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Role of Topical NSAID’s
In Post-operative CME
Ahmed El-Sawy Habib, MD
Cairo University
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No financial interest
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Value of NSAID in ocular
surgery
 Prevention and treatment of cystoid macular edema
(CME) following cataract surgery1,2
 Management of postoperative inflammation3
 Prevention of intraoperative miosis during cataract
surgery3
 Reduction of pain and discomfort following surgery
or injury4-7
1. Jampol LM. Pharmacologic therapy of aphakic cystoid macular edema: a review. Ophthalmology 1982;89:891-897. 2. Jampol LM.
Pharmacologic therapy of aphakic and pseudophakic cystoid macular edema: 1985 update. 3. Flach, AJ. Topical nonsteroidal
antiinflammatory drugs in ophthalmology. Int Ophthalmol Clin. 2002;42(1):1-11. Ophthalmology 1985;92:807-810. 4. Yee RW, Ketorolac
Radial Keratotomy Study Group. Analgesic efficacy and safety of nonpreserved ketorolac ophthalmic solution following radial
keratotomy. Am J Ophthalmol 1998;125:472-480. 5. Eiferman RA, Hoffman RS, et al. Topical diclofenac reduced pain following
photorefractive keratectomy. Arch Ophthalmol 1993;111:1022. 6. Szerenyi K, Sorken K, et al. Decrease in normal human corneal
sensitivity with topical diclofenac sodium. Am J Ophthalmol 1994;118:312-315. 7. 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 ;20(12):2015-9.
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NSAIDw
Mechanism
of Action
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 Prostaglandins are the main causative factor of postoperative
inflammation and CME
 NSAIDs inhibit the cyclooxygenase (COX) pathway, limiting
prostaglandin formation1
 Steroids act by reducing prostaglandin synthesis through
inhibition of Phospholipase A2 and decreasing availability of
cellular arachidonic acid4
 Combined administration of corticosteroids and NSAIDs shown
to provide synergistic action resulting in more rapid resolution of
symptomatic CME2,3
1. McColgin AZ, Heier JS. Control of intraocular inflammation associated with cataract surgery. Curr Opin Ophthalmol. 2000
Feb;11(1):3-6. 2. Heier JS, Topping TM, et al. Ketorolac vs prednisolone vs combination therapy in treatment of acute
pseudophakic cystoid macular edema. American Academy of Ophthalmology. 2000;107(11):2034-9. 3. Flach AJ. Discussion:
ketorolac vs prednisolone vs combination therapy in the treatment of acute pseudophakic CMD. Ophthalmology. 2000;107:2039.
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NSAIDs
Mechanism
of Action
Phospholipids
Inhibited by
Corticosteroids
Phospholipase A2
(Inflammatory pathway)
Arachidonic Acid
Inhibited
by NSAIDs
Cyclooxygenase
Lipoxygenases
Endoperoxides
(PGG2 PGH2)
Leukotrienes
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NSAIDs
and CME
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Thromboxane A2
PGE2
PGF2α
PGD2
Prostacyclin
(PGI2)
Jampol LM. Pharmacologic therapy of aphakic cystoid macular edema. Ophthalmology. 1982; 80:891-897.
 CME is the most common
cause of visual decline
following uncomplicated
cataract surgery (estimated
to occur in 12% of low-risk
cataract cases2 ).
 CME development is due to
prostaglandins release and
the break down of bloodretinal barrier3
 Late onset (4 to 6 weeks
post-operatively) 1
Courtesy of University of Pittsburgh Visual Imaging
1. Samiy N, Foster CS. The role of nonsteroidal antiinflammatory drugs in ocular inflammation. Int Ophthalmol Clin. 1996;36:195206. 2. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema.
Invest Ophthmol Vis Sci. 1999; 40 S289. 3. Mishima H, Masuda K, et al. The putative role of prostaglandins in cystoid macular
edema. Prog Clin Res. 1989;31:251-264.
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CME
 Asymptomatic CME
– May not be associated with significant visual loss,
but mild fluorescein angiographic or OCT
evidence of macular oedema
 Symptomatic CME
– Described as angiographic or OCT evidence of
vessel leakage associated with visual acuity of
20/40 or worse
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ROptical sCoherence
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Tomography
(OCT)
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Heier JS, Topping TM, et al. Ketorolac vs prednisolone vs combination therapy in treatment of acute pseudophakic cystoid macular
edema. American Academy of Ophthalmology. 2000;107:2034-9.
 Main diagnostic tool for CME
 Can measure even subtle postoperative retinal
thickening
– Along with contrast sensitivity test
Courtesy of
University of
Pittsburgh
Visual Imaging
Heier, JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic
treatment may avert vision loss. Ophthalmology Management. 2004;63-72.
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High risk CME Patients
 Uveitic patients with pre-existing ocular
inflammation
 Patients with ocular vascular disorders sp.
Diabetic patients
 Epi-retinal membranes or vitreo-retinal
interface disorders
 Glaucoma patients &Retinitis pigmentosa
Prophylaxis should be started earlier and extended
longer for high-risk patients1
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Hypothesis on
Mechanism of CME
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FormationwFollowing Cataract Surgery
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1. Heier, JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic treatment may avert vision
loss. Ophthalmology Management. 2004;63-72.
High levels of PGs in aqueous
and vitreous in high risk
patients
Breakdown of the
Blood Aqueous
Barrier & Blood
Retina Barrier
accentuated by
Operative
Irritation/Inflammation
Cystoid Macular Edema
Adapted from Miyake K, et al. Jpn J Ophthalmol. 2000;44:58-67.
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Role of NSAIDs in Prevention of
CME??
Preoperative and postoperative topical
NSAIDs help in preventing and treating
post-surgical CME1 by reducing
intraocular PG levels
Visual acuity
Angiographic and
OCT findings
 Achieving adequate intraocular therapeutic concentrations is important to
maximize effect of therapy on target tissue - retina2
 Steroids alone do not effectively prevent or treat CME3
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Efficacy Comparison
of Topical NSAIDs &
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Steroids inw
Reducing Incidence of CME
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Patients undergoing cataract surgery (N = 60)
1. Samiy N, Foster CS. The role of nonsteroidal antiinflammatory drugs in ocular inflammation. Int Ophthalmol Clin.
1996;36:195-206. 2. Gaynes BI, Fiscella R. Topical nonsteroidal antiinflammatory drugs for ophthalmic use: a safety
review. Drug Saf. 2002;25:233-50. 3. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence
of post operative cystoid macular edema. Invest Ophthmol Vis Sci. 1999;40:S289.
 Group 1: Post-Op NSAID + Corticosteroid
NSAID +
Corticosteroid
NSAID
-2 Day
-1 Day
Day of Surgery
Week 1
Week 2
Week 3
Week 4
 Group 2: Post-Op Corticosteroid alone
Corticosteroid
NSAID
-2 Day
-1 Day
Day of Surgery
Week 1
Week 2
Week 3
Week 4
McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema. Invest
Ophthalmol Vis Sci.1999;40:S289.
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Efficacy Comparison of Topical NSAIDs &
Steroids in Reducing Incidence of CME
Results (evaluation at week 6)1
 Group 1: 0% CME
 Group 2: 12% CME
 NSAID used pre-operatively and postoperatively minimizes the incidence of
patient treatment for CME
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Cataract NSAID
Treatment Regimen
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1. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema. Invest
Ophthalmol Vis Sci.1999;40:S289.
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Recommended
NSAID Dosing
At-Risk Patients
Preoperative: 1 week
Postoperative: 4 weeks to several months
Not At-Risk Patients
Preoperative: 1-2 Days
Postoperative: 4 weeks
1. O’Brien TP. Emerging guidelines for use of NSAID therapy to optimized cataract surgery patient care. Curr Med Res & Opin.
2005;21:1131-1137.
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Adverse Events Commonly Associated
with Conventional NSAID Therapy
 NSAIDs frequently associated with unpleasant
side effects1:
– Burning and irritation
– Superficial punctate keratitis
– Delayed wound healing
 Rare but Severe corneal issues also reported
with conventional NSAIDs2,3
– Corneal thinning, melting or perforation
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Conventional
NSAIDs*
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1. Flach, AJ. Topical nonsteroidal antiinflammatory drugs in ophthalmology. Int Ophthalmol Clin. 2002;42:1-11. 2. Mah
FS, et al. Do NSAIDs cause wound melting following uncomplicated, small incision, scleral tunnel phacoemulsification?
Paper presented at the American Society of Cataract and Refractive Surgical Meeting. May 2000, Boston,
Massachusetts. 3. Prescribing Information: VOLTAREN*; ACULAR*; ACULAR* LS. *Trademarks are the properties of
their respective owners.
 Diclofenac 0.1% and Ketorolac 0.5% shown
to be equally effective in:
– Treating post-cataract CME1
– Treating post-operative inflammation2
 Ketorolac 0.4% indicated for post-refractive
pain*
 Newly introduced now is Nepafenac
(Nevanac, Alcon)
1.
Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac vs ketorolac. Cataract Refract
Surg. 2003;29(12):2378-84.
Flach AJ et al. Comparative effect of diclofenac 0.1% and ketorolac 0.5% on inflammation after cataract.
Ophthalmology.1998;105: 1775-1779.
* Comparison based on US package inserts.
2.
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Nepafenac Ophthalmic Suspension 0.1%
(NEVANAC®)
Advantages over conventional NSAID in
treating ocular inflammation and CME:
 Smaller dose to reach thrapeutic levels (One drop
TID one day pre-op, DOS, 14 days post-op) 
minimizes side effects
 Physiologic pH (7.4)  and reduced burning &
irritation
 Only Ophthalmic NSAID prodrug better
penetration and less ocular surface sideeffects and
high selectivity in CME.
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Prodrug .Structure:
Metabolic
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Nepafenac
Amfenac
 Nepafenac is converted to a potent
cyclooxygenase inhibitor, Amfenac, by
intraocular hydrolases
Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the
treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular
barriers. Inflammation. 2000;24:371-84.
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Prodrug
High permeation and penetration
power over cornea and to
posterior segment
– Less ocular surface side
effects as the drug rapidly
penetrates into anterior and
posterior segments 1
Higher selectivity to target
cells In Retina
– Retina/choroid » iris ciliary
body > cornea2 = minimal
systemic absorption (1,700X
Amfenac
Amfenac
less single oral dose)
Amfenac
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Prodrug
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1. Gamache DA, et al. Nepafenac, a uni,teroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I.
assessment of antiinflammatory efficacy. Inflammation. 2000;24:357-70.
2. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of
trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation.
2000;24:371-84.
amfenac formation 
high intraocular
therapeutic levels in small
administered doses
Bromfenac
Concentration (ng/mL)
 Prodrug structure of
nepafenac serves as a
reservoir for continued
Ketorolac
250
200
150
100
50
0
0 hr
0.5 hr
1 hr
2 hr
3 hr
4 hr
Amfenac
Nepafenac
Nepafenac + Amfenac
Commercial nepafenac 0.1% suspension (amfenac plus nepafenac)
demonstrated significantly greater ocular bioavailability of drug than either
ketorolac 0.4% or bromfenac 0.09% solutions
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Degree of Corneal Permeation
of Various NSAIDs
Ketorolac
Covalently bound and
uncharged nepafenac molecule
increases corneal permeability
coefficient and drug distribution
within ocular tissue
Bromfenac
Diclofenac
Nepafenac
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RRole of NEPAFENAC
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Cataract
surgery
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0
1
2
3
4
5
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Corneal Permeability (cm/sec x 10-5)
Lindstrom R, Kim T. Nepafenac: ocular permeation and inhibition of retinal inflammation: an examination
of data and opinion of clinical utility. Curr Med Res & Opin.2006;22:397-404.
 NEVANAC® Suspension is effective in treatment of
anterior segment inflammation and ocular pain after
surgery1-2
 NEVANAC® Suspension helps in the prevention and
treatment of CME specially in high risk patients
Lane SS, Modi SS, Holland EJ, et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative anterior
segment inflammation. Paper presented at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC.
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FDA Registration Trials
Percent Cures for post cataract anterior segment
inflammation (0 cell/flare)
% Cures by Visit
70%
*
60%
50%
40%
*
30%
20%
10%
0%
**
**
Day 1
Day 3
Day 7
Day 14
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NEVANAC® Suspension
Placebo
*P ≤ 0.0038
Lane SS, Modi SS, Holland EJ, et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative
anterior segment inflammation. Paper presented at: American Society of Cataract and Refractive Surgery; April 18, 2005,
Washington, DC.
Nepafenac maintains its action in prevention and
treatment of CME through:
 Enzymatic effect
– Targeting and inhibitting intraocular
cyclooxygenase
– Maintains stability of all ocular blood barriers
 Arachidonic acid pathway similarity (by having a metabolic pathway
similar to arachidonic acid)
– Inhibits all prostaglandins of the ICB
– Inhibits retina PGE2 synthesis
– Maintains the integrity of the BRB
Gamache DA, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of traumainduced ocular inflammation: I. assessment of anti-inflammatory efficacy. Inflammation. 2000;24:357-370.
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In conclusion
– Nepafenac 0.1% gives an enhanced therapeutic
potential for a variety of conditions associated
with retinal edema as it has superior
pharmacodynamic properties in the posterior
segment compared to Diclofenac 0.1% and
Ketorolac 0.5%¹.
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1.Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the rabbit is inhibited by topical
nepafenac. Inflammation. 2003;27:281-291.
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