The evolution of therapeutic management of ocular disease by eye care practitioners has placed an ever-growing number of medications at our disposal. One underutilized and underappreciated class of medications in eye care is non-steroidal anti-inflammatory drugs (NSAIDs).

Commonly prescribed to reduce pain and inflammation in a variety of tissues, NSAIDs are among the most widely used medications in the world because of their demonstrated efficacy in reducing pain and inflammation.¹ Though available in both topical and systemic formulations, topically applied NSAIDs are more commonly used in the prevention and management of non-infectious ocular inflammation and cystoid macular edema following cataract surgery.

These drugs are also used in the management of ocular pain following corneal procedures and in the treatment of allergic conjunctivitis.²

Episcleritis is inflammation of the episclera that occurs without an infection. It is a common condition that is usually mild. Treatment with topical anti-inflammatories may relieve the symptoms faster.

A corneal abrasion is probably the most common eye injury. The pain may be severe and should be treated with non-steroidal anti-inflammatory drops.

Mechanism of Action
In the inflammation pathway, NSAIDs specifically inhibit the action of cyclo-oxygenase, an enzyme vital to prostaglandin synthesis.³ Animal studies have shown that trauma to the anterior segment of the eye—especially the iris—increases prostaglandin synthesis and may contribute to the development of ocular inflammation.⁴ NSAIDs inhibit prostaglandin synthesis, which makes them very useful in controlling pain and inflammation without adversely impacting the immune system. The NSAIDs’ action takes place further down the arachidonic acid pathway than steroids.

What does that mean clinically? The drugs are not as effective as steroids in reducing inflammation, but are still quite potent and lack the side effects seen in steroid usage.²

As a group, though, NSAIDs are excellent analgesics and are even more effective than intramuscular morphine for acute pain.⁵ The historical development of NSAIDs is closely related to the historical development of aspirin.² In fact, topical NSAIDs are often referred to as “aspirin for the eye.” The drugs are very useful in the management of ocular pain following cataract surgery and corneal procedures.

There are a number of NSAIDs approved for topical ophthalmic use. These include:
• Nevanac (nepafenac 0.1%, Alcon).
• Acuvail (ketorolac tromethamine 0.4%, Allergan).
• Acular (ketorolac tromethamine 0.5%, Allergan).
• Voltaren (diclofenac sodium 0.1% , CIBA Vision).
• Xibrom (bromfenac 0.09%, ISTA Pharmaceuticals).
• Profenal, (suprofen 1%, Alcon).
• Ocufen (flurbiprofen 0.3%, Allergan).

Topical NSAIDs and Analgesia
NSAIDs are FDA-approved for the reduction of pain following refractive surgery. Patients treated postoperatively with NSAIDs reported significantly greater pain relief, less pain intensity, fewer symptoms of ocular discomfort and less sleep discomfort than those who were not treated with NSAIDs postoperatively.⁷ Also, many doctors have found it beneficial to use topically applied NSAIDs in reducing pain after a corneal abrasion, but effectiveness seems to be greater if the drugs are administered preoperatively. In fact, studies have shown that this approach in refractive surgery has the potential to more effectively inhibit pain.⁶

Postoperative pain has been a significant complication of photorefractive keratectomy (PRK), and using bandage contact lenses, cycloplegia and oral narcotics alone yielded limited success. Much of this pain and discomfort is modulated once the cornea re-epithelializes. Indeed, hyperesthesia may occur following excimer laser ablation.⁸ The immediate postoperative use of 0.1% diclofenac in combination with topical fluorometholone 0.1% and a bandage contact lens significantly reduced pain, discomfort and photophobia following PRK in several studies.^9,10

These studies also showed that diclofenac did not interfere with wound healing. One study reported that diclofenac significantly decreases corneal sensitivity in the human eye.¹¹ While the mechanism by which this NSAID decreases corneal sensitivity isn’t known, this finding explains the pain relief patients experience after receiving this drug. Limited-dose administration in a compromised cornea is recommended. NSAIDs should be administered three to four times a day while the patient experiences pain, usually two to three days postoperatively. They should be avoided in patients with severe dry eye, as most of the reported cases of corneal complications with NSAID use occurred in patients whose tear production was insufficient (and who were concurrently using topical steroids).¹²

What are some other surgical uses of NSAIDs that have proved appropriate? Instillation of NSAIDs for three days prior to and one day following cataract surgery can prevent ocular pain and discomfort in the first 24 hours after surgery.¹³ More importantly, NSAID use has been shown to significantly lessen the risk and severity of cystoid macular edema, which can occur after cataract surgery.^14-16

Many surgeons now use them routinely for three to four weeks postoperatively to reduce the chance of CME.While steroids offer an effective treatment for CME, NSAIDs are not associated with pressure spikes or other ocular side-effects. While significant corneal abrasions that are not associated with contact lens use generally resolve spontaneously without complications, they may cause debilitating pain during the first 24 to 48 hours after the injury. And, this pain is what drives the patient to present for treatment. Several studies have been undertaken to evaluate the role of NSAIDs in the management of corneal abrasions not due to infections, contact lens trauma or foreign body removal. Patients receiving a topical NSAID required significantly fewer additional oral analgesics and resumed normal activities sooner.^17,18 In patients with acute corneal abrasions, ophthalmic NSAIDs reduce pain without a delay in healing; NSAID use can make the difference for those individuals unable to miss work because of ocular discomfort.¹⁹

Many forms of uveitis require prolonged steroid therapy to control inflammation. Therapy may need to be escalated to include oral steroids or periorbital injections in recalcitrant cases, with the risk of local toxicity and adverse events increasing substantially. NSAIDs are a safer alternative treatment in certain forms of uveitis.²⁰ Painful ocular conditions, such as episcleritis and corneal limbal ulcers, may benefit not only from the steroid-sparing effects of NSAIDs but from their analgesic properties as well.²¹

Anterior uveitis presents with anterior chamber cell and flare, and chronic uveitis often shows posterior synechiae and keratitic precipitates, as seen here.

Recurrent corneal erosion often presents following a previous corneal abrasion. The epithelium is loose around the defect and can be recalcitrant to treatment.

Oral NSAIDs and Pain Relief
There are hundreds of proprietary analgesics in the marketplace, and, of course, all of their manufacturers claim their effectiveness. Many physicians and patients are confused as to which analgesic works best for their pain, and often the choice is based on personal experience rather than evidence.^22,23 Evidence in favor of NSAIDs is generally overwhelming when the test drug is compared to placebo in acute or chronic pain conditions.²⁴ However, there is a controversy about the relative efficacy of NSAIDs when compared with each other.

In the past, some authors have stated that there is little difference in the analgesic efficacy between the different types of NSAIDs.⁵ But, recent evidence has shown that individual NSAIDs do differ in their analgesic effect. The Oxford League Table has been suggested as a tool for assessing the relative efficacy of analgesics—it assigns each analgesic a number with which to grade its efficacy.²⁵ Analgesic efficacy is expressed as the “number needed to treat” (NNT), the number of patients who need to receive the active drug to achieve at least 50% relief of pain vs. placebo over a four- to six-hour treatment period. The most effective drugs have a low NNT: just over two, which means that for every two patients who receive the drug, one patient will experience at least 50% relief thanks to of the treatment. Many doses of NSAIDs have NNT values between two and three; ibuprofen 800mg, ketorolac 20mg and diclofenac 100mg have NNT values of less than two.25 Ibuprofen 800mg is at the top of the Oxford League Table with a NNT of 1.6 and with 100% of patients achieving at least 50% pain relief. By comparison, other analgesics, such as aspirin 600mg (NNT: 4.4) and acetaminophen 100mg (NNT: 3.8) are significantly less effective. While NSAIDs are more effective than acetaminophen, acetaminophen has a better safety profile than NSAIDs.²⁶

But, oral NSAIDs offer an additional benefit: They are not controlled substances, which allows those eye care practitioners without DEA privileges the ability to provide pain control to their patients.

Risks of Topical NSAID Therapy
While topical ocular NSAIDs show excellent absorption and penetration into ocular tissues and display dramatic results, they may have some adverse effects. Frequently reported adverse reactions of NSAIDs are local in nature and include transient burning, stinging and ocular irritation upon instillation.¹⁸ Hypersensitivity reactions, including itching, redness and photosensitivity, may also occur.¹⁸

Although manufacturers have used various methods and formulations to minimize potential discomfort, the use of NSAIDs without concomitant steroids following PRK has been associated with the development of corneal infiltrates.⁹ More serious but less common local corneal complications include superficial punctate keratitis, epithelial defects, corneal melting and delayed wound healing.^27,28 There have been rare reports of corneal infiltrates and corneal perforation.²⁹

As a prodrug, nepafenac may offer an additional safety factor, since less active drug would be present on the cornea. Studies have shown that nepafenac inhibits retinal inflammation and exhibits superior corneal penetration vs. other NSAIDs.^30,31 Patients with a history of herpes simplex keratitis should be monitored while using NSAIDs. And, there are no adequate studies in pregnant women, so topical NSAIDs should be avoided in these patients.

Systemic adverse reactions, while rare, have been reported in the literature. These include exacerbation of bronchial asthma due to the systemic absorption of topical NSAIDs, as well as gastrointestinal irritation and ulceration, inhibition of platelet function and renal disease.^32,33 The high-risk group includes geriatric patients; users of alcohol, tobacco and antacids; and those with a history of systemic steroid or anticoagulant therapy.³⁴ While the systemic absorption of topically applied medication is generally considered minimal, idiosyncratic drug reactions may occur. It is wise to obtain a complete medical and drug history to see if there are any potential adverse reactions before starting topical NSAID therapy.

Safe, Effective Treatment
The development of a safe alternative to steroids in the treatment of ocular inflammation is a significant advancement in ocular therapeutics. Unlike topical steroids, topical NSAID therapy rarely results in serious local or systemic complications. Topical NSAIDs also provide an analgesic effect and reduce the need for additional oral analgesics. This class of drugs provides yet another weapon in our battle against ocular disease. 

Dr. Bowling is center director at Vision America, a surgical comanagement center in Gadsden, Ala. He is also a diplomate in the Primary Care Section of the American Academy of Optometry. Dr. Russell is in group practice with the Marietta Eye Clinic in Georgia. He is a diplomate in the Section on Cornea, Contact Lenses and Refractive Technologies of the American Academy of Optometry. 

1. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology. 2001 Feb;120(3):594-606.
2. Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007;67(9):1291-308.
3. Janpol LM. Pharmacologic therapy of aphakic cystoid macular edema. Ophthalmology. 1985 Jun;92(6):807-10.
4. Keulen-DeVos HCJ, Van Rij G, Renardel DeLavalette JCG, et al. Effect of indomethacin in preventing surgically induced miosis. Br J Ophthalmol. 1983 Feb;67(2):94-6.
5. Ong CKS, Lirk P, Tan CH, et al. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007 Mar;5(1):19-34.
6. Colin J, Paquette B. Comparison of the analgesic efficacy of nepafenac ophthalmic suspension compared to diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: a phase 2 randomized, double masked trial. Clin Ther. 2006 Apr;28(4):527-36.
7. Yee RN, The Ketorolac Radial Keratotomy Study Group. Analgesic efficacy and safety of nonpreserved ketorolac tromethamine ophthalmic solution following radial keratotomy. Am J Ophthalmol. 1998 Apr;125(4):472-80.
8. Ishikawa T, Cerro M, Liang FQ, et al. Hypersensitivity following excimer laser ablation through the corneal epithelium. Refract Corneal Surg. 1992 Nov-Dec;8(6):466-74.
9. Sher NA, Frantz JM, Talley A, et al. Topical diclofenac in the treatment of ocular pain after excimer photorefractive keratectomy. Refract Corneal Surg. 1993 Nov-Dec;9(6):425-36.
10. Eiferman RA, Hoffman RS, Sher NA. Topical diclofenac reduces pain following photorefractive keratectomy. Arch Ophthalmol. 1993 Aug;111(8):1022.
11. Szerengi K, Sorken K, Garbus JJ, et al. Decrease in normal human corneal sensitivity with topical diclofenac sodium. Am J
Ophthalmol. 1994 Sep 15;118(3):312-5.
12. Donzis PB, Mondino BJ. Management of noninfectious corneal ulcers. Surv Ophthalmol. 1987 Sep-Oct;32(2):94-110.
13. Price MO, Price FW. Efficacy of topical ketorolac tromethamine 0.4% for control of pain or discomfort associated with cataract surgery. Curr Med Res Opin. 2004 Dec;20(12):2015-9.
14. Flach AJ, Stegman RC, Graham J, Kruger LP. Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study. Ophthalmology. 1990 Oct;97(10):1253-8.
15. Flach AJ, Dolan BJ, Irvine AR. Effectiveness of ketorolac tromethamine 0.5% ophthalmic solution for chronic aphakic and pseudophakic cystoid macular edema. Am J Ophthalmol. 1987 Apr 15;103(4):479-86.
16. Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac. J Cataract Refract Surg. 2003 Dec;29(12):2378-84.
17. Goyal R, Shankar J, Fone DL, et al. Randomized controlled trial of ketorolac in the management of corneal abrasions. Acta Ophthalmol Scand. 2001 Apr;79(2):177-9.
18. Kaiser PK, Pineda R, Corneal Abrasion Patching Study Group. A study of topical nonsteroidal anti-inflammatory drops and no pressure patching in the treatment of corneal abrasions. Ophthalmology. 1997 Aug;104(8):1353-9.
19. Weaver CS, Terrell KM. evidence-based emergency medicine. Update: do ophthalmic nonsteroidal anti-inflammatory drugs reduce the pain associated with simple corneal abrasion without delaying healing? Ann Emerg Med. 2003 Jan;41(1):134-40.
20. Samiy N, Foster CS. The role of non-steroidal anti-inflammatory drugs in ocular inflammation. Int Ophthalmol Clin. 1996 Winter;36(1):195-206.
21. Koay P. The emerging role of topical non-steroidal anti-inflammatory agents in ophthalmology. Curr Med Res Opin. 2005 Jul;21(7):1131-7.
22. Connolly TP. Cyclooxygenase-2 inhibitors in gynecologic practice. Clin Med Res. 2003 Apr;1(2):105-10.
23. Ong CK, Seymour RA. Pathogenesis of postoperative oral surgical pain. 2003 Winter;50(1):5-17.
24. McQuay HJ, Edwards JE, Moore RA. Evaluating analgesia: the challenges. Am J Ther. 2002 May-Jun;9(3):179-87.
25. Oxford League Table of Analgesics in Acute Pain. Available at: www.medicine.ox.ac.uk/bandolier/Extraforbando/APain.pdf. (Accessed February 2010).
26. Ong CKS, Lirk P, Tan CH, et al. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 2007;5(1):19-34.
27. Gills JP. Voltaren associated with medication keratitis. J Cataract Refract Surg. 1994 Jan;20(1):110.
28. Shimazaki J, Saito H, Yang HY, et al. Persistent epithelial defect following penetrating keratoplasty: an adverse effect of diclofenac eye drops. Cornea. 1995 Nov;14(6):623-7.
29. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration and perforation associated with topical non-steroidal ant-inflammatory drugs. Ophthalmology. 2001 May;108(5):936-44.
30. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: In vitro bioactivation and permeation of external ocular barriers. Inflammat. 2000 Aug;24(4):371-84.
31. Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the rabbit is inhibited y topical nepafenac. Inflammation. 2003 Oct;27(5):281-91.
32. Sharir M. Exacerbation of asthma by topical diclofenac. Arch Ophthalmol. 1997 Feb;115(2):294-5.
33. Campbell WB, Halushka PV. Lipid derived autocoids. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, 9th ed. New York: McGraw-Hill. 1990:601-33.
34. Estes LL, Fuhs DW, Heaton AH,et al. Gastric ulcer perforation associated with the use of injectable ketorolac. Ann Ann Pharmacother. 1993 Jan;27(1):42-3.