Topical nonsteroidal anti-inflammatory agents in ophthalmology
`John Nichols, MD; and Robert W. Snyder, MD, PhDt
`
`Nonsteroidal anti-inflammatory agents or NSAIDs are potent
`inhibitors of prostaglandin synthesis. As such, they have found
`many useful roles in ophthalmology. NSAIDs are approved by
`the FDA to prevent intraoperative miosis during cataract
`surgery, reduce postoperative inflammation following cataract
`surgery, and control symptoms of allergic conjunctivitis and
`pain following refractive surgery. In addition, they have been
`shown to be effective in preventing cystoid macular edema
`following cataract surgery or treating cystoid macular edema
`once it occurs.
`
`'Tucson Hospital Medical Education Program, Tucson Medical Center, Tucson;
`and 'Department of Ophthalmology, University of Arizona, Tucson, AZ 85719,
`USA.
`
`Current Opinion in Ophthalmology 1998, 9;1V:40-44
`
`Abbreviations
`
`AA
`CME
`NSAIDs
`PRK
`
`arachidonic acid
`cystoid macular edema
`nonsteroidal anti· inflammatory drugs
`photorelractive keratectomy
`
`© 1998 Lippincott Williams & Wilkins
`ISSN 1 040-8738
`
`40
`
`Nonsteroidal ami-inflammatory drugs (NSAIDs) inhibit
`the production of prostaglandins. When used preopera(cid:173)
`tively and postoperatively they can reduce or alleviate un(cid:173)
`wanted sequelae of prostaglandin synthesis and release.
`During the past few years, NSAIDs have been widely in(cid:173)
`vestigated and their use in ophthalmology is expanding.
`The NSAIDs are useful in preventing prostaglandin-medi(cid:173)
`ated miosis during intraocular surgery, minimizing postop(cid:173)
`erative photophobia, reducing postoperative inflammation
`and discomfort, decreasing the incidence of cystoid macu(cid:173)
`lar edema (CME), and speeding the resolution of CME if
`it should occur. They are also useful in diminishing the
`symptoms associated with seasonal allergies.
`
`Nonsteroidal anti-inflammatory drugs
`mechanism of action
`There are a wide range of inflammatory responses in the
`eye following mechanical, chemical, and thermal stimuli.
`I\[ any of these responses are to be mediated by the form a(cid:173)
`tion of prostaglandins from the fatty acid, arachidonic acid
`(AA), which is generated from phospholipids in the plasma
`membrane. Once formed , these prostaglandins can cause
`breakdown of the blood aqueous barrier, lower the pain
`threshold, and augment photophobia. They can also po(cid:173)
`tentiate effects of other inflammatory mediators [1]. The
`NSAIDs achieve their ami-inflammatory effects by in(cid:173)
`hibiting cyclooxygenase and thus, preventing the forma(cid:173)
`tion of prostaglandins from AA.
`
`Tissue injury or manipulation may initiate the chain of
`reactions that result in prostaglandin synthesis. Early on,
`AA may be liberated directly from cellular membrane
`phospholipids by phospholipase A2 (PLA2). The AA
`may then be converted into prostaglandins by cyclooxy(cid:173)
`genase. Phospholipase A2 and the inducible form of cy(cid:173)
`clooxygenase (COX-2) are inhibited by glucocorticoids
`[2""], whereas the NSAIDs inhibit both the constitutive
`form of cyclooxygenase (COX-I) and COX-2. However,
`in the presence of NSAIDs, the AA instead may be con(cid:173)
`verted to leukotrienes resulting in polymorphonuclear
`leukocyte chemotaxis (Fig. 1).
`
`Phospholipase A2 is also important in transforming 1-0-
`alkyl-2-acly-glycerol to lyso-PAF (platelet activating fac(cid:173)
`tor). Lyso-PAF is then converted into PAF which stimu(cid:173)
`lates phospholipase C (PLC) via a G-protein. The PLC
`then liberates AA-diacylglycerol that is further lysed into
`AA and diacylglycerol. This AA can also be transformed
`into prostaglandins via cyclooxygenase.
`
`SENJU EXHIBIT 2117
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`Page 1 of 5
`
`

`
`Topical nonsteroidal anti-inflammatory agents in ophthalmology Nichols and Snyder 41
`
`Surgical trauma
`
`~
`I
`
`Cell membrane phospholipids
`
`(Phospholipase A2)
`
`~
`
`Arachidonic acid
`
`/
`(lipoxygenase)
`
`/
`~
`
`Leukotrienes
`
`Chemotaxis
`
`(Cycle-oxygenase)
`
`Endoperoxides
`
`!
`~
`
`.-------.-- Prostaglandins ---,--------,
`
`~
`
`Vasodilation
`
`Miosis
`
`Increased
`vascular
`permeability
`
`Intraocular Disruption of
`pressure
`ocular blood
`changes
`barriers
`
`Enzyme
`Phospholipase A2
`Cycle-oxygenase
`Lipoxygenase
`
`Inhibitor
`Corticosteroids
`Salicylates, fenamates, phenylalkanoic
`acids, indoles, pyraxolones,
`phenylacetic acids
`
`Fig.1. Prostaglandin and leukotriene synthesis. (Adapted from Flach [30]; with
`permission.)
`
`Maintenance of intraoperative mydriasis
`Small pupils or intraoperative miosis make cataract
`surgery more challenging and increase the risk of capsule
`rupture [3]. Adrenalin in the irrigating bottle, as well as
`preoperative NSAIDs have been used to maintain a di(cid:173)
`lated pupil. Currently, suprofen 1% and fluorbiprofen
`0.03% are approved by the FDA for use in the preven(cid:173)
`tion of intraoperative miosis. Diclofenac and ketorolac
`are currently not approved by the FDA for prevention of
`intraoperative miosis but have also been found to be ef(cid:173)
`fective [4•,5•,6, and RW Snyder, unpublished data, 1998].
`When preoperative diclofenac or ketorolac has been
`compared with fluorbiprofen, there was no statistical dif(cid:173)
`ference in the size of the pupil following cataract surgery
`[6, and RW Snyder, unpublished data, 1998] suggesting
`that they are equally as effective.
`
`Although suprofen or fluorobiprofen is frequently used
`to prevent intraoperative miosis, their routine use to pre(cid:173)
`vent miosis is not universally accepted. The addition of
`0.3 mL of 1:1000 epinephrine without preservative to
`each 500-mL bottle of buffered saline irrigating solution
`
`may be more effective than NSAID alone [7]. However,
`there is probably an additive effect with NSAID and epi(cid:173)
`nephrine and, as will be discussed later, the NSAID may
`provide the additional benefit of minimizing postopera(cid:173)
`tive discomfort and photophobia.
`
`Pain
`Prostaglandins appear to be very potent mediators of
`pain. Once they are released it is difficult to reverse the
`prostaglandin-mediated effect. The NSAIDs effectively
`block the production of the prostaglandins and are very
`potent analgesics. In well-controlled studies comparing
`systemic NSAIDs to narcotics for relief of dental and
`postoperative pain, 30 and 90 mg of ketorolac were found
`to be more effective than 12 mg of morphine for pain
`control [8]. Because NSAIDs could be delivered easily
`via topical preparation, they were used early on to control
`pain following photorefractive keratectomy (PRK). Ar(cid:173)
`shinoff et a/. [9] were the first to propose the use of
`NSAIDs for post-PRK pain. They found that topical
`0.1% diclofenac or 0.5% ketorolac with a bandage contact
`lens was an effective regimen for post-PRK pain control.
`This has been confirmed by others [ 10, 11] and has be(cid:173)
`come standard practice for PRK, PTK (phototherapeutic
`keratectomy), RK (radial keratotomy) and LASIK (laser
`in situ keratomileusis). In addition to control of postoper(cid:173)
`ative pain, photophobia also appears to be diminished.
`Acular Preservative Free (0.5% ketorolac tromethamine)
`(Allergan, Irvine, CA) has recently been approved by the
`FDA for pain and photophobia control following refrac(cid:173)
`tive surgery. We have also investigated the use of
`NSAIDs in clear cornea cataract surgery with topical
`tetracaine and intracameral lidocaine as anesthetics. In
`patients who are continued on topical ketorolac, there is
`minimal discomfort in the early 24-hour postoperative
`period. We believe the same analgesic effect as seen in
`postrefractive surgery patients occurs following topical
`anesthetic cataract surgery in which the patient is not
`patched. This can be an important adjunct in optimizing
`patient comfort in the postoperative period.
`
`Postoperative inflammation
`There are numerous studies that demonstrate the effec(cid:173)
`tiveness of NSAIDs in preventing or minimizing postop(cid:173)
`erative inflammation. Both 0.1% diclofenac and 0.5% ke(cid:173)
`torolac have been approved by the FDA for prevention
`of postoperative inflammation following cataract extrac(cid:173)
`tion. (It should be noted that cortical steroids do not
`carry this indication). In its most severe form, excess
`breakdown of the blood aqueous barrier can lead to a
`plasmoid aqueous with resulting synechia of the iris to
`the implanted intraocular lens or chamber angle, devel(cid:173)
`opment of a pupillary membrane, or formation of cystoid
`macular edema. In prospective, randomized controlled
`studies both 0.1% diclofenac and 0.5% ketorolac have
`been shown to be as effective or more effective than a
`
`Page 2 of 5
`
`

`
`42 Retina and vitreous disorders
`
`corticosteroid in mm1m1zmg postoperative inflammation
`following cataract surgery [4",12,13,14",15-18]. A prospec(cid:173)
`tive study of 52 patients who were randomly assigned to
`receive either 1.0% diclofenac eyedrops or 0.1% pred(cid:173)
`nisolone eyedrops were examined at day one, 1 week, and
`I month after surgery. Postoperative inflammation was de(cid:173)
`termined subjectively by slit lamp, or objectively with a
`laser cell and flare meter. There was no statistical differ(cid:173)
`ence in inflammation between the corticosteroid and the
`NSAID treatment [19].
`
`In a different large multicenter study, ketorolac was
`compared with 1% prednisolone and 0.1% dexametha(cid:173)
`sone for postoperative inflammation control following
`extracapsular cataract extraction or phacoemulsification
`with posterior chamber intraocular lens implantation. Pa(cid:173)
`tients were evaluated postoperatively for slit-lamp evi(cid:173)
`dence of cell and flare as well as for fluorescein leakage
`across the blood aqueous barrier as measured by fluo(cid:173)
`rophotometry. No significant difference was seen be(cid:173)
`tween ketorolac and glucocorticoid with respect to sub(cid:173)
`jective or objective evaluation of inflammation [14"].
`
`Prevention of cystoid macular edema
`The NSAIDs have been evaluated for both prophylaxis
`and treatment of postoperative CME. The Italian Di(cid:173)
`clofenac Study Group [5"] looked at the prevention of
`postoperative angiographic-identified CME following ex(cid:173)
`tracapsular cataract extraction. They found
`that di(cid:173)
`clofenac 0.1% eye drops were effective in reducing the
`incidence of angiographic-demonstrated CME. This
`complication rate occurs in approximately 20% of eyes.
`After 140 days, the incidence of CME was two times
`higher in the control group (1% dexamethasone plus 0.1 %
`diclofenac days 1-5 postoperative, and placebo days
`6-140 versus the 0.1% diclofenac group which was 0.1%
`diclofenac plus 0.1% dexamethasone days 1-5 postopera(cid:173)
`tive and diclofenac days 6-140 postoperative). There
`were no undesirable side effects such as increased in(cid:173)
`traocular pressure or ocular discomfort noted in this
`study. A double-masked study of prophylaxis of CME in
`which NSAIDs alone (without concurrent corticosteroid)
`was used showed that 0.5% ketorolac decreased angio(cid:173)
`graphic CME when compared with placebo [20]. Other
`studies by Flach eta!. [12,13] have shown that 0.5% ke(cid:173)
`torolac is more effective than dexamethasone phosphate
`when used postoperatively
`following extracapsular
`cataract surgery in maintaining the blood aqueous barrier.
`
`The NSAIDs have also been shown to be effective in
`treating postoperative CME. In a prospective random(cid:173)
`ized study [21] evaluating 61 patients with either apha(cid:173)
`kic or pseudophakic cystoid macular edema treated with
`ketorolac 0.5% or placebo, there was a statistically signif(cid:173)
`icant improvement of at lease two lines of visual acuity at
`30, 60, 90, and 120 days with patients taking ketorolac.
`
`Other uses for nonsteroidal
`anti-inflammatories
`Topical nonsteroidal anti-inflammatories have recently
`been advocated as an adjunct to pain control following
`traumatic corneal abrasion [22]. Jayamanne et a!. [23"]
`showed that diclofenac was effective in relieving discom(cid:173)
`fort following traumatic corneal abrasion and suggested
`that a regimen of topical diclofenac 0.1% in antibiotic
`four times daily provided a superior alternative to tradi(cid:173)
`tional antibiotic ointment, cycloplegics, and oral anal(cid:173)
`gesics. Donnenfeld eta!. [22] also examined a regimen of
`0.5% ketorolac and topical 0.3% ofloxacin for manage(cid:173)
`ment of traumatic corneal abrasions and found the pa(cid:173)
`tients were comfortable with this regimen.
`
`As noted earlier, 0.5 % Ketorolac Preservative Free (Al(cid:173)
`lergan, Irvine CA) has recently been approved by the
`FDA for use in controlling postoperative pain following
`incisional refractive surgery. This is an important adjunct
`because postoperative photophobia in refractive surgery,
`as well as cataract surgery, is troublesome to the patient
`and eradication of light sensitivity provides significant
`improvement in their comfort during the immediate 24
`to 48 hours following surgery.
`
`Allergic conjunctivitis
`Ketorolac 0.5% was first approved by the FDA for the
`treatment of symptoms of allergic conjunctivitis. In a
`large double-masked paired comparison of ketorolac
`0.5% versus placebo eye drops in the treatment of sea(cid:173)
`sonal allergic conjunctivitis [24], ketorolac was found to
`be superior to placebo in reducing conjunctival inflam(cid:173)
`mation and itching. Similar results have also been re(cid:173)
`ported by Ballad eta!. [25] In this study as well as others,
`there was mild transient burning and stinging reported
`with a higher frequency in the ketorolac-treated eyes
`versus the placebo. This is not found in patients treated
`for postoperative cataract inflammation and may repre(cid:173)
`sent a subset of patients with "more sensitive eyes."
`
`Diclofenac 0.1 % has also been shown to be effective for
`seasonal allergic conjunctivitis [25], while suprofen has
`been shown to be effective in giant papillary conjunctivi(cid:173)
`tis [26] and neural conjunctivitis [27].
`
`Toxicity
`Nonsteroidal anti-inflammatory drugs are known to have a
`high incidence of burning and stinging upon application.
`However, as noted earlier this was reported in patients
`who had allergic conjunctivitis and arguably were more
`sensitive from the onset. In published studies, however, a
`small subset of patients do complain of burning upon in(cid:173)
`stillation. Experience with cataract extraction [5",21] has
`nor identified chis as a significant side effect. There is also
`concern that nonsteroidal anti-inflammatory drops may in(cid:173)
`hibit epithelial healing. In a presentation to the Castro-
`
`Page 3 of 5
`
`

`
`Topical nonsteroidal anti-inflammatory agents in ophthalmology Nichols and Snyder 43
`
`Photoablative keratectomy/Corneal wound healing rate
`
`Fig. 2. Corneal wound healing with ketorolac versus di(cid:173)
`clofenac.
`
`"' E
`E
`~
`!!!
`"" "'C
`c:
`"' 0 s
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`0
`
`12
`
`24
`
`36
`
`48
`
`54
`
`60
`
`72
`
`78
`
`Postoperative hours
`
`viejo Society in 1996 [29], we reported our assessment of
`topical diclofenac and ketorolac on epithelial healing in a
`rabbit model. Initially, we evaluated a 7.2-mm epithelial
`defect created by mechanical scraping. Animals were
`treated postoperatively with 0.5% ketorolac, 0.1% di(cid:173)
`clofenac, or phosphate buffered saline as the control using
`two drops every 6 hours until the epithelial healing was
`completed. At 0, 12, 36, 48, 54, 60, 66, 72, and 78 hours,
`the rabbit's epithelial defect was stained with fluorescein,
`photographed, and digitized. The digital photography was
`then analyzed. There was no statistical difference in the
`healing between ketorolac, diclofenac, and phosphate
`buffered saline in this surface scrape model. A second set
`of experiments were also performed in which a 5-mm pho(cid:173)
`totherapeutic keratectomy (300 pulses) was created in a
`rabbit eye. These animals were then treated postopera(cid:173)
`tively with 0.5% ketorolac, 0.1% diclofenac, 0.5% preserv(cid:173)
`ative-free ketorolac, or phosphate buffered saline, two
`drops every 6 hours until the epithelium was complete.
`The wound healing was again assessed using digital fluo(cid:173)
`rescein photography and wound healing curves generated.
`
`As can be seen in Figure 2, there was a significant delay in
`epithelial healing when diclofenac and ketorolac were
`compared with saline. There was significantly less delay
`when preservative-free ketorolac was compared with ke(cid:173)
`torolac (Fig. 3). However, in all cases the epithelium was
`healed within 78 hours and the delay appeared minimal.
`This suggests that the nonsteroidals do exhibit a moderate
`to modest delay in epithelial wound healing and their use
`should be monitored closely in situations where epithelial
`healing may be problematic.
`
`Conclusions
`In summary, NSAIDs provide effective prevention of in(cid:173)
`traoperative miosis, good control of postoperative pain
`and inflammation, prophylaxis of postoperative CME
`following cataract surgery, and are even effective at treat(cid:173)
`ing cystoid macular edema following cataract surgery.
`They have minimal adverse effects. They play a very im(cid:173)
`portant role in optimizing surgical outcome and may cir(cid:173)
`cumvent some of the unwanted side effects that occur
`with corticosteroid treatment.
`
`"'
`E
`E
`~
`!!!
`""
`"'C c:
`"' 0
`s
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`-5
`
`Corneal wound healing rate
`
`------ Acular
`--l':r- Preservative free ketorolac
`------ Saline
`
`Fig. 3. Corneal wound healing with ketorolac versus
`preservative free ketorolac.
`
`Postoperative hours
`
`Page 4 of 5
`
`

`
`44 Retina and vitreous disorders
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as
`
`Of special interest
`Of outstanding interest
`
`1.
`
`2.
`
`Greaves MW, McDonald-Gibson W: Itch: role of prostaglandins. BMJ
`1973, 3:608-609.
`
`Masferrer JL, Kulkarni PS: Cyclooxygenase-2 inhibitors: a new approach to
`the therapy of ocular inflammation. Surv Ophthalmol 1997, 41 (suppl
`2):S35-S40.
`
`This article reviews the mechanism of action of anti-inflammatory agents but em(cid:173)
`phasizes NSAIDs. Briefly, NSAIDs nonselectively inhibit cyclooxygenase-1 (COX-
`1 ), responsible for constitutive prostaglandin expression, and cyclooxygenase-2
`(COX-2), responsible for prostaglandin synthesis in response to inflammation.
`Corticosteroids inhibit only COX-2 but have other undesirable systemic and ocu(cid:173)
`lar effects. Systemic selective COX-2 inhibitors are effective anti-inflammatory
`agents but do not cause gastrointestinal irritation and ulcers, and are postulated
`as effective ocular anti-inflammatories delivered either topically or systemically.
`
`3.
`
`4.
`
`Guzek JP, Holm M, Cotter JB, Cameron JA, Rademaker WJ, Wissinger DH,
`et al.: Risk factors for intraoperative complications in 1 000 extracapsular
`cataract cases. Ophthalmology 1 98 7, 94:461 -466.
`
`Antcliff RJ, Trew DR: The maintenance of peri-operative mydriasis in pha
`coemulsification with topical diclofenac sodium. Eye 1997, 11 :389-391.
`
`This study showed statistically significant differences in pupillary diameters be(cid:173)
`tween eyes treated with diclofenac (n = 32) and untreated eyes (n = 32) post(cid:173)
`phacoemulsification (P = 0.03), postinfustion/postaspiration (P = 0.008), and 1
`day postoperatively (P= 0.003).
`
`5.
`
`Italian Diclofenac Study Group: Efficacy of diclofenac eyedrops in prevent(cid:173)
`ing postoperative inflammation and long term cystoid macular edema. J
`Cataract Refract Surg 1997, 23:1183-1189.
`
`This study addressed several questions regarding NSAID use during and after
`cataract extraction. The findings were as follows. No difference was noted in in(cid:173)
`flammation between post-ECCE eyes treated with diclofenac (n = 141) and a
`control group (n = 140) receiving a 5-day postoperative course of dexametha(cid:173)
`sone followed by placebo. Pupil size in the diclofenac group (n = 141) was signif(cid:173)
`icantly larger (P < 0.05) than pupil size in the control group (n = 140) at aspira(cid:173)
`tion during ECCE. There was no significant difference in intraocular pressure
`between eyes treated with diclofenac and control eyes, and no statistically signif(cid:173)
`icant difference between burning and blurry vision as assessed by patient ques(cid:173)
`tionnaire after instillation of diclofenac or placebo. A statistically significant de(cid:173)
`crease in incidence of CME was noted at 36 and 140 days postoperatively (P =
`0.033 and P= 0.05, respectively).
`
`6.
`
`7.
`
`8.
`
`9.
`
`Roberts CW: A comparison of diclofenac sodium to fluorobiprofen for the
`inhibition of surgically induced miosis. J Cataract Refract Surg 1996, 22
`(suppl1 ):780-787.
`
`Gimbel HV: The effect of treatment with topical nonsteroidal anti-inflamma(cid:173)
`tory drugs with and without intraoperative epinephrine on the maintenance
`of pupillary mydriasis during cataract surgery. Ophthalmology 1989,
`96:585-588.
`
`Fricke JR, Angelocci D, Fox K, McHugh D, Bynum L, Yee JP, et al.: Com(cid:173)
`parison of the efficacy and safety of ketorolac and meperidine in the relief
`of dental pain. J Clin Pharmacal 1992, 32:376-384.
`
`Arshinoff S, D'Addario D, Sadler C, Bilotta R, Johnson TM, et al.: Use of
`topical non steroidal anti-inflammatory drugs in excimer laser photorefrac(cid:173)
`tive keratectomy. J Cataract Refract Surg 1994, 20:216-222.
`
`10. Sher NA, Barak M, Daya S, DeMarchi J, Tucci A, Hardten DR, et al.: Ex(cid:173)
`cimer laser photorefractive keratectomy in high myopia: a multicenter
`study. Arch Ophthalmol 1992, 110:935-943.
`
`11. Sher NA, Frantz JM, Talley A, Parker P, Lane SS, Ostrov C, et al.: Topical
`diclofenac in the treatment of ocular pain after excimer photorefractive ker(cid:173)
`atectomy. Refract Corneal Surg 1993, 9:425-436.
`
`12. Flach AJ, Kraff MC, Sanders DR, Tanenbaum L: The quantitative effect of
`0.5% ketorolac tromethamine solution and 0.1% dexamethasone sodium
`phosphate solution on postsurgical blood-aqueous barrier. Arch Ophthal(cid:173)
`mol 1988, 1 06:480-483.
`
`13. Flach AJ, Graham J, Kruger LP, Stegman RC, Tanenbaum L: Quantitative
`assessment of postsurgical breakdown of the blood-aqueous barrier fol(cid:173)
`lowing administration of 0.5% ketorolac tromethamine. Arch Ophthalmol
`1 988, 1 06:344-34 7.
`
`14. Ostrov CS, Sirkin SR, Deutsch WE, Masi RJ, Chandler JW, Lindquist TD:
`Ketorolac, prednisolone, and dexamethasone for postoperative inflammation.
`Clin Ther 1997, 19:259-272.
`
`There was no difference between ketorolac (n =56), prednisolone (n =58), and
`dexamethasone (n = 41) with respect to indicators of inflammation (ie, slit-lamp
`examination and laser cell and flare meter) after cataract extraction. Ketorolac
`also showed greater efficacy than either prednisolone or dexamethasone against
`breakdown of blood-aqueous barrier by photofluorometrics at day 5 and week 2
`(P < 0.001 and P = 0.016, respectively).
`
`15. Roberts CW: A comparison of non-steroidal anti-inflammatory drugs to
`steroids for postoperative inflammation [abstract]. Ophthalmology 1992,
`99:122.
`
`16. Roberts CW: Voltaren ophthalmic is as effective as Pred Forte for post
`cataract inflammation. Presented at IXth Congress of Societas Ophthalmo(cid:173)
`logica Europaea, May 23-28, 1992.
`
`17. Roberts CW: Voltaren ophthalmic is as effective as Pred Forte for post
`cataract inflammation. Presented at American Society of Cataract and Re(cid:173)
`fractive Surgery, April 1 2-15, 1992.
`
`18. Roberts CW, Brennan KM: A comparison of topical diclofenac sodium
`with prednisolone acetate for post cataract inflammation. Arch Ophthalmol
`1995, 113:725-727.
`
`19. Roberts CW, Brennan KM: A comparison of topical diclofenac with pred(cid:173)
`nisolone for post cataract inflammation. Arch Ophthalmol 1 995,
`113:725-727.
`
`20. Flach AJ, Stegman RC, Graham J, Kruger LP: Prophylaxis of aphakic cystoid
`macular edema without corticosteroids. Ophthalmology 1990,
`97:1253-1258.
`
`21. Flach AJ, Jampol LM, Weinberg D, Kraff MC, Yannuzzi LA, Campo RV, et
`al.: Improvement in visual acuity in chronic aphakic and pseudophakic cys(cid:173)
`toid macular edema after treatment with topical 0.5% ketorolac
`tromethamine. Am J Ophthalmol1991, 112:514-519.
`
`22. Donnenfeld ED, Selkin BA, Perry HD, Moadel K, Selkin GT, Cohen A, et
`al.: Controlled evaluation of bandage contact lens and topical non(cid:173)
`steroidal anti-inflammatories in the treatment of traumatic corneal abra(cid:173)
`sions. Ophthalmology 1 995, 1 02:9 79-984.
`
`23.
`
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