Pain with Intraocular Injections and Is One Injection Enough?

I recently received a question that I’ll paraphrase for brevity.

My 97-year old father recently developed wet AMD. He received an injection of Avastin® from a retinal doctor. The injection was very painful. He returned in two months, was told by the doctor that the leakage had stopped, and that therefore he didn’t need another injection. He didn’t have an OCT done though. I was wondering whether he should have another injection and what could be done about the pain?

An injection into the eye is painful for at least a few second unless an anesthetic is used. Some retina experts use Lidocaine® gel which is a topical anesthetic. The gel is placed under the lids and left in place for five or ten minutes. I’ve found that the gel works well in two out of three patients. The other patients feel a little or a lot of pain.

For this reason, I still inject an anesthetic under the conjunctiva before giving the intraocular injection. The disadvantage of the first injection is that it often causes a little bleeding under the conjunctiva. The blood makes the eye look fire engine red for a week. The blood goes away however and doesn’t cause harm. After the injection of anesthetic, I try to wait five minutes before doing the intraocular injection. Very few patients feel anything after a subconjunctival injection of anesthetic. That’s what should be used in your father.

I usually see a patient back six weeks after an injection of Avastin®. I think all patients should have an OCT to make sure there is no residual fluid because it can be missed on the examination. The goal of treatment is to get rid of all of the fluid. Often the best acuity is gained only after multiple injections. The exception to this rule may be if the eye already has a lot of scarring and the doctor doesn’t think additional injections are going to help.

So, I would take your father to another doctor and get an OCT. If it shows no fluid, then the first doctor was right and I apologize for doubting him. If it shows residual fluid, I would give your father another injection of Avastin® or maybe Lucentis®. He should be given a subconjunctival injection of anesthetic first and the doctor should wait five minutes before giving the intraocular injection. I predict your father will be very pleased.

related posting: Pain after Avastin injection (May 26, 2006)

related posting: Pain with Intraocular Injection (February 26, 2007)

More from the AAO 2006 Annual Meeting

Peter Kaiser presented an update on new treatments for wet AMD that have not yet been approved. I thought the most promising new therapy was the VEGF Trap. The VEGF trap is a small protein that tightly binds VEGF. It prevents VEGF from binding to receptors on other cells such as vascular endothelial cells. In addition the VEGF trap is small and can penetrate the retina. A preliminary study showed that six weeks after an intravitreal injection of the VEGF trap, patients had average gain of almost 5 letters. The advantage of the VEGF trap is that it lasts longer in the eye and may have to be injected only every three months.

Squalamine was isolated from shark cartilage and also has an anti-VEGF effect. It’s given intravenously once a week. The advantages of this drug would be that it would eliminate the need for injection into the eye and, since it is given IV, it could work on both eyes. The initial results showed that 39/40 patients had improved or stable vision and ten patients had three or more lines of improvement. The drug was well tolerated. The FDA has granted fast-track status to this drug. Another trial is underway.

John Thompson discussed a RNA interference drug called bevasiranib. This drug interferes with the production of VEGF. A small study showed that patients who had intraocular injections of this drug continued to have visual loss over the next three months. This loss was thought to be due to VEGF that was already present in the retina. Bevasiranib may be able however, to prevent the production of new VEGF for a long period of time. Therefore a patient could be injected with Avastin or Lucentis to block the VEGF that is already present along with bevasiranib to prevent the future production of VEGF. The combination may result in long-term control of the neovascularization without the need for multiple injections.

Dr. Ronald Danis presented the results of the Rheophoresis Study for Age-Related Macular Degeneration. Rheophoresis involves the pumping of a patient’s blood through a set of filters and is analogous to hemodialysis for patients with kidney failure. The rheophoresis removes high-density macromolecules and possibly inflammatory mediators from the blood. The problem is that these molecules come back to their normal levels a few days after the procedure and we don’t even know if they play a major role in AMD. The study contained 183 patients who were randomized to sham treatment or rheophoresis. They found no difference in the visual acuity between these groups of patients. They then “removed” patients who had cataract surgery during the study, advanced AMD, or who didn’t meet the original study guideline. When they analyzed the remaining 121 patients, there was a modest gain of almost one line of vision in the treated group. It’s dangerous to start analyzing subgroups in any study and then make conclusions. Overall I was not impressed with the results.

More Treatments for Wet AMD from the AAO Meeting

Retinal experts are trying various combinations of VEGF inhibitors, (Macugen®, Avastin®, Lucentis®), Visudyne®, and intraocular steroids. The goal of these combination treatments is to either obtain better visual results than Lucentis or obtain the same visual results with fewer intraocular injections.

Augustin and Offerman, reported at the AAO meeting, the results of their treatment of 186 patients with triple therapy. The patients first had Visudyne, (PDT). The next day, the doctors performed a small vitrectomy followed by intraocular injections of 800µg of dexamethasone, (a steroid), and 1.5mg of Avastin. They reported the results on 104 of the patients. Presumably the other 82 patients were eliminated from the analysis because of short follow-up but whenever patients are eliminated from a study, it casts doubt upon the results. The 104 patients were followed for a mean of 40 weeks after treatment. The average visual gain was nine letters which is the same or a little better than seen with Lucentis. Only 18 patients needed another single injection of Avastin and only 5 needed another round of PDT, Avastin, and dexamethasone to control the neovascularization. This means that 81 of the 102 patients were stable after the first combination treatment. This would be an advantage over monthly injections over a long period of time.

Other retinal experts are going to try this triple treatment. The vitrectomy part however, is probably not necessary. It’s too early to determine however, whether patients with wet AMD should ask for this triple treatment rather than intraocular Avastin or Lucentis.

The consensus at the meeting is that Visudyne (PDT) should be given first followed by the VEGF inhibitor and/or a steroid. The VEGF inhibitor and steroid can be given right after the PDT or a day later. If the VEGF inhibitor is given before the PDT, the results don’t seem to be as good. That may mean, that the VEGF inhibitor is all used up by the time the PDT is given. Therefore, when the PDT causes the production of more VEGF, there is nothing to block its effect. Or it may mean that the VEGF inhibitor causes the vessels in the neovascularization to close off which reduces the accumulation of dye in the vessels and thus the effect of the subsequent PDT.

A few months ago, I wrote that two patients who received full-dose PDT develop choroidal capillary loss and vision loss. Both of these patients have recovered their pre-op VA, (20/80, 20/100) but one had a recurrence of the neo in the very center of the atrophy. As I mentioned, many clinicians are using half-dose PDT in combination treatments. There may be less of a risk from full-dose however, when it’s done before the injection of the VEGF inhibitor.

Typically for PDT, 1000µ is added to the greatest linear diameter of the CNV to determine the size of the laser spot. Therefore a lot of normal choroid surrounding the CNV is treated with the laser. Recently with combination treatments, I have been adding only 500µ to the greatest linear diameter provided that I can easily see the margins of the CNV. This results in less area that is treated and presumably less inflammation and VEGF production. Reducing the margin for error could be risky however since most of the recurrences after PDT are edge recurrences. We don’t know however, if these edge recurrences are from areas of the CNV that were not fully covered by the laser. I would argue that the recurrences are due to damaged surrounding choroid and VEGF production. Treatment with anti-VEGF therapy after the PDT may also allow for a reduced spot size. We will see.

I tried to play the slots with my quarter but the slots now only take bills or prepaid cards. I left the casino in a huff.

Live from The Meeting of the American Academy of Ophthalmology, Las Vegas

I’ll write about the new information that was presented and discussed at the AAO meeting in this and the next blog(s).

The updated and excellent results from the various Lucentis® trials were presented again. Interestingly, retinal experts are still using Avastin® more often than Lucentis to treat patients with wet AMD. Their reasons are: that Avastin works well; Avastin has to be given only every six weeks instead of every four; and that Avastin is much less expensive. Some retinal experts believe however, that Lucentis too works just as well if given only every six week instead of every four. I’ve now treated many patients with either Avastin or Lucentis, or both. My “impression” is that Lucentis is probably a little better than Avastin. I think it gets rid of the swelling beneath and in the retina more often. I don’t know if there is a downside however, in trying Avastin once or twice and then only switching to Lucentis if needed.

No one really knows if Lucentis is better than Avastin or vice versa. The National Institutes of Health is sponsoring a study to compare the two drugs head to head. The study hopefully will start this coming spring. The tentative plan is for the study to contain twelve hundred patients total. Each patient will be randomized to one of four groups:

1. Lucentis- 0.5 mg every month for two years.
2. Avastin- 1.25 mg every month for two years.
3. Lucentis- 0.5 mg as needed for two years.
4. Avastin- as needed for two years.

“As needed” generally means an injection will be given whenever the patient has fluid in or under the retina, vision loss, new hemorrhage, or leakage on a fluorescein angiogram. I have also left out the dosage in the Avastin “as needed” group. In the US, most retinal doctors use 1.25mg of Avastin whereas in Europe, they tend to use 2.5 mg and say they have good results. Therefore the Avastin dose in this group is still being discussed.

I’m off to play the slots. I’m limiting myself to a quarter. If I lose that, I’ll quit. I’ll write again in a day or two.

Good Vessels- Bad Vessels

Two readers have written that they’re confused about the various bad and good vessels in AMD. I mentioned that Avastin® and Lucentis® stops the “bad vessels” from growing and leaking beneath the retina but doesn’t kill or get rid of them. That means that either of these drugs often has to be given repeatedly because the vessels can leak or even grow after the drug wears off.

I also mentioned that one possible solution would be combine treatment with either of these drugs with a low dose Visudyne or PDT treatment. Visudyne can get rid of abnormal vessels in AMD. The problem with Visudyne is that it can also damage normal capillaries in the choroid which can cause vision loss and increases the stimulus, (VEGF), for the abnormal vessels to return. It makes sense to use lower light doses to limit the damage. The Avastin or Lucentis is used to block any VEGF that is caused by the PDT. In this way, we hope that the vessels can be eradicated permanently without the need for repeated injections.

So we have the “bad vessels” in AMD. These vessels are called choroidal neovascularization because the start growing from the choroid. These vessels grow in places where they shouldn’t be and cause fluid, hemorrhage, and scarring.

The good vessels are the capillaries in the choroid which nourish the outer retina. Therefore we want to kill the choroidal neovascularization and not harm the choroidal capillaries.

This is analogous to chemotherapy for cancer. Cancer drugs selectively kill cancer cells because they are growing and spare most of the normal cells of the body. Of course these drugs aren’t perfect because our cells in the bone marrow, hair follicles, and gut also replenish themselves. That’s why cancer drugs can cause reduced blood counts, hair loss, and digestive problems as side-effects. Researchers are working feverishly to find cancer drugs that affect only the cancer cells. We are working feverishly to develop treatments that affect only the abnormal choroidal neovascularization.

I hope this helps clarify things for you.

Complications of AMD Trial (CAPT) Results Announced

You may have heard about the recent article in the journal Ophthalmology about the Complications of AMD Trial or CAPT for short. This trial involved 1052 people who had at least 10 large drusen in both eyes. They were randomized to receive light laser treatment to one eye only. There were 22 clinical centers that performed the study. I was the principal investigator of this study at the The University of Iowa center. My colleagues, Drs. Boldt, Gehrs, and Russell were also investigators. The patients in this study were followed for at least five years and in many cases, six years after the laser treatment.

The result of the study showed that there was no difference between the eyes that were treated with laser when compared to the eyes that were not treated. There was no difference in the visual acuity, the risk of developing new blood vessels (wet AMD), or the risk in developing atrophy from dry AMD.

You may ask why did we ever think that laser could help? Well, drusen are collections of many different molecules beneath the retinal pigment epithelium. Drusen increase the distance between the RPE and the nourishing capillaries in the choroid. They may also impede the flow of nutrients. We thought therefore, that the photoreceptors, which are nourished by the RPE, might suffer and even die especially in areas of thick drusen. In fact, areas of atrophy often develop directly over large drusen. We also thought that the photoreceptors and drusen might produce molecules to attract new blood vessels because they weren’t getting enough oxygen and nourishment and that this could be a cause of wet AMD.

For these reasons, we believed that if we reduced the number and extent of drusen, this may help to preserve vision in AMD. Unfortunately it didn’t seem to make a difference. Therefore laser treatment for the sole purpose of getting rid of drusen is not advisable.

The 1052 patients in CAPT were followed closely. We collected a lot of information on each patient and performed color photography and fluorescein angiography on a yearly basis. CAPT contains a wealth of information that many doctors and statisticians are reviewing right now. This information will give us insights into the cause and course of AMD. So stay tuned!

Reference:
Laser Treatment in patients with bilateral large drusen. The Complications of Age-Related Macular Degeneration Prevention Trial Research Group. Ophthalmology. 2006; 113(11):1974-1986