Recent Trends in NSAIDs

Therapy in Ophthalmic Surgery

Dr. Suresh K Pandey,
MS (Ophthalmology, PGIMER, CHANDIGARH),
Anterior Segment Fellowship (USA)
Director, SuVi Eye Hospital & Research Centre
C-13, TALWANDI, KOTA, RAJASTHAN, INDIA

Dr. Vidushi Sharma, MBBS (AIIMS, New Delhi),

MD (Ophthalmology,
AIIMS, New Delhi),
FRCS (UK)

Email- suvieye@gmail.com
Phone +91 9351412449, 0744 2433575
www.suvieye.com
SuVi Eye Institute & Research
Center, Kota, Rajasthan, India
www.suvieye.com
 Recent Trends in NSAIDs
Therapy in Ophthalmic Surgery
 Use of NSAIDs
• In cataract surgery

• In refractive surgery

• For retinal disorders (CME)

Cataract Surgery
Implantation of First IOL by
Sir Harold Ridley (1950)
 Topical Phaco & Implantation of
Accommodating CrystaLens (2010)
TORIC & RESTOR MULTIFOCAL
IOL IMPLANTATION
 Changing surgery

• Extensive inflammation now rare

• Focus on providing not just 6/6, but good

contrast sensitivity etc. (specially with
multifocal/Refractive IOLs)
 What are the Goals of NSAID
Prophylaxis?
• Prevention of intraoperative miosis
• Reduction of pain and discomfort
• Management of
postoperative inflammation
• Inhibition and treatment of CME
 Role of Prostaglandin in Ocular Inflammation

Surgical Trauma

Cell Membrane Phospholipids

Phopholipase A2
Arachidonic Acid

Lipoxygenase Cycloxygenase

Leukotrienes Endoperoxides

Chemotaxis Prostaglandins
 COX1 and COX2

COX-1 – GI protective prostaglandins & thromboxanes

COX-2 – inflammatory PGs
 NSAIDs Phospholipids
Inhibited by
Corticosteroids

Mechanism Phospholipase A2
of Action
Arachidonic Acid

Inhibited
by NSAIDs
Cyclooxygenase Lipoxygenases

Endopreoxides
Leukotrienes
(PGG2 PGH2)

PGE2 Prostacyclin
Thromboxane A2
PGF2α (PGI2)
PGD2
 Mechanism of Action of NSAID
• NSAIDs inhibit the COX pathway, limiting
prostaglandin formation

• Prostaglandin formation is a major causative

factor of postoperative inflammation and CME

• Concurrent administration of corticosteroids and

NSAIDs provide synergistic activity resulting in
more rapid resolution of symptomatic CME
 Review of Common
Conventional NSAIDs
• Diclofenac 0.1% and ketorolac 0.5% shown to
be equally effective in:
– Treating post-operative CME1
– Treating post-operative inflammation2

• Ketorolac 0.5% indicated for relief of ocular

itching due to all. conjunctivitis and post-
cataract inflammation
• Ketorolac 0.4% indicated for post-refractive
pain

1. Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac Cataract Refract Surg.
2003;29(12):2378-84. 2. Flach AJ et al. Comparative Effect of diclofenac 0.1% and ketorolac 0.5% on inflammation after cataract.
Ophthalmology. 1998. 105: 1775-1779.
 Adverse Events Commonly Associated
with Conventional NSAID Therapy
• NSAIDs associated with some unwelcome corneal
effects1:
– Burning and irritation
– Superficial punctate keratitis
– Delayed wound healing

• Severe corneal issues also reported with some

generic NSAIDs2,3
– Thinning
– Perforation due to melts
1. Flach, AJ. Topical nonsteroidal antiinflammatory drugs in ophthalmology. Int Ophthalmol Clin. 2002;42(1):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, 20-24, 2000, Boston, MA. 3. Prescribing Information: VOLTAREN*; ACULAR*;
ACULAR* LS. *Trademarks are the properties of their respective owners.
Corneal Complications
 New development in
Non-Steroidal
Anti-Inflammatory Therapy

Bromfenac sodium (0.09%)

Nepafenac (0.1%)
Addition of Bromine
distinguishes
Bromfenac
from other NSAIDs
 BROMFENAC

Inhibitory effect of Bromfenac on COX - 2

3.7 times 4.4 times 6.5 times 18 times

Bromfenac > Diclofenac > Flurbiprofen > Amfenac > Ketorolac

Common Ocular ADR
Ocular ADR Bromfenac Vehicle
Iritis 7.0 18.1
Abnormal Sensation in the eye 6.5 8.2
Eye Pain 4.2 11.7
Eye Pruritis 3.9 2.9
Posterior Capsule Opacification 3.9 4.1
Partial Vision Loss 3.1 9.4
Burning & Stinging 1.4 4.7
Eye Redness 2.2 7.6
Conjunctival Hyperemia 2.2 11.1
Photophobia 2.0 11.1
Total Number 356 171
 Nepafenac- Prodrug Structure:
Metabolic Conversion

Nepafenac Amfenac
• Nepafenac is converted to a potent
cyclooxygenase inhibitor, amfenac,
by intraocular hydrolases

Ke TL, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced
ocular inflammation. II. In vitro band permeation of external ocular barriers. Inflammation. 2000;24(4):371-84.
Nepafenac Ophthalmic Suspension 0.1%

Indication:
• Treatment of pain and inflammation following cataract surgery
• Dosing:
– One drop TID one day pre-op, DOS, 14 days post-op

Formulation:
• First and only ophthalmic
non-steroidal prodrug
• Preservative: 0.005% BAK

• pH: 7.4 (physiologic)

Drug Indication(s)

Bromfenac 0.09% Postop inflammation secondary to cataract surgery

Ocular pain following cataract surgery

Diclofenac 0.1% Postop inflammation secondary to cataract surgery

Temporary relief of pain and photophobia in
patients undergoing corneal refractive surgery
Flurbiprofen Inhibition of intraoperative miosis
0.03%

Ketorolac Seasonal allergic conjunctivits

Postop inflammation secondary to catract surgery
Reduction of pain and photophobia with refractive
surgery
Nepafenac Treatment of pain and inflammation associated with
cataract surgery
Advantages
of NSAID
Therapy
 Prevention of post cataract
CME
• CME is the most frequent
cause of visual decline
following uncomplicated
cataract surgery

• Late onset (4 to 6 weeks

post-operatively)1

• Estimated to occur in up to
12% of low-risk cataract
cases2

1. Samiy N, Foster CS. The role of nonsteroidal antiinflammatory drugs in ocular inflammation. Int Ophthalmol Clin.
1996;36(1):195-206. 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.
 Definition of CME
• Angiographic CME (traditional)
– May not be associated with significant visual loss, but
fluorescein angiographic evidence of macular edema

• Clinical CME (present day)

– Described as vessel leakage associated with visual
acuity of 20/40 or worse
– Today’s definition is becoming stricter (20/25 or
worse) due to higher patient expectation

Heier JS, Topping TM, et al. Ketorolac versus prednisolone versus combination therapy in treatment of acute
pseudophakic cystoid macular edema. American Academy of Ophthalmology. 2000;107(11):2034-9.
 Role of Optical Coherence
Tomography (OCT)
• Measures subtle postoperative retinal thickening for
diagnosis of CME
– Along with contrast sensitivity test
• The new standard for quick, accurate diagnosis

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.
Better Quality of Vision with NSAID Therapy

--- 20/20 ---

• Stress of a multifocal IOL on the visual system and even the mildest CME result in a
significant reduction in quality of vision and patient satisfaction.

• Due to this, proper NSAID prophylaxis is key to surgical outcomes.

 Risk Factor for CME
• General • Retinal
– DM – Prior CME
– Uveitis – ERM
– Prior Ocular Surgery – Existing ME
– Chronic topical – (BRVO, CRVO)
medications
 CME: Surgical Risk Factors
• Uncomplicated Surgery • Complicated Surgery
– Large Incision – Posterior cap. rupture
– Prol. surgical time – Vitreous loss
– Iris trauma • Retained lens material
• Iris prolapse
– Intraocular bleeding
• Surgical Manipulation
– TASS
– Residual cortex
– AC-IOL/SF IOL
 Mechanism of CME Formation
Following Cataract Surgery
Operative
irritation/inflammation
aging
systemic vasculopathy
glaucoma

Breakdown of the
Prostaglandins in blood aqueous
aqueous & vitreous barrier & blood retina
barrier

Cystoid macular edema

Adapted from Miyake K, et al. Comparison of diclofenac and fluoromethalone in preventing cystoid macular edema after
small incision cataract surgery: A multicentered prospective trial. Jpn J Ophthalmol 2000;44:58-67.
 Treatment of CME
• Topical NSAIDs and
steroids
• Stop prostaglandin
analogues
• Posterior subtenon
Triamcinolone
acetonide
• Intravitreal TA
Efficacy Comparison of Topical NSAIDs &
Steroids in Reducing Incidence of CME

Patients undergoing cataract surgery (N = 60)

• Group 1: Post Op NSAID + Corticosteroid

NSAID +
NSAID Corticosteroid
-2 Day -1 Day Day of Surgery Week 1 Week 2 Week 3 Week 4

• Group 2: Post Op Corticosteroid alone

NSAID Corticosteroid
-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 Ophthmol
Vis Sci. 1999; 40 S289.
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 post-operatively

minimizes the incidence of patient treatment due
to CME

1. 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.
 Cataract NSAID Treatment Regimen1

Recommended
NSAID Dosing

At-Risk Patients Not At-Risk Patients

Preoperative: 1 week Preoperative: 1-2 Days
Postoperative: 6 weeks to several months Postoperative: 6 weeks

• CME the most frequent cause of visual decline post routine cataract surgery
• Normally occurs 4 to 6 weeks post-op
• Studies show CME occurs in up to 12% of cases
Refractive Surgery
 Use in Refractive surgery
• For control of pain during and after
procedure and reduction of photophobia

• NSAIDs safer with

– Less risk of elevated IOP
– Cataract formation
– No increased risk of infection
 Use in Refractive surgery
• Photophobia and discomfort cause
blepharospasm striae foll. LASIK
• NSAIDS reduce this tendency
• Specially useful in the first few hours
following LASIK
• Bromfenac very useful because of longer
duration of action and less stinging
 Refractive NSAID Treatment Regimen
Recommended
NSAID Dosing

LASIK Surface Ablation

Dry stromal bed for 1 minute Dose after bandage contact lens
Remove speculum, Dose post-operatively Dose post-operatively for 2-3 days

• NSAIDs in refractive surgery used primarily for analgesic effect

• Immediate post-op use
• NOT to be dosed for the entire epithelial wound healing process
 Selection of the Ideal NSAID
• Ability to penetrate target intraocular tissues at
therapeutic levels:
– Aqueous humor: cell/flare reduction
– Posterior segment: CME prevention

• Excellent anti-inflammatory efficacy

• Excellent analgesic properties

• Safe and comfortable

• Convenient dosing regimen for compliance

 BROMFENAC Vs NEPAFENAC
• BROMFENAC
– BID Dosing
– Excellent Penetration
– Maximum COX2 Inhibition
• NEPAFENAC
– TID Dosing
– Good Penetration
– Good COX2 Inhibition
 Safety Issues
• Avoid in contact lens users
• Avoid in children less than 10 years
• Avoid in pregnant and nursing mothers
• Use with caution in patients with corneal
pathology, RA, dry eye
 Conclusion
• Optimum NSAID therapy
– Highly effective anti-inflammatory activity
– Rapid onset of action
– Sustained relief of inflammation and pain
– Excellent safety profile (ocular and systemic)
– Well-tolerated formulation
– Convenient dosing regimen for compliance
For relatively pain free
surgery and prevention
of CME
Thank you for your attention
 Recent Trends in NSAIDs
Therapy in Ophthalmic Surgery
Dr. Suresh K Pandey,
MS (Ophthalmology, PGIMER, CHANDIGARH),
Anterior Segment Fellowship (USA)
Director, SuVi Eye Hospital & Research Centre
C-13, TALWANDI, KOTA, RAJASTHAN, INDIA

Dr. Vidushi Sharma, MBBS (AIIMS, New Delhi),

MD (Ophthalmology,
AIIMS, New Delhi),
FRCS (UK)

Email- suvieye@gmail.com
Phone +91 9351412449, 0744 2433575
www.suvieye.com