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New thinking in the treatment of postoperative inflammation
Topical steroids working synergistically with NSAIDs may help reduce the risk of cystoid macular edema.
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Clinicians are often taught to use topical steroids with caution when managing postoperative inflammation because of the risk of complications such as cataract, steroid dependence, exacerbation of viral or fungal infections, and intraocular pressure (IOP) elevation. As a result of these complications, treatment must often be discontinued prematurely or at least reduced in dosage or concentration. At times, steroid treatment is avoided altogether, consequently treating a condition suboptimally that may recur or become chronic.
“Topical steroids, however, are irreplaceable for addressing inflammation,” said Stephen S. Lane, MD,professor of ophthalmology at the University of Minnesota in Minneapolis.
“They are the primary broad-spectrum, anti-inflammatory ophthalmic product available. Their mechanism of action affects all levels of the inflammatory response, and they are therefore immediately effective in patients with ocular inflammation.”
Dr. Lane explained that at a nuclear level, corticosteroids decrease the production of inflammatory precursor proteins. At a cellular level, they suppress proliferation of important inflammatory cells, including mast cells and lymphocytes, and stabilize the extracellular membranes. At a biochemical level, corticosteroids inhibit the production of histamine and enhance its breakdown. The main biochemical mechanism of action is the inhibition of production of arachidonic acid, which is the precursor of prostaglandins and leukotrienes.
“We have been waiting a long time for an optimal corticosteroid that conjugates efficacy with a higher degree of safety,” Dr. Lane said.
A steroid molecule modified to increase safety and efficacy
“The ideal steroid has broad-spectrum anti-inflammatory properties, with a rapid response to action that is targeted and site-specific. We would also want it to have complete symptom control for any pain, discomfort, or irritation,” Dr. Lane said.
In addition, the steroid should be “potent but safe” so that it can be used on an extended basis with minimal adverse effects. It should also work synergistically with other anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants.
Loteprednol etabonate (Lotemax, Bausch & Lomb), for example, is a topical corticosteroid obtained from the modification of prednisolone to eliminate or reduce adverse events while maintaining its efficacy.
| “The ester steroid molecule is hydrolyzed and inactivated by tissue esterases in a single step, reducing the incidence of side effects, such as IOP elevation.” —Stephen S. Lane, MD |  |
Prednisolone, like all other classes of steroids, has a ketone group at position 20, which is replaced in loteprednol etabonate by an ester group (Figure 1).
“When the ketone steroids are broken down, their byproducts remain as active metabolites, while the molecule of ester steroids, having carried out its anti-inflammatory task, is hydrolyzed and inactivated by tissue esterases in a single step. This reduces the incidence of side effects, such as IOP elevation and cataract, typically associated with the presence of a residual, unbound active drug. The inactive metabolites are rapidly cleared from the system,” Dr. Lane said.
From an efficacy standpoint, the advantage of the ester group is the high lipophilicity that leads to better penetration.
“The lipophilic index of loteprednol etabonate is 10 times higher than that of dexamethasone,” Dr. Lane said.
In addition, the rapid and targeted receptor binding leads to enhanced therapeutic effect.
“The binding affinity of loteprednol etabonate to steroid receptors is 4.3 times greater than that of dexamethasone,” he said.
Dr. Lane has been using loteprednol etabonate for several years and has not encountered steroid-induced cataract or IOP elevation in any patient.
“Some of my patients, especially those who have had penetrating keratoplasty requiring long-term steroid treatment, have been using loteprednol etabonate chronically, at least once a day for years, without complication,” he said.
Loteprednol Etabonate: An Ester Corticosteriod  Figure 1. Prednisolone has a ketone group at position 20 that is replaced in loteprednol by an ester group. |
Synergy with NSAIDs
Another advantage of loteprednol etabonate is its capability to work synergistically with NSAIDs, blocking the inflammation in two different manners. NSAIDs primarily act on the cyclooxygenase (COX-1 and COX-2) pathway, minimizing prostaglandin formation, whereas the steroids primarily act on phospholipase A, inhibiting the release of arachidonic acid, Dr. Lane said.
The association with NSAIDs is important in the postoperative management of both refractive and cataract surgery, he said.
In refractive surgery, particularly after surface ablation procedures, NSAIDs provide the analgesic effect, minimizing pain and discomfort. NSAIDs also reduce pain in cataract surgery and are used to prevent cystoid macular edema (CME).
CME is the most frequent cause of vision decline after uncomplicated cataract surgery, Dr. Lane said. CME often has a late onset, at 4 to 6 weeks’ postoperatively, and is estimated to occur in up to 12% of patients after low-risk cataract surgery.
“Of course, there are risk factors for CME that should be analyzed preoperatively, such as pre-existing ocular inflammation, epiretinal or vitreoretinal interface problems, diabetic retinopathy, and retinitis pigmentosa. Patients with ocular vascular or cardiovascular disease should also be considered high-risk patients,” Dr. Lane said.
If any of these risk factors is present, prophylaxis treatment with nonsteroidal and even steroidal anti-inflammatory medications should be started at least 1 week before surgery to minimize postoperative inflammation, he said.
The definition of CME has evolved over the years. The angiographic definition was based on fluorescein angiographic evidence of macular edema, with or without significant visual loss. A more recent clinical definition described CME as vessel leakage, associated with visual acuity of 20/40 or worse. Due to the higher patient expectations, the definition is becoming stricter, changing the threshold of visual acuity to 20/25 or worse.
“Now, thanks to OCT technology, we can diagnose mild degrees of CME more accurately, measuring even subtle postoperative retinal thickening,” Dr. Lane said. “Along with contrast sensitivity testing, OCT is gaining popularity for the diagnosis of cystoid macular edema.”
Prevention of CME
A growing body of evidence shows that topical NSAIDs are effective in preventing postsurgical CME.
A study conducted in Boston compared two groups of patients undergoing routine cataract surgery. The first group received both NSAIDs and corticosteroids preoperatively and postoperatively, whereas the second group was treated with steroids alone. Results at 6 weeks showed that the group that used both agents had a 0% CME rate compared with the 12% CME rate (evidenced by fluorescein angiography) in the second group.
NSAIDs are frequently associated with adverse corneal effects, such as burning and irritation, superficial punctate keratitis, and delayed wound healing. More severe corneal complications, such as thinning and perforation due to melts, are also reported.2
However, Dr. Lane said, adverse effects do not alter the favorable benefit-risk ratio of topical NSAIDs when used in an appropriate and judicious manner.
“They must be used with a certain amount of care and supervision, and cannot be used indefinitely, except in the acute postoperative period when combined with loteprednol,” he said.
“For prevention of CME, I use NSAIDs three times a day starting the day before surgery in patients undergoing routine procedures, and 1 week before surgery in high-risk patients, such as patients with diabetes. On the day of surgery, I use a fourth-generation fluoroquinolone for 3 doses in addition to the nonsteroidal medication. Postoperatively, I prescribe loteprednol etabonate in addition to the NSAID and fluoroquinolone for 1 week. At 1 week, the antibiotic is discontinued, whereas the NSAID and loteprednol are continued for another 3 to 5 weeks. In high-risk patients, I continue the NSAID and loteprednol for up to 6 months,” Dr. Lane said (Figure 2).
He emphasized that an appropriate anti-inflammatory treatment is becoming increasingly important for cataract surgery patients, particularly young patients undergoing refractive lens exchange (RLE), where CME is a major complication.
To exploit the potential of new intraocular lenses (IOLs), surgeons should “minimize even the mildest complication.”
“In the past, 20/25 vision would have been regarded as a good result,” Dr. Lane said. “But with the new IOLs available, and with the rising expectations of postcataract patients, this is no longer the case.”
| Figure 2. Preventing CME Preoperative Dosing:
Postoperative Dosing:
|
Steroid-induced IOP complications
The safety profile of loteprednol etabonate allows for effective control of post-LASIK inflammation without the drawbacks of other corticosteroids. A characteristic form of late-onset diffuse lamellar keratitis (DLK) is associated with increased IOP and can therefore be induced by using corticosteroids after LASIK, Dr. Lane said.
In a study of 10 eyes from 6 LASIK patients with late-onset DLK, occurring between 7 and 34 days, mean IOP was 37 mm Hg, ranging between 32 and 43 mm Hg. Eight of these eyes were treated at presentation with prednisolone acetate. In the other two eyes, the use of topical steroids was contraindicated.
“This particular form of DLK has a similar appearance to classic DLK but has a late onset, is associated with increased IOP, and is refractory to steroid treatment alone. The pathophysiology of this complication has been recently associated with the IOP elevation caused by the use of steroids postoperatively. In this case, treatment with steroids is not only ineffective, but detrimental,” Dr. Lane said.
Therefore, post-LASIK patients should be watched closely in the first months for steroid response, and IOP assessment should be part of DLK prevention and evaluation, Dr. Lane said.
Also in this case, prevention is the best course of action.
“Because of its lower potential to produce IOP elevation, Lotemax prevents this and other IOP-related complications, and is the best choice for post-LASIK patients,” Dr. Lane said.
In summary, loteprednol etabonate, due to its target-specific efficacy and improved safety profile, is a good choice of steroid for modern anterior segment surgery, according to Dr. Lane.
“It provides optimal control of postoperative inflammation and can be used synergistically with NSAIDs,” he said.
“Lotemax,” he concluded, “has changed the traditional application of steroids to corneal external disease conditions because indications can be expanded, and extended, so that safe treatment is now possible.”
For more information:
- Stephen S. Lane, MD, is clinical professor of ophthalmology at the University of Minnesota and is in private practice in St. Paul, Minn. He can be reached at 2950 Curve Crest Blvd., Stillwater, MN 55082; 651-275-3000; fax: 651-275-3099; e-mail: sslane@associatedeyecare.com.
References
- McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999;40:S289.
- Congdon, Schein, et al. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27:622-631.