. This can cause a lot of evaporation at nighttime when the fan is situated right over their bed. So in these situations where there is a delay in epithelial healing, I treat the patient like there is a neurotrophic cornea. They have had laser ablation of their cornea. There has been damage to the corneal nerves from the laser, and the corneal nerve functions may be suppressed. I routinely put plugs in the lower ducts preoperatively, so I will add punctal plugs in the upper ducts. If I switch their contact lens, I will use a steeper lens to help reduce epithelial irritation, especially in patients with hyperopic corrections.

Dr. Lindstrom: Do you stay with the same contact but steeper?

Dr. Trattler: Yes, if it comes in a steeper contact. However, the Oasys has only one base curve, so I will have to switch to a different contact lens brand that has a steeper base curve. The last thing is just getting them to use a lot of gels and ointments, again thinking of this as a neurotrophic-like picture.

Dr. Lindstrom: Will you stop anything?

Dr. Trattler: I would definitely stop the NSAID. I would dramatically reduce the topical steroid to maybe once a day, or one can temporarily stop it. Obviously, you would want to continue the topical antibiotic because the patient is still at risk of infection.

Dr. Durrie: Let’s take the scenario that you have a 3-mm defect at 5 days. I want to look carefully, take the lens out and then look at the edges of the epithelium because in some cases, you can tell that they are still healing really well — the epithelial edges are tight, and it is still marching in. Then I will stop the NSAID, but I will just put it on a different contact lens and then I am pretty confident they are going to heal.

But if I look and they have this kind of white edge around the epithelium that looks like a chronic epithelial defect neurotrophic keratitis or epithelial defect that is not going anywhere, I will patch them, get them off most of everything and just have them use an antibiotic ointment.

I think that many times the contact lens itself is causing the problem, and those cases really worry me. I have had a couple that I have just patched, and the next day they look just great. Then you are also controlling what they are doing wrong because they are not putting anything in their eye with a patch on, and many times, as we have mentioned, some of the things that they are doing can be a problem.

Dr. Lindstrom: And they are not going to put anything more in.

Dr. Durrie: Right. They are not going to do anything else bad if they have a patch on there.

Dr. Lindstrom: I find, as a clinician, the work that I was influenced significantly by was a study I did years ago when we were trying to evaluate epithelial growth factor in non-healing epithelial defects. We had a washout, and in a washout, you had to discontinue all the medications that patient was on and put them on non-preserved tears, and 100% of our patients healed. We did not have anyone to test the drug on because if we stopped all the toxic meds, took out the contact and simply put them on frequent artificial tears, they all healed. And so I tend to go to that therapeutic nihilism, if you will, when this is happening, and I just stop everything. I even stop the antibiotic. I am certainly OK with putting in a little bacitracin or erythromycin ointment in, and I do not put a contact back in. It is amazing how well non-healing epithelial defects heal if you stop everything toxic, and the contact lens can certainly be toxic and cause hypoxia.

Dr. O’Brien: I certainly agree with all of those points. The only thing is that some of the patients will show up several hours later if there still is a significant central defect, complaining about both their vision as well as their comfort, so that is why sometimes replacing the lens can get them back to functioning. Usually by day 5, they are starting to worry about their function and lack thereof.

For more information:

• Daniel S. Durrie, MD, can be reached at Durrie Vision, 5520 College Blvd., Suite 200, Overland Park, KS 66211; 913-491-3737; fax: 913-491-9650; e-mail: ddurrie@durrievision.com. Dr. Durrie is a paid consultant for Alcon and a clinical investigator for IntraLase.
• Johnny L. Gayton, MD, can be reached at 216 Corder Road, Warner Robins, GA 31088-3604; 478-923-5872; fax: 478-929-6266; e-mail: eyesightwr@aol.com. Ocular Surgery News was unable to confirm whether Dr. Gayton has a direct financial interest in the products mentioned in this article or if he is a paid consultant for any companies mentioned.
• Richard L. Lindstrom, MD, is the Chief Medical Editor of Ocular Surgery News. He is in private practice at Minnesota Eye Consultants, 710 E. 24th St., Suite 106, Minneapolis, MN 55404-3810; 612-813-3600; fax: 612-813-3660; e-mail: rllindstrom@mneye.com. Dr. Lindstrom is a consultant for Alcon and Bausch & Lomb.
• Terrence P. O’Brien, MD, can be reached at Bascom Palmer Eye Institute, 7108 Fairway Drive, Palm Beach Gardens, FL 33418; 561-515-1544; fax: 561-515-1588; e-mail: tobrien@med.miami.edu. Dr. O’Brien is a non-salaried ad hoc consultant for Alcon, Allergan, AMO/VISX, Bausch & Lomb, Inspire, ISTA and Santen.
• William B. Trattler, MD, can be reached at 8940 N. Kendall Drive, #400, Miami, FL 33176; 305-598-2020; fax: 305-274-0426; e-mail: wtrattler@earthlink.net. Dr. Trattler is a consultant for Allergan and Inspire. He performs research for Allergan, Ista and Vistakon and receives speaking honoraria from Allergan and Inspire.