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Nonsteroidal antiinflammatory drugs and treatment of cystoid macular edema Nesteroidni protuupalni lijekovi u liječenju cistoidnog makularnog edema

Marijana Bilen Babić*, Maja Merlak, Renata Gržetić-Lenac, Ivana Valković Antić, Petra Grubešić

Department of Ophthalmology, Clinical Hospital Center Rijeka, Rijeka Abstract: Nonsteroidal antiinflammatory drugs (NSAIDs) have become a significant therapeutic adjunctive tool in the routine and complicated intraocular surgery. Topical NSAIDs prevent intraoperative miosis, reduce pain, postoperative inflammation and incidence of cystoid macular edema (CME). Although there is no established protocol for prophylaxis of pseudophakic CME, due to the relationship between proinflammatory prostaglandins and CME, using corticosteroids and NSAIDs could prevent CME. NSAIDs have a synergistic antiinflammatory effect with steroids, but can also be used alonewhen corticosteroid therapy could be harmful. Prospective clinical trials need to define treatment protocol for topical NSAIDs use, due to their powerful influence to prevent perioperative complications.

Key words: cataract; cyclooxygenase inhibitors; macular edema; prostaglandins

Sažetak: Nesteroidni protuupalni lijekovi (NSAID, engl. nonsteroidal antiinflammatory drugs) postali su značajna dodatna terapija u rutinskim i kompliciranim intraokularnim operacijama. Topički NSAID-i sprječavaju intraoperativnu miozu, smanjuju bol, postoperativnu upalu i učestalost cistoidnog makularnog edema (CME). Iako nema uspostavljenog protokola za profilaksu pseudofakičnog CME-a, zbog veze između proupalnih prostaglandina i CME-a primjena topičkih kortikosteroida i topičkih NSAID-a može spriječiti CME. NSAID-i imaju sinergistički protuupalni učinak sa steroidima, ali se mogu upotrijebiti i sami kadabi kortikosteroidna terapija mogla biti rizična. Zbog njihovog snažnog utjecaja na prevenciju perioperativnih komplikacija potrebna su prospektivna klinička istraživanja za definiranje protokola terapijske primjene topičkih NSAID-a.

Ključne riječi: inhibitori ciklooksigenaze; katarakta; makularni edem; prostaglandini

*Corresponding author: Marijana Bilen Babić, MD Department of Ophthalmology, Clinical Hospital Center Rijeka Krešimirova 42, 51000 Rijeka e-mail: [email protected]

http://hrcak.srce.hr/medicina

142 medicina fluminensis 2019, Vol. 55, No. 2, p. 142-147 M. Bilen Babić et al.: Nonsteroidal antiinflammatory drugs and treatment of cystoid macular edema

surgery in a healthy population. Macular edema INTRODUCTION (ME) is often self-limiting with spontaneous reso- Nonsteroidal antiinflammatory drugs (NSAIDs) lution within 3–12 months, but a small - propor have become an significant therapeutic adjunctive tion of people with chronic persistent macular tool in routine and complicated intraocular sur- edema and formation of cystic spaces may be dif- gery. Topical NSAIDs reduce pain, prevent intra­ ficult to treat. operative miosis, decrease postoperative In patients with diabetes, it is sometimes difficult inflammation and reduce the incidence of cystoid but crucial to differentiate diabetic macular ede- 1 macular edema (CME) . Although prevention of ma (DME) from postsurgical CME. Munk et al de- CME with the use of topical NSAIDs is controver- scribed optical coherence tomography (OCT) sial, their prevalent use following cataract surgery criteria to differentiate PCME from DME5,6. is caused with prophylactic measures to reduce the incidence of pseudophakic CME (PCME) which can cause decreased visual acuity following an un- Combination of topical nonsteroidal antiinflammatory eventful cataract surgery. Topical NSAIDs have a drugs (NSAIDs) and steroids appears to be effective synergistic antiinflammatory effect with steroids, than either agent alone in the treatment of cystoid ma- but can also be used alone when corticosteroid cular edema (CME). NSAIDs and steroids have a synergi- therapy could be harmful. Prophylactic use of stic effect but topical NSAIDs can be used as individual NSAIDs is cost effective and less harmful com- therapy in high-risk eyes in which steroids can be harm- pared to burden of developed CME treatment as ful. periocular or intravitreal injections. Prospective clinical trials are needed to define treatment pro- tocol for topical NSAIDs use, due to their powerful RISK FACTORS FOR CME influence to prevent perioperative complications. Because of wide disparity of opinion about the Incidence of visually significant PCME varies from most effective antiinflammatory drops for the- pre 0,1% to 3,5%1. Subclinical pseudophakic CME is vention of CME, it is necessary to select and treat detected in almost 30% of patients with fluores- high risk eyes for CME2. cein angiography and 11%–41% with OCT7. Clini- According to a survey in 2012 by the American cal CME that persists for more than 6 months is Society of Cataract and Refractive Surgery, 90% considered chronic, with incidence 9,4%–12,8% of members routinely prescribes a NSAID in addi- of CME cases8. tion to, but not as a replacement for a corticos- Risk factors increase the incidence of CME: post- teroid therapy after cataract surgery3. surgical CME in the contralateral eye, African- American origin, diabetes mellitus (DM), uveitis, CYSTOID MACULAR EDEMA (CME) retinal vein occlusion, retinal degeneration, mac- Cystoid macular edema, also known as Irvine– ular degeneration, radiation retinopathy, epireti- Gass syndrome, is a complication of cataract sur- nal membranes, choroidal tumors, prostaglandin gery with multifactorial pathogenesis that occurs analog use, age4,5,9. The incidence may be 20% in secondary to breakdown of the blood–aqueous surgery complicated with retained lens material, and blood–retinal barrier and cystic accumula- posterior capsule rupture, vitreous loss and vitre- tion of extracellular intraretinal fluid with subse- omacular traction, excessive intraoperative- ma quent decreased and distorted central vision1,4,5. nipulations, the presence of an anterior chamber During the intraocular surgery, inflammatory me- intraocular lens5. diators diffuse from lens epithelial cells and uveal CME is more common in diabetic patients, espe- tissue in the anterior and posterior segment and cially those with preexisting retinopathies10. The cause inflammatory response with vasodilatation rate of development of macular edema in diabet- and fluid accumulation in the inner nuclear and ic population (with or without diabetic retinopa- outer plexiform layers of the retina4,5. CME usual- thy) varies from 31% to 81% after cataract ly occurs at approximately 5 (4–12) weeks after surgery5.

medicina fluminensis 2019, Vol. 55, No. 2, p. 142-147 http://hrcak.srce.hr/medicina 143 M. Bilen Babić et al.: Nonsteroidal antiinflammatory drugs and treatment of cystoid macular edema

Chen et al reported the incidence of ME after cat- (Nevanac® 0,1% Alcon/Novartis; Ilevro® 0,3% Al- aract surgery as 22,8% in patients with diabetic con/Novartis)1. retinopathy (DR) related to increased level of in- NSAIDs available in Europe are Yellox® (brom- flammatory mediators in the vitreous and aque- fenac), Naclof® (diclofenac), Indocollyre® (in- ous humor causing subclinical intraocular domethacin), Voltaren® (diclofenac), Ocufen® inflammation, which may worsen macular edema (flurbiprofen), Ketorolac® 0,4%/0,5% (ketorolac after cataract surgery8,9. tromethamine), Nevanac® (nepafenac)1. All of mentioned NSAIDs have therapeutic indication NONSTEROIDAL ANTIINFLAMMATORY for treatment of postoperative inflammation and DRUGS (NSAIDS) reduction of pain after cataract surgery, exept The use of NSAIDs to treat CME has a long history Ocufen® (flurbiprofen) which is used 2 hours be- 1 back to the 1980s, with reviews of the treatment fore surgery for intraoperative mydriasis . Ketoro- of aphakic or pseudophakic CME1. Nonsteroidal lac is the only topical NSAID available in a 1 antiinflammatory drugs block the conversion of preservative-free formulation (Acuvail®, 0,45%) . arachidonic acid by COX-1 (cyclooxygenase-1) NSAIDs are used for 4 to 6 weeks postoperatively and COX-2 (cyclooxygenase-2) enzymes into pros- and treatment can be prolonged for up to 12 taglandin intermediates1. Prostaglandins play a weeks in potentially high-risk patients. The new- key role in the manifestation of ocular inflamma- er NSAIDS have been reformulated to increase tion: contribute to leukocyte migration, cause their potency in less frequent dosing with effect vasculture dilation and hyperpermeability, in- on anterior segment inflammation and postoper- 1 crease proteins in the aqueous humor, cause ery- ative pain . thema and hyperemia11. Prostaglandins also Nonsteroidal antiinflammatory drugs are not ap- modulate iris smooth-muscle contraction, thus proved by Food and Drug Administration (FDA) NSAIDs play a role in preventing miosis during for the prevention or treatment of pseudophakic surgery5. CME and are used off-label. They are also used Nonsteroidal antiinflammatory drugs can be ad- off-label in treatment of CME caused by other ministered systemically, topically or intracamer- eye pathology: diabetic retinopathy, small CME ally. Topically applied NSAIDs are commonly used caused by retinal vein occlusion or uveitis. to manage both anterior and posterior ocular PROPHYLACTIC USE OF TOPICAL NSAIDS segment inflammation1,12. The ocular penetration and efficacy of systemic NSAIDs is questionable In this review, current literature available to May compared to topical. Intracameral formulation 2018 is analyzed to answer is the prophylactic for cataract surgery to potentially increase - my use of topical NSAIDs, either in addition to topi- driasis and reduce pain is available (phenyle- cal steroids or as individual use, reducing the in- phrine 1,0% and ketorolac 0,3% injectable cidence of macular edema and associated visual solution, Omidria®)1. This review refers to topical function pathology? Is the combination of NSAIDs in CME treatment as most common NSAIDs and corticosteroids more effective than method of application. the use of NSAIDs alone? Currently available topical ophthalmic NSAIDs are: Several trials about PCME following cataract sur- Bromfenac (Bromday® 0,09% Bausch & Lomb; Pro- gery showed positive effect of NSAIDs on postop- lensa® 0,07% Bausch & Lomb; Xibrom® 0,09% erative ME. The topical use of 0,1% diclofenac in ISTA; Yellox® 0,9% Croma/Bausch & Lomb); patients with DR, 4 times a day for 7 days before Indomethacin (Indocollyre® 0,1% Bausch & Lomb), cataract surgery and for 30 days, resulted in sig- Dicofenac (Voltaren® 0,1% Alcon, Naclof 0,1% Al- nificantly lower intraocular levels of inter- con), Flurbiprofen (Ocufen® 0,03% Allergan), Ke- leukin-12 (IL-12) and a lower increase in central tololac tromethamine (Ketorolac® 0,4%, 0,5% foveal thickness (CFT) compared to standard Generic; Acular® 0,5% Allergan; Acular® LS 0,4% postoperative therapy with 0,1% topical dexame- Allergan, Acuvail® PF 0,15% Allergan), Nepafenac thasone 4 times a day for 30 days9. In report by

144 http://hrcak.srce.hr/medicina medicina fluminensis 2019, Vol. 55, No. 2, p. 142-147 M. Bilen Babić et al.: Nonsteroidal antiinflammatory drugs and treatment of cystoid macular edema the American Academy of Ophthalmology, NSAID ods resulted in a significant reduction in CME and therapy was found effective in reducing PCME and significant improvement in visual acuity18. increasing the speed of visual recovery after sur- Studies comparing bromfenac with other NSAIDs gery when compared directly with placebo or topi- observed no significant differences in the CME cal corticosteroid formulations with limited rates between bromfenac and nepafenac when intraocular penetration. However, efficacy of given alone or in combination with corticoster- NSAID use on long-term visual outcomes was un- oid7,19. clear5,13. Shields et al reported significant reduc- Warren et al. compared four topical NSAIDs (bro- tions in the incidence of clinical PCME with mfenac 0,09% 2 times/day, diclofenac 0,1% 3 prophylactic use of topical NSAIDs, ketorolac 0,4% times/day, ketorolac 0,4% 3 times/day, nepafenac or nepafenac 0,1%, adjunctive to topical steroids14. 0,1% 3 times/day) in patients with chronic pseu- McCafferty et al. reported CME incidence 19,5% in dophakic CME. At 16 weeks, reductions in mean eyes with contralateral PCME and 13,1% in DR and retinal thickness were significantly greater for bro- found that topical nepafenac 0,3% reduces PCME mfenac (36%, P=0,011) and nepafenac (49%, in patients with preoperative risk factors com- P=0,004), but not for diclofenac and ketorolac pared to placebo but shows no benefit in patients compared with placebo (14%). Visual acuity im- 4 without risk factors . Kessel et al. reviewed 6 rand- proved significantly only in the nepafenac group20. omized clinical trials and found that the incidence of postoperative CME was higher at 1 month in PROPHYLAXIS OF CYSTOID MACULAR EDEMA the steroid-only patients (25,3%) versus the The prevention of Irvine–Gass syndrome is chal- NSAID-only patients (3,8%)15. In study that retro- lenge because it also affects healthy individuals af- spectively reviewed more than 16 000 phacoemul- ter uneventful phacoemulsification. Some studies sification surgeries defined clinical postoperative affirm negligible benefit with NSAIDs use after- un macular edema as a visual acuity of 20/40 or complicated cataract surgery in patients without worse with positive OCT for CME16. Compared risk factors, but others support their use as acute with eyes that received prophylaxis with topical CME prophylaxis in uncomplicated cases5. In low prednisolone alone, the eyes that were addition- risk patients, the routine use of preoperative ally treated with postoperative NSAIDs had a 55% nepafenac was suggested necessary only to reduction of macular edema16. achieve a faster visual recovery5,21. Prophylactic In their metaanalysis, Wielders et al. suggested topical NSAIDs therapy should be considered in that a topical NSAID should always be part of the high risk patients, like diabetic patients especially preventive treatment after surgery in nondiabet- those with DR. It seems logical to prevent acute ic patients, but whether the use of corticosteroid PCME rather than treat it, since treatment of eyedrops can be avoided cannot be concluded chronic CME usually involves more invasive meth- from the results17. Bromfenac 0,09%, has good ocular penetration ods, like intravitreal anti-vascular endothelial with insignificant systemic reactions following growth factor injections, subtenon triamcinolone topical administration. Bromfenac has been or intravitreal dexamethasone implant injections. found to be more potent as a COX-2 inhibitor Boscia et al suggested that all diabetic patients un- than diclofenac and ketorolac7. Studies have dergoing cataract surgery should be treated with 22 shown that nepafenac may be more potent than topical NSAIDs to prevent acute PCME . ketorolac or diclofenac. Nepafenac seems superi- UNIVERSAL AND SELECTIVE NSAIDS THERAPY or to other NSAIDs in terms of ocular penetration allowing higher and sustained therapeutic levels Combination of topical NSAIDs and steroids ap- in retina and choroid5. pears to be more effective than either agent Rho in his prospective study compared diclofenac alone in the treatment of acute CME. NSAIDs and 0,1% and ketorolac 0,5% in 34 patients with CME, steroids have a synergistic effect on CME preven- which developed after uncomplicated cataract tion but NSAIDs can be used as individual therapy surgery. After 3 months, both treatment meth- in high-risk eyes in which topical steroids can be

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potentialy harmful. Monotherapy with NSAIDs cluded that using topical NSAIDs may reduce the may be useful in patients at risk for adverse risk of developing ME after cataract surgery, but events from topical steroids: glaucoma steroid current CME reduction statistics could possibly be responders, diabetics sensitive to systemic ab- ‘exaggerated’. Also it is unclear the extent to which sorption, recurrent herpetic keratitis and delayed NSAID use and reduction in CME incidence has an wound healing cases. Warren et al affirm that -ef impact on the visual function and quality of life of fectiveness of topical bromfenac was as effective patients25. as the topical steroid (prednisolone acetate) in controlling postoperative inflammation in routine SIDE EFFECTS OF NSAID THERAPY 23 cataract surgery . Systemic absorption of most topical NSAIDs is minimal13. There are many reports of NSAIDs There are 2 basic equally valuable approaches to the worsening asthma, but in preexisting asthmat- topical nonsteroidal antiinflammatory drugs (NSAIDs) ics1. Burning, stinging, conjunctival injection, and use in patients undergoing cataract surgery. The univer- contact dermatitis are the most commonly re- 1 sal approach uses topical NSAIDs in combination with ported adverse side effects of NSAIDs . There are topical steroids in all patients. The selective method reports of superficial punctate keratitis, subepi- uses topical NSAIDs for high-risk cases only. thelial and stromal infiltrates and epithelial de- fects. Comparative study of over 4500 eyes that received diclofenac, flurbiprofen or ketorolac re- There are 2 basic equally valuable approaches to vealed no corneal melts or other significant cor- the topical NSAIDs use in patients undergoing cat- neal events, just 1 case of temporary mild corneal aract surgery. The universal approach uses topical thinning in an eye treated with prednisolone NSAIDs in combination with topical steroids in all alone in a patient with rheumatoid arthritis26. patients. The selective method uses topical Special care during NSAID therapy and additional NSAIDs for high-risk cases only. The selective cost monitoring are mandatory in corneal denerva- effective method is designed for low-risk eyes to tion, corneal epithelial defects, rheumatoid- ar prevent potential NSAID side effects in eyes1. thritis, rosacea, keratitis sicca1. Kim et al. in ther study suggest that there is no DISCUSSION AND CONCLUSION greater therapeutic effect of an NSAID on reducing CME if compared with equivalent dosing of a corti- This controversy in topical NSAID and/or corticos- costeroid with adequate intraocular penetration13. teriod therapy for acute CME led to a first inter- Donnenfeld et al concluded that NSAIDs preopera- national multicenter randomized controlled tive use for up to 3 days before cataract surgery clinical study organized by European Society of acclerate visual recovery in the immediate period Cataract & Refractive Surgeons (ESCRS): the PRE- after surgery24. These results are consistent with vention of Macular EDema after cataract surgery other published reports that demonstrate a short- (PREMED) study. The PREMED study was de- term therapeutic visual function benefit of an signed to answer questions relating prevention of NSAID use before surgery, but there is no evidence acute CME after cataract surgery in diabetic pa- that this practice affects prevents vision loss from tients and nondiabetic patients. The patients CME at 3 months or more after cataract surgery13. were randomized to receive topical bromfenac Lim et al in their review from 2016 wanted to an- 0,09% twice daily for 2 weeks, dexamethasone swer is there evidence for postoperative prophy- 0,1% 4 times daily and then decreasing to 1 drop lactic use of topical NSAIDs either in addition to less per day for the following week, or a combi- topical steriods or as monotherapy. They identi- nation of both drugs. The patients were then an- fied 34 studies over 5000 people with follow up alyzed 6 and 12 weeks postoperatively. The final from 1 to 12 months, with variety of NSAIDs used: conclusion was that ‘patients treated with a com- ketorolac, diclofenac, nepafenac, indomethacin, bination of topical bromfenac 0,09% and dexam- bromfenac, flurbiprofen and pranopfen. They con- ethasone 0,1% had a lower risk for developing

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