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Focus On The Future Of Pharmaceuticals | Jul 2013

Unique Applications of Steroids and NSAIDs

The latest formulations offer advantages in terms of on- and off-label applications.

Thanks to the newest steroids and nonsteroidal antiinflammatory drugs (NSAIDs), along with our better understanding of ocular surface disease (OSD), we cataract surgeons can achieve better outcomes than ever before. As our awareness of OSD has increased, so has our need for safer, more effective ophthalmic preparations that are easier to administer and more comfortable for our patients. When deciding on our pre- and postoperative drug regimens, we therefore look to simplify the dosing schedule and reduce the preservative load. How have the most recently released agents made a difference?


The newest steroid agents, loteprednol etabonate ophthalmic gel 0.5% (Lotemax 0.5% Gel Drop; Bausch + Lomb) and difluprednate ophthalmic emulsion 0.05% (Durezol; Alcon Laboratories, Inc.), offer significant advantages over older formulations. For example, neither requires shaking, a real benefit because patients simply do not take this step even when instructed to do so.1 The new formulations also offer uniform dosing: every drop contains a consistent concentration of medication. Although loteprednol gel and difluprednate are indicated for q.i.d. dosing, many of us have been tremendously successful with b.i.d. schedules after cataract and other surgeries, because less frequent dosing has increased compliance.

Also worth mentioning with regard to loteprednol gel are the addition of propylene glycol and glycerin and a decrease in benzalkonium chloride. These two known active demulcents and a lower amount of preservative have the potential to help maintain the integrity of the ocular surface, since many of us routinely use this agent to combat OSD.

The newest NSAIDs, bromfenac (Prolensa; Bausch + Lomb) and nepafenac (Ilevro; Alcon Laboratories, Inc.), also have enhanced formulations. Prolensa is actually halogenated amfenac, now available in a 3-mL bottle. Its pH has been lowered from 8.3 (Bromday) to 7.8, making the molecule more lipophilic to enhance corneal penetration. Prolensa's concentration is also lower than its predecessor Bromday, now at 0.07%. Ilevro is a modification of Nevanac (Alcon Laboratories, Inc.). At 0.3%, the concentration of the former is three times higher than that of the latter, and Ilevro contains guar gum, which prolongs its retention time on the cornea. These changes have maintained the efficacy of both molecules with q.d. dosing indications.


OSD and Meibomian Gland Dysfunction
The report of the International Dry Eye WorkShop in 2007 suggested the administration of antiinflammatory agents for the treatment of patients with level 2 or higher dry eye disease.2 Many of us therefore use a loading dose of steroids as a part of our regimens. Steroids also have a potential application in the treatment of meibomian gland dysfunction. A 2011 report by the International Workshop on Meibomian Gland Dysfunction suggested antiinflammatory therapy for patients with clinical signs and symptoms of moderate meibomian gland dysfunction, including ocular discomfort, itching, and photophobia.3

What makes steroids and NSAIDs effective in their mode of action? The inflammatory cascade involves sites that require specific blockade by steroids and NSAIDs. Together, these drugs effectively inhibit the phospholipase A2 and cyclooxygenase 2 enzymes, thereby preventing the conversion of arachidonic acid into prostaglandins (Figure). These lipid compounds stimulate (1) white blood cells, causing pain, and (2) vascular permeability, creating flare. This gives rise to the well-known cell-flare-pain reaction.

Because Lotemax has the unique properties of an ester, any steroid not bound to a glucocorticoid receptor is rapidly converted to an inactive metabolite, which explains the drug's excellent safety profile. Because the agent does not significantly increase IOP and cause cataract formation, many of us have selected it for longer-term use. The drug's availability in a new dose-consistent gel formulation with hydrating agents may more effectively quiet inflammation of the ocular surface and lids as well as postoperative inflammation.

Cystoid Macular Edema
In an overview of pharmaceutical strategies to minimize complications after cataract surgery, Roger Steinert, MD, wrote that the exact incidence of cystoid macular edema (CME) remains unclear but that it is a frequent cause of vision loss after even routine cataract surgery.4 Studies suggest that the rate of clinical CME ranges from 1% to 12%5-8 and that the incidence of angiographic CME ranges from 9.1% to 39%.7,9-11 (See Case Example.)

Wittpen and colleagues found an association between small amounts of retinal thickening (>10 μm) and reduced contrast sensitivity after phacoemulsification, even in healthy patients with a low risk of CME.5 Mean visual acuity in patients with less than 10 μm of retinal thickening was approximately 20/22, but it worsened to a mean of 20/25 in patients with 40 μm of thickening or more. In other research, preoperative NSAID dosing improved the visual acuity of all study patients compared to that of controls.8

This broad category of subclinical CME may explain why some patients who have excellent visual acuity after cataract surgery complain that they see poorly. We are probably underdiagnosing minor CME. Because the cost of ophthalmic care is higher among Medicare patients who develop CME than those who do not,7 the cost of an NSAID is not sufficient reason for avoiding this method of prophylaxis.


The latest formulations of NSAIDs and steroids broaden our options for the prevention and treatment of surgical complications, and they have other off-label applications.

In addition, as recommended in the American Society of Cataract and Refractive Surgery's recent alert, all viscous drops should be used after the placement of a bandage contact lens, not under it.12

Sheri Rowen, MD, is an assistant clinical professor of ophthalmology at the University of Maryland and the founder and medical director of the Eye & Cosmetic Surgery Center at Mercy Medical Center and the Rowen Laser Vision & Cosmetic Center in Baltimore. She is a consultant to Alcon Laboratories, Inc.; Allergan, Inc.; and Bausch + Lomb. Dr. Rowen may be reached at (410) 332-9500 or (410) 821-5333; srowen10@gmail.com.

  1. Apt L, Henrick A, Silverman LM. Patient compliance with use of topical ophthalmic corticosteroid suspensions. Am J Ophthalmol. 1979;87(2):210-214.
  2. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):163-178.
  3. Geerling G, Tauber J, Baudouin C, et al. The International Workshop on Meibomian Gland Dysfunction: report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050-2064.
  4. Steinert RF. Pharmaceutical strategies to minimize cataract complications. Cataract & Refractive Surgery Today. Insert. http://bmctoday.net/crstoday/2010/02/insert/article.asp?f=pharmaceutical-strategies-tominimize- cataract-complications. February 2010. Accessed June 21, 2013.
  5. Wittpenn JR, Silverstein S, Heier J, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs. steroid alone in low-risk cataract surgery patients. Am J Ophthalmol. 2008;146(4):554-560.
  6. Henderson BA, Kim JY, Ament CS, et al. Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg. 2007;33(9):1550-1558.
  7. Rossetti L, Chaudhuri J, Dickersin K. Medical prophylaxis and treatment of cystoid macular edema after cataract surgery. The results of a meta-analysis. Ophthalmology. 1998;105(3):397-405.
  8. Ray S, D'Amico DJ. Pseudophakic cystoid macular edema. Semin Ophthalmol. 2002;17(3-4):167-180.
  9. Mentes J, Erakgun T, Afrashi F, Kerci G. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Ophthalmologica. 2003;217(6):408-412.
  10. Lobo CL, Faria PM, Soares MA, et al. Macular alterations after small-incision cataract surgery. J Cataract Refract Surg. 2004;30(4):752-760.
  11. Gulkilik G, Kocabora S, Taskapili M, Engin G. Cystoid macular edema after phacoemulsification: risk factors and effect on visual acuity. Can J Ophthalmol. 2006;41(6):699-703.
  12. ASCRS Cornea and Refractive Surgery Committees. Attention: medication alert for LASIK and PRK. ASCRS website. http://www.ascrs.org/Press-Releases/attention-medication-alert-lasik-and-prk. February 14, 2013. Accessed June 21, 2013.
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