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Steroids and NSAIDs can be synergistic
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Steroids and NSAIDs in drop form are used by cataract surgeons to reduce inflammation and pain after cataract and other ocular surgery. In the most common study protocol used for FDA approval in the United States, both pain and inflammation are graded vs. placebo for 14 to 15 days after cataract surgery.
Many approved drops and more recently a couple of extended-release delivery drugs have shown a statistically significant reduction in pain, inflammation or both after cataract surgery. These drugs are used in all forms of ocular surgery, which number about 6 million per year in the U.S. and more than 30 million a year in the world. Many studies have also supported the use of steroids and NSAIDs for the treatment and prophylaxis of cystoid macular edema (CME).
As I read the literature and review my personal experience, both drug classes are effective treatments alone, but they are also synergistic. Topical steroids, starting with dexamethasone, have been available for more than 50 years. NSAIDs have been an area of interest for me, and I have participated in several clinical studies and product launches, starting with flurbiprofen from Allergan, which was originally labeled as being effective in retaining pupil dilation during cataract surgery. Diclofenac was approved in 1991 and ketorolac in 1992, with significant acceleration in product development thereafter. Diclofenac is rarely used today because of issues with corneal melt, primarily associated with generic versions. Ketorolac is still widely used in generic form and is also available branded. The most popular branded topical NSAIDs utilize bromfenac and nepafenac.
Commonly used topical steroids available today include dexamethasone in solution or suspension, fluorometholone, prednisolone in solution or suspension, loteprednol and difluprednate. Some of the NSAIDs are approved for once-a-day therapy, while all steroids were labeled for use four times a day until the recent approval of Inveltys (loteprednol etabonate ophthalmic suspension 1%, Kala Pharmaceuticals) with a twice-daily label.
It is amazing that there remains controversy and a wide variety of treatment patterns after decades of use in millions of patients, but such is the case. It is the rare surgeon who uses these drops “on label.” I will share a few observations after 45 years of clinical experience.
I find steroids and NSAIDs to be synergistic in the management of pain and inflammation and in the treatment of/prophylaxis against CME. If I were told I could use only one class of drugs, I would choose NSAIDs over topical steroids. For me, NSAIDs have a lower complication rate with no concern about IOP elevation in the steroid responder. They are better for pain, better if used preoperatively or intraoperatively in maintaining pupillary dilation and reducing discomfort during surgery, equally effective in managing postoperative pain and inflammation, and better for CME treatment/prophylaxis. Some would disagree, but that is my impression, which is also supported by most publications. However, I find the two drugs to be synergistic and prefer to use them in combination.
We are all aware of the significant costs associated with the use of some branded drops, especially for patients with high deductible insurance plans or no insurance. We also have an issue with compliance when topical drops are prescribed. Compliance improves with shorter courses of therapy, which is the case in most ocular surgery. Compliance also improves when a reduced dosage frequency is required. Compliance can actually be eliminated as an issue if the surgeon delivers the required drug at the close of surgery in one or another extended-release approach. Multiple extended-release approaches are now becoming available, and I am an advocate and see them replacing drops for most patients in the next decade.
I will disclose that I consult widely in this field. That consultation is driven by my strong belief that drops are not the best approach for most of my patients. I no longer use topical antibiotics with my cataract surgery, having replaced them with a compounded specialty pharmaceutical intracameral injection of moxifloxacin at the close of the case. I have used intraoperative Omidria (phenylephrine 1% and ketorolac 0.3% intraocular solution, Omeros) to good effect and find that it helps maintain pupillary dilation, especially in floppy iris cases, and enhances intraoperative comfort during surgery and in the early postoperative period. As an alternative to postoperative topical steroids, I have used compounded specialty pharmaceutical steroids intravitreally, intracamerally and subconjunctivally. Except in high-risk complex cases, I do not prescribe a topical steroid after surgery. I am excited to access extended-release Dexycu (dexamethasone intraocular suspension 9%, EyePoint Pharmaceuticals) and Dextenza (dexamethasone ophthalmic insert 0.4 mg, Ocular Therapeutix) as they become available.
My single postoperative pharmaceutical today in a routine case is a topical NSAID, and I never use it, whether branded or generic, more frequently than twice daily. The duration of therapy for me is 1 month in routine cases, and in high-risk cases, I start 3 to 7 days before surgery and continue for 6 to 8 weeks after surgery. Dry eye requires management preoperatively, intraoperatively and postoperatively. I follow carefully for punctate epithelial keratopathy and will discontinue topical NSAIDs in the face of significant ocular surface staining.
I look forward to the day when I can provide my patients with a postoperative regimen that includes an antibiotic along with synergistic steroid and NSAID therapy that requires no drops and is appropriately reimbursed. That day is coming, and it will be a big win for the patient, the surgeon and, if appropriately reimbursed, the manufacturer.
Disclosure: Lindstrom reports he is a consultant for Alcon/Novartis, Bausch Health, Imprimis, Ocular Therapeutix and Omeros.