Cataract surgery and nonsteroidal 

antiinflammatory drugs 
Richard S. Hoffman, MD, Rosa Braga-Mele, MD, Kendall Donaldson, MD, Geoffrey Emerick, MD, 
Bonnie Henderson, MD, Malik Kahook, MD, Nick Mamalis, MD, Kevin M. Miller, MD, Tony Realini, 
MD, MPH, Neal H. Shorstein, MD, Richard K. Stiverson, MD, Barbara Wirostko, MD, for the ASCRS 
Cataract Clinical Committee and the American Glaucoma Society 
Nonsteroidal antiinflammatory drugs (NSAIDs) have become an important adjunctive tool for sur- geons performing 
routine  and  complicated  cataract  surgery.  These  medications have been found to reduce pain, prevent intraoperative 
miosis,  modulate  postoperative  inflammation,  and  reduce  the  incidence  of  cystoid macular edema (CME). Whether 
used  alone,  synergistically  with  steroids,  or  for  specific  high-risk  eyes  prone  to  the  development  of  CME,  the 
effectiveness  of  these  med-  ications  is  compelling.  This  review  describes  the  potential preoperative, intraoperative, 
and  post-  operative  uses of NSAIDs, including the potency, indications and treatment paradigms and adverse effects 
and  contraindications.  A  thorough  understanding  of  these  issues  will  help  sur-  geons  maximize  the  therapeutic 
benefits of these agents and improve surgical outcomes. 
Financial Disclosure: Proprietary or commercial disclosures are listed after the references. 
J Cataract Refract Surg 2016; 42:1368–1379 Q 2016 ASCRS and ESCRS 
Modern  cataract  and  lens  surgery  is  commonly  facili-  tated  by  the  use  of  topical  medications  before  and  after  the 
surgical  procedure.  These  topical  medications  may  include  antibiotics,  steroids,  nonsteroidal  antiinflam-  matory 
drugs  (NSAIDs),  and  the  full  array  of  glaucoma  medications  to  modulate  intraocular  pressure  (IOP)  in  the 
perioperative  period.  Many  surgeons  have  found  NSAIDs to be an indispensable tool for providing the best surgical 
outcomes  in  both  routine  and  complicated  cataract procedures. As a class of drugs, NSAIDs have been proven to be 
a  safe  and  effective alternative to cor- ticosteroids in the topical prevention and management of noninfectious ocular 
inflammation  and  cystoid  mac-  ular  edema  (CME).1,2  They  have  also  been  valued  as  a  means  of  maintaining 
intraoperative mydriasis and moderating postoperative pain. Whether used alone, 
synergistically  with  corticosteroids,  or  for  specific  high-risk  eyes  prone  to  the  development  of  CME,  the 
effectiveness of these medications is compelling. 
This  paper  reviews  the  literature  on  currently  avail-  able  topical  and intracameral NSAIDs and their various uses 
in  cataract  and  lens  surgery,  with  specific  attention  to  the  prevention  and  treatment  of  pseudo-  phakic CME and to 
the  assorted  treatment  paradigms  for  addressing  both  routine  and  high-risk  cases.  In addition, special consideration 
of  patients  with  coexis-  tent  glaucoma  having  cataract  surgery  will focus on the potential effectiveness and benefits 
of using NSAIDs in these patients. Possible adverse reactions and contraindications will also be reviewed. 
Mechanism of Action 
Commercially available NSAIDs consist of a chemi- cally heterogeneous group of compounds that can be 
Submitted: October 26, 2015. Final revision submitted: April 4, 2016. Accepted: April 11, 2016. 
grouped  into  6  major  classes:  salicylates,  fenamates,  indoles,  phenylalkanoic  acids,  phenyl  acetic  acids,  and 
pyrazolones.2,3 Despite their chemical heterogene- 
Shan Lin, MD, and Louis R. Pasquale, MD, reviewed the final paper. 
ity, all NSAIDs act by blocking the cyclooxygenase (COX) enzymes, COX-1 and COX-2, thereby reducing 
Corresponding author: Richard S. Hoffman, MD, Drs. Fine, Hoffman 
 or blocking the production of prostaglandins. The Sims, 
LLC, 1550 Oak Street, Suite 5, Eugene, Oregon 97401, USA. 
COX-2 enzyme is more prevalent in the 
inflammatory E-mail: rshoffman@finemd.com. 
response than COX-1,3,4 and thus the potency of 
1368 
Q 2016 ASCRS and ESCRS 
http://dx.doi.org/10.1016/j.jcrs.2
016.06.006 Published by Elsevier Inc. 
0886-3350 

REVIEW/UPDATE 
 
1369 REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
inhibition of COX-2 tends to determine the clinical ef- 
Penetration and Efficacy of Topical Ophthalmic 
ficacy of the NSAID. 
Nonsteroidal Antiinflammatory Drugs 
Mode of Delivery 
Due to the physiologic barrier of the ocular surface and the composition of the aqueous, many NSAID mol- 
Nonsteroidal antiinflammatory drugs can be adminis- 
ecules must be altered to enhance their availability. 
tered systemically, topically, or, more recently, intracam- 
These agents are primarily weakly acidic drugs that 
erally. Topically applied NSAIDs are commonly used to 
ionize at the pH of the tear film, therefore limiting 
manage ocular inflammation, and many forms are avail- 
corneal permeability since the cornea has an 
isoelectric able. Local side effects due to topical instillation may 
point of 3.2.4 To increase permeability, the pH 
must occur, but ocular penetration of most commercially avail- 
generally be raised, thereby increasing the 
unionized able topical NSAIDs seems to be adequate for both ante- 
fraction of the drug. Since the formulation is acidic, 
rior and posterior segment inflammation.1,3,4 The ocular 
this increases the irritant potential while improving 
penetration and efficacy of systemic NSAIDs is question- 
corneal penetration and decreasing aqueous 
solubility.5 able compared with those of topical treatment, and given 
Preservatives such as benzalkonium chloride 
(BAK) the larger potential systemic side effects associated with 
have been added to the formulations to increase 
pene- oral NSAIDs, it is unlikely that systemic NSAIDs will 
tration; however, these preservatives also increase 
play a significant role in the treatment of intraocular 
ocular surface irritation.6,7 inflammation. A recent 
formulation for intracameral use during cataract surgery to potentially assist with mydriasis and reduce pain during 
surgery is available. 
Bromfenac The bromfenac molecule has been altered to make it more lipophilic to improve corneal penetra- 
CURRENTLY AVAILABLE TOPICAL OPHTHALMIC NONSTEROIDAL ANTIINFLAMMATORY DRUGS 
tion, increase duration of action, and enhance COX-2 inhibition.8 It has good ocular penetration with insig- nificant 
systemic reactions following topical adminis- The currently available topical ophthalmic NSAIDs 
 tration. Bromfenac has been found to be 3.7, 6.5, 
and including generic and brand drug names, manufacturer, 
18.0 times more potent as a COX-2 inhibitor than 
diclo- dosage, bottle size, and indications are listed in Table 1. 
fenac, amfenac, and ketorolac, respectively.9–11 It has 
Table 1. Currently available topical ophthalmic NSAIDS in USA and Europe. 
Drug (Generic) Drug (Brand) Manufacturer Dosage 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
USA/ Europe Indication 
Bromfenac Bromday 
0.09% 
Bottle Size (mL) 
Bausch & Lomb QD 1.7 USA Treatment of postop inflammation and 
reduction of pain after cataract surgery Prolensa 0.07% 
Bausch & Lomb QD 1.6, 3 USA 
Xibrom 0.09% ISTA; now generic BID 2.5, 5 USA 
Yellox 0.9% mg/mL 
BID 5 Europe 
Indomethacin Indocollyre 
0.1% 
Croma Pharmaceuticals Bausch & Lomb QID 5 Europe Treatment of postop inflammation and 
reduction of pain after cataract 
surgery Dicofenac Voltaren 0.1% Alcon QID 2.5, 5 USA/Europe Treatment of postop inflammation and 
reduction of pain after cataract 
surgery Flurbiprofen Ocufen 0.03% Allergan 2 h before 
surgery 
2.5 USA/Europe Intraoperative mydriasis 
Ketololac 
tromethamine 
Generic QID 3, 5, 10 USA/Europe Treatment of pain and inflammation 
following cataract surgery 
Ketololac 
tromethamine 
Ketorolac 0.4%, 0.5% Acular 0.5% Allergan QID 3, 5, 10 USA/Europe Treatment of pain and inflammation Acular LS 0.4% 
Allergan QID 5 USA 
following cataract surgery Acuvail, PF 
Allergan QID 0.4 cc vials USA 
Treatment of pain and inflammation 0.45% 
associated with cataract surgery 
Nepafenac Nevanac 
0.1% 
Alcon/Novartis TID 3 USA/Europe Treatment of pain and inflammation 
associated with cataract surgery Ilevro 0.3% 
Alcon/Novartis QD 1.7 USA 
BID Z twice daily; NSAID Z nonsteroidal anti-inflammatory drug; QD Z once daily; QID Z 4 times daily 
 
1370 
REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
been found to be a very potent inhibitor of prosta- 
has been debated, and there are mixed opinions 
about glandin production.12 
the true benefits of administering the drug in this form. 
Diclofenac  In  its  usual  phenyl  acetic  acid  form,  diclofe- nac has poor aqueous solubility; thus, it is typically used in 
the  sodium  salt  form  to  increase  its  solubility.13  Additionally,  at  the  physiologic  pH  of  the  eye,  diclofe-  nac  has 
limited  permeability  and  must  be  buffered  to  a  lower  pH  (6.0)  to  increase  corneal  penetration.7Howev-  er, 
decreasing  the  pH  of  the  solution results in precipi- tation, and thus stabilizers must be used.14 To improve the poor 
aqueous solubility and corneal penetration, an oily formulation (in sesame oil) was created. 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
Intracameral Ketoralac–Phenylephrine 
A recently approved combination of phenylephrine 1.0% and ketorolac 0.3% injectable solution, Omidria, was 
designed to prevent intraoperative miosis and reduce intraoperative pain. It is added to the irrigating solution used 
during cataract surgery and is thus deliv- ered throughout the surgical procedure. Since ketorolac inhibits both COX 
enzymes (COX 1 and COX 2), it is able to dramatically reduce prostaglandin synthesis that oc- Flurbiprofen The 
flurbiprofen molecule is an inhibitor 
curs in the anterior chamber due to surgical trauma. 
of prostaglandin synthesis that is essentially insoluble 
Phenylephrine is an a-adrenergic agent that 
promotes in water. Penetration of flurbiprofen was found to be 
pupillary mydriasis through contraction of the 
radial highest at a pH of 6.4 and decreased as the pH was 
muscle of the iris. In combination, phenylephrine 
and increased into the physiologic range.6 Corneal penetra- 
ketorolac function through 2 different mechanisms 
to tion also increased with the presence of BAK due to an 
promote pupillary dilation during cataract surgery. 
increase in lipid solubility and through the addition of phenyl mercuric nitrate. Adding cyclodextrin has also 
increased corneal permeability. Reducing the pH of the cyclodextrin-containing formulation has further 
OPHTHALMIC USES FOR NONSTEROIDAL ANTIINFLAMMATORY DRUGS improved permeability.15 
Nonsteroidal antiinflammatory drugs block the conver- 
Ketorolac  Ketorolac  is  commercially available as a tro- methamine salt, which has better aqueous solubility than the 
native  ketorolac  molecule.  The  molecule  is  extremely  irritating  to  the  ocular  surface;  thus,  lower  concentrations 
(0.4%)  have  been  advocated  to  reduce  this  bothersome  side  effect.  Reducing  the  pH  of  the  molecule  increases 
corneal  permeation,  so  the  formula-  tion  is  prepared  in  a  phosphate  buffer  that  reduces  the  pH  to  4.5.  Because 
ketorolac  is  a  very  unstable  molecule  that  has  improved  stability  at  higher  pH  (6.5  to  8.5),  there  is  a  fine  balance 
between  efficacy  and  penetration  of  the  medication.16  Preservation  of  the  molecule  with  BAK  (or  similar 
preservatives  except  thimerosal)  also  in-  creases  corneal  penetration  but  may  be  associated  with  increased  ocular 
surface  irritation.  Preparing  ketorolac  with  a  combination  of  BAK  and  ethylenediaminetetra-  acetic  acid  0.01% 
provided  the  best  corneal  penetration  relative  to  other  available  preservatives.17  Ketorolac  is  the  only  topical 
NSAID  available  in  a  preservative-free  formulation  (Acuvail,  0.45%),  which  is  more  gentle  on  the  ocular  surface 
and may be better tolerated in pa- tients sensitive to preservatives such as BAK. 
sion  of  arachidonic  acid  by  COX-1 and COX-2 into pros- taglandin intermediates and subsequently into a variety of 
eicosanoids  including  prostacyclin,  thromboxane,  and  prostaglandins.21,22  Of  these, prostaglandins play a key role 
in  the  manifestation  of  ocular  inflammation.  They  contribute  to  leukocyte  recruitment and migra- tion, and through 
their  effects  on  the  vasculature  (dila-  tion  and  permeability)  may  contribute  to  protein  in  the  aqueous  humor, 
erythema, and hyperemia.23 
Prostaglandins  are  also  implicated  in  causing  smooth-muscle  contraction  in  the  iris.  In  addition  to  blocking  the 
inflammatory  cascade  to  prevent  inflam-  mation  and  pain  postoperatively, NSAIDs play a role in preventing miosis 
during  surgery.24  This  has  been  widely  accepted  as  an  important  role  of  NSAIDs  to  improve  visualization  during 
cataract surgery as poor iris dilation has been associated with an increased risk for complications.25 
Another and arguably the most important use of NSAIDs in cataract surgery is for prevention of CME. Although the 
incidence of pseudophakic CME is rela- tively low, it is problematic when it occurs and raises concern in patients 
who develop it. Most surgeons Nepafenac Nepafenac is a prodrug that rapidly pene- 
use topical steroids with or without topical NSAIDs 
trates the cornea. In comparisons of nepafenac and di- 
as their postoperative medication regimen. 
However, clofenac, nepafenac penetrated the cornea 6 times 
some studies have shown that topical NSAIDs are 
faster in vitro.18 Once the molecule enters the aqueous, 
more effective in preventing CME than steroids 
alone. it is deaminated by intraocular hydrolases to amfenac, a 
Nonsteroidal antiinflammatory drugs have been 
found potent COX-1 and COX-2 inhibitor.19 Studies have 
to be well tolerated with few side effects in 
appropriate shown that nepafenac may be more potent than ketoro- 
patients and are therefore recommended to prevent 
lac or diclofenac.20 The prodrug nature of the molecule 
CME, especially for high-risk patients.26,27 
 
1371 REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
A less known use of NSAIDs is for prevention of 
surgery in which topical NSAIDs were started the 
lens epithelial cell (LEC) proliferation. Nishi et al.28 
day before surgery and continued through the 
postop- first reported the suppressive effect of diclofenac so- 
erative study period, only 2 reports have examined 
dium on LEC metaplasia and proliferation in 1991. 
whether preoperative prophylaxis decreases the 
likeli- When diclofenac sodium was added to cultured hu- 
hood of developing postoperative CME.38,39 The 
first man LECs, the authors found cell degeneration and 
was a double-masked randomized study in which 
ke- death on histopathologic examination. They hypothe- 
torolac 0.4% was administered 3 days, 1 day, or 1 
hour sized that NSAIDs use might deter posterior capsule 
preoperatively and continued for 3 weeks 
postopera- opacification (PCO) by preventing the anterior LECs 
tively.38 The control group received a vehicle 
placebo from multiplying and migrating. 
1 hour before surgery and for 3 weeks after surgery. All patients with a corrected distance visual acuity 
NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND CYSTOID MACULAR EDEMA Pseudophakic CME 
is a complication of cataract sur- gery that occurs secondary to accumulation of fluid in the macula and causes 
swelling with subsequent decreased vision. The incidence of pseudophakic CME varies and depends on how CME is 
defined. Earlier studies using fluorescein angiography have found that CME is not uncommon following cataract 
surgery but is often noted without loss of visual acuity. When loss of visual acuity is used to define the diag- nosis of 
CME, the incidence drops considerably. The incidence of visually significant CME varies from 0.1% to 3.5% in 
general studies that included eyes with comorbidities, such as diabetes mellitus and epi- retinal membranes, and in 
studies that included large- incision extracapsular surgeries.29–37 These are large national studies that would be 
expected to have similar rates of ocular comorbidity. When studies that include significant numbers of large-incision 
sur- geries are removed, leaving cases performed 95% or more of the time by phacoemulsification, the incidence of 
visually significant CME drops to 2% or less.32–36 In 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
worse  than  20/30  at  2  weeks  had  retinal  OCT.  No  pa-  tients  in  the  3-day  or  1-day  ketorolac  group  had  CME.  One 
patient  in  the  1-hour  ketorolac  group  and  3  patients  in  the  placebo  group had CME at 2 weeks. This was somewhat 
compelling but not statistically significant, perhaps due to the small sample size. 
The  second  randomized  prospective  study  of  189  patients  consisted  of  1  group  starting  topical  indometh-  acin 
0.1%  three  days  preoperatively  and  continuing  for  1  month  postoperatively,  1  group  starting  indometh-  acin 
postoperatively  only,  and  the  control  group  receiving  no indomethacin.39 Fluorescein angiography of all patients at 
3  months  showed  no CME in the group treated with indomethacin preoperatively and the pres- ence of CME in 15% 
of  patients  in  the  indomethacin  postoperatively  only  group  (P  Z  .001)  and  33%  in  the  control  group  (P  !  .001). 
Visual acuity at 3 months was also better in the pretreatment group than in the other 2 groups (P Z .005). 
 Both  studies  were  limited  by  a  small  sample  size  and  the use of topical steroid by all participants. However, they 
suggest that preoperative use of topical NSAIDs might be beneficial in preventing CME. 
1  study,36  the  incidence  of  CME  detectable  by  optical  coherence  tomography  (OCT)  was  0.1%  following 
phacoemulsification. 
Cystoid  macular  edema  is  thought  to be caused by the release of inflammatory mediators such as prosta- glandins 
during  cataract  surgery,  which  can  lead  to  an  increase  in  vascular  permeability  with  subsequent  edema  in  the 
macula.  This  condition  has  been  noted  more  frequently  in  patients  with  any  type  of  increased  postoperative 
inflammation  or  a  complicated  cataract  surgery  that  can  lead  to  increased  inflammation.  Due  to  the  relationship 
between  prostaglandin  release  and  CME,  using  topical  corticosteroids  and  topical  NSAIDs  to  reduce postoperative 
inflammation following cata- ract surgery may prevent CME. 
Postoperative Use for Prevention of Cystoid Macular Edema 
The  evaluation  of  NSAIDs  for  the  prevention  of  CME  includes  older  NSAIDs  as  well  as  newer  NSAID 
medications.  Diclofenac  has  been  around  the  longest.  Miyake  et  al.40,41found  that diclofenac was more effec- tive 
in  preventing  CME  than  a  topical  corticosteroid  eyedrop,  fluorometholone. Asano et al.42 also found a reduction in 
angiographic  CME  when  comparing  topical  diclofenac  and  betamethasone.  Newer  NSAIDs  that  have  been 
evaluated  in  this  manner  include  nepa-  fenac.  Miyake  et  al.43  found  that  nepafenac  0.1%  was  more  effective  in 
preventing  CME  following  cataract  surgery than fluorometholone 0.1%. Another newer NSAID is bromfenac 0.1%. 
Miyanaga et al.44 reported 
Preoperative Use for Prevention of Cystoid Macular Edema 
that bromfenac 0.1% was effective in decreasing ocular inflammation following cataract surgery. Wang et al.45 
showed that bromfenac 0.1% was superior to both flu- Although numerous studies have examined the inci- 
orometholone and dexamethasone in preventing 
CME dence of postoperative CME following cataract 
following phacoemulsification. 
 
1372 
REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
Some older topical NSAIDs are officially approved 
Another recent study that retrospectively 
reviewed for the maintenance of mydriasis during cataract sur- 
more than 16 000 phacoemulsification surgeries by 
17 gery and for controlling postoperative pain. The use 
surgeons defined clinical postoperative macular of 
these medications for CME prevention is therefore 
edema as a visual acuity of 20/40 or worse with 
confir- considered off-label. The newer NSAIDS have been re- 
matory findings on OCT.49 Compared with eyes 
that formulated to increase their potency and to allow less 
received prophylaxis with topical prednisolone 
alone, frequent dosing postoperatively and have also been 
the eyes that were additionally treated with 
postoper- approved by evaluating their effect on anterior 
ative NSAIDs experienced a 55% reduction in the 
inci- segment inflammation as gauged by cell and flare as 
dence of macular edema. well as postoperative pain. 
Another important question is whether the combi- 
Kessel et al.26 reviewed the literature regarding the ef- 
nation of NSAIDs and corticosteroid is more 
effective ficacy of topical steroids and topical NSAIDs in reducing 
than the use of NSAIDs alone. In their 
metaanalysis, postoperative inflammation and preventing CME. They 
Wielders et al.46 concluded that although a 
combina- identified 7 randomized clinical trials that compared the 
tion of NSAIDs and corticosteroids significantly 
prevalence of CME following cataract surgery with the 
reduced the chances of developing CME compared 
use of topical steroids or NSAIDs. One study comprised 
with topical corticosteroids alone, the combination 
patients with diabetes and was excluded from the au- 
did not show any benefit over topical NSAIDs in an 
in- thors' analysis. A review of the other 6 studies in a meta- 
direct treatment comparison. They suggested that a 
analysis of the incidence of CME found that 4 evaluated 
topical NSAID should always be part of the 
preventive the presence of CME by fluorescein angiogram 5 weeks 
treatment after surgery in nondiabetic patients, but 
after surgery and the remaining 2 evaluated the presence 
whether the use of corticosteroid eyedrops can be of 
CME using retinal OCT evaluation 1 month after cata- 
avoided cannot be concluded from the results. ract 
surgery. When the patients receiving steroids were 
The duration of postoperative treatment using an 
compared with those receiving NSAIDs, the metaanaly- 
NSAID for the prevention of CME is not clear as 
there sis found that the incidence of CME was higher at 
are no good randomized studies evaluating this 
issue; 1 month in the steroid-only patients (25.3%) versus the 
however, there is a trend toward prolonged use of 
NSAID-only patients (3.8%). Further analysis of the 
NSAIDs for 4 to 6 weeks postoperatively following 
un- studies showed that so-called potent and weaker steroids 
eventful cataract surgery to prevent CME. The use 
of were less effective than NSAIDs in preventing CME.26 
NSAIDs can be prolonged for up to 12 weeks in 
poten- An even more recent systematic review and meta- 
tially high-risk patients.50 analysis of the 
prevention of CME after cataract sur- gery in nondiabetic and diabetic patients has been reported by Wielders et 
al.46 They described 17 trials that reported incidence rates and found that topical 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
Postoperative Edema 
Use for Treatment of Cystoid Macular 
NSAIDs significantly reduced the odds of developing 
As important as the prevention of CME is the 
treat- CME compared with topical corticosteroids in nondia- 
ment of CME if it develops after cataract surgery. 
Cys- betic and mixed populations. A combination of topical 
toid macular edema can be subclinical and 
relatively corticosteroids and NSAIDs notably reduced the odds 
self-limiting, with little effect on visual acuity. 
Studies of developing CME compared with topical corticoste- 
looking at the prevalence of CME have reported 
that roids alone in nondiabetic and diabetic patients. 
when fluorescein angiography is used to make the 
diag- The question of whether a combination of an NSAID 
nosis, the prevalence is much higher than when loss 
of and a steroid is more effective than a steroid alone was 
visual acuity is used to make the diagnosis. Thus, 
many evaluated in a recent study by Zaczek et al.47 The 
milder subclinical episodes of CME are 
unrecognized study found that a combination of nepafenac plus 
and resolved without treatment. However, it is 
impor- dexamethasone reduced subclinical macular swelling 
tant that patients with clinically significant CME be 
and inflammation compared with dexamethasone 
treated before the edema can damage the macula.51 
alone. However, the low rate of CME in this study 
The use of NSAIDs to treat CME has a long 
history, made it difficult to find a significant difference when 
with reviews of the treatment of aphakic or pseudo- 
looking at frank CME. The authors used an increase 
phakic CME dating back to the 1980s.52 Although 
the in macular thickness evaluated with OCT as a surro- 
use of topical NSAIDs is critical in the treatment of 
gate marker for the development of CME. Wittpenn 
CME, there is some evidence that combination 
therapy et al.48 found that adding perioperative ketorolac to 
of a topical NSAID and a corticosteroid may act 
syner- postoperative prednisolone reduced the incidence of 
gistically and be superior to either medication used 
CME and macular thickening in cataract surgery pa- 
alone.53 A small randomized controlled study tients 
already at low risk for CME. 
compared topical ketorolac and topical prednisolone 
 
1373 REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
with combination therapy for the treatment of pseudo- 
was treated with latanoprost and fluorometholone 
phakic CME.54 The authors found that the combination 
and 1 group with latanoprost and diclofenac. At of 
the 2 medications led to improvement in Snellen vi- 
5 weeks, angiographic CME was seen in 30 of 37 
sual acuity over 3 months. Patients treated with either 
eyes in the PGA–steroid group and 3 of 35 eyes in 
combination therapy or ketorolac alone responded 
the PGA–NSAID group. No difference in visual 
acuity more quickly than patients in the corticosteroid group. 
was found. The authors concluded that latanoprost 
This early study is indicative of a possible synergistic ef- 
disrupts the blood–aqueous barrier (BAB) and in- 
fect of combining NSAIDs and corticosteroids. Howev- 
creases the incidence of angiographic CME after 
cata- er, it is difficult to assess the efficacy of steroids in CME 
ract surgery and that these effects can be prevented 
as many of the results are confounded by concomitant 
when an NSAID is given concurrently.60 use of 
NSAIDs in many of the studies reported.55 
In clinical practice, many ophthalmologists discon- 
There are no recent reports of the use of oral 
tinue PGA around the time of cataract surgery 
despite NSAIDS in the treatment of postoperative CME. How- 
the lack of evidence that this influences visual out- 
ever, in their 1979 study of the use of oral indometh- 
comes. Fortunately, cataract surgery alone may 
result acin pretreatment on aphakic CME,56 Klein et al. 
in IOP reduction, decreasing the need for topical 
ther- reported a decrease in the incidence of aphakic CME 
apy. In addition, other agents such as a fixed 
dorzola- compared with the incidence in a control group. There 
mide–timolol combination are more effective than 
has also been 1 report of an intravitreal NSAID used 
PGAs in lowering IOP immediately after surgery.61 
for the treatment of CME of various etiologies. Sohei- 
Prostaglandin analogues can be added later as 
needed lian et al.57 reported the use of intravitreal diclofenac 
for IOP control in combination with an NSAID if 
used 500 mg/0.1 mL in 1 eye with pseudophakic CME. 
in the first few weeks after surgery and on their 
own if While no toxic effects were noted, there was no signif- 
added later. A study of 41 eyes by Moghimi et al.62 
icant improvement in the central macular thickness. 
found that latanoprost started at least 4 months after 
Chronic CME can be difficult to treat and often re- 
uneventful cataract surgery did not cause angio- 
quires the use of NSAIDs in combination with cortico- 
graphic CME or a change in macular thickness. 
steroids or other treatments including antiangiogenesis 
Although the evidence for or against using PGAs 
in drugs. Warren et al.58 evaluated various combination 
the cataract perioperative period is limited, a 
general therapies including different topical NSAIDs or placebo 
statement can be made that when PGA use is 
required combined with intravitreal steroids and antiangiogene- 
in the early postoperative period, the concomitant 
use sis treatments. They concluded that the NSAID therapy 
of an NSAID may reduce the risk for angiographic 
helped the improvement produced by the steroids and 
CME. antivascular endothelial growth factor 
therapy. The NSAIDs also showed a benefit in reducing retinal thick- ness compared with a placebo in this study. 
Effectiveness of Nonsteroidal Antiinflammatory Drugs in Preventing Pseudophakic Cystoid Macular 
SPECIAL CONSIDERATIONS FOR GLAUCOMA PATIENTS HAVING CATARACT SURGERY Perioperative 
Use of Prostaglandin Analogs and the Need for Nonsteroidal Antiinflammatory Drugs 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
Edema in the Glaucoma Patient 
The effectiveness of NSAIDs in preventing CME af- ter standalone cataract surgery in glaucoma patients has not 
been extensively studied. The occurrence of clinically significant CME after extracapsular cataract Prostaglandin 
analogues (PGAs) are the most 
surgery in glaucoma patients has been reported to 
be commonly prescribed ophthalmic medication. Many 
high (11.6%), although no comparable comparison 
patients having cataract surgery are on a topical 
group was studied.63 However, it is unclear 
whether PGA for the treatment of glaucoma and/or ocular hy- 
 this finding is related to the use of specific 
glaucoma pertension. Several case reports and 1 case series have 
medications available in the mid-1980s when this 
shown an association between PGA use and postoper- 
report was published. A subsequent retrospective 
re- ative CME after uneventful cataract surgery, which is 
view by Law et al.64 did not find a notable 
difference consistent with the mechanism of PGAs in their role of 
in the incidence of clinical CME after standalone 
cata- increasing vascular permeability. In the series by Yeh 
ract surgery between glaucoma patients (700 
[5.14%]) and Ramanathan,59 NSAIDs were not used after sur- 
and nonglaucoma patients (553 [5.79%]). This 
study gery and CME developed in eyes receiving latanoprost 
also found that glaucoma medications used 
preopera- only. The CME resolved in all cases after latanoprost 
tively or postoperatively were not associated with 
clin- was discontinued and ketorolac was initiated. 
ical CME (P O.05). The lack of prospective 
multicenter In an open-label trial, Miyake et al.60 compared 
studies with an appropriate control group and a 
clear glaucomatous eyes after cataract surgery; 1 group 
definition for macular edema limits any concrete 
 
1374 
REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
comparisons of the incidence of CME between glau- 
syndrome, is an additional risk factor for the 
develop- coma patients and nonglaucoma patients having cata- 
ment of CME.75 Considering all the potential risk 
ract extraction. 
factors for CME, the use of preoperative and postoper- ative NSAIDs in individuals with PXF syndrome 
Nonsteroidal Antiinflammatory Drugs with 
should be considered.71 Combined Cataract and 
Glaucoma Procedures 
The role and value of NSAIDs in the perioperative management of cataract surgery in combination with 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
TREATMENT PARADIGMS Monotherapy for Postoperative Inflammation glaucoma surgery are incompletely 
characterized 
Although a combination of topical NSAIDs and 
ste- in the medical literature. A single small study65 
roids appears to be more effective than either agent 
compared diclofenac and dexamethasone following 
alone in the treatment of CME, a more interesting 
ques- combined cataract and trabeculectomy procedures, re- 
tion is how NSAIDs alone compare with steroids in 
the porting higher and broader blebs and a trend toward 
treatment of inflammation following cataract 
surgery. lower IOP in the NSAID group than in the steroid 
Monotherapy with NSAIDs may be extremely 
useful group. Given the paucity of data to guide the use of 
in patients at risk for adverse events from topical 
ste- NSAIDs following cataract surgery combined with 
roids. This includes steroid responders, brittle 
diabetics trabeculectomy, tube shunt implantation, or mini- 
(sensitive to systemic absorption), and individuals 
with mally invasive glaucoma procedures, NSAID use 
recurrent herpetic keratitis and delayed wound 
healing. should be based on the nature of surgery planned, in- 
A recent study comparing the effectiveness of 
topical dividual patient characteristics, and the anticipated 
bromfenac and prednisolone acetate found that the 
risks and benefits of their use. 
NSAID was as effective as the topical steroid in control- ling postoperative inflammation in routine cataract sur- 
Nonsteroidal Antiinflammatory Drug Use in Cataract Patients with Pseudoexfoliation Syndrome 
To our knowledge, there are no published studies of 
gery.76  The  potential  for monotherapy with NSAIDs offers a simplified effective postoperative regimen without the 
possible adverse effects of topical steroids.77 
the  role  of  NSAIDs  in eyes with pseudoexfoliation (PXF) syndrome having cataract surgery. Despite this, the use of 
NSAIDs  in  some  of  these  patients  may  be  warranted.  Pseudoexfoliation  syndrome is the most common identifiable 
cause  of  open-angle  glaucoma.66  Although  cataract  extraction  will  have  a  long-term  beneficial  effect  in  lowering 
IOP  in  patients  with  PXF  syndrome,67–69  the  eyes  of  these  patients  may  have  significant  IOP  elevation  in  the 
immediate  postoperative  period.70  Many  of  the  patients  may  be  on  multiple  topical  glaucoma  medications,  and 
some  may  require  continuation or addition of PGAs to con- trol their IOP. As stated previously, the concomitant use 
of NSAIDs with PGAs may reduce the incidence of anterior chamber flare and angiographic CME in these patients. 
Cataract  surgery  has  been  demonstrated  to  have  a  notably  higher  incidence  of  surgical  complications  in  patients 
with  PXF  syndrome  than  in  those  without  this  condition.  The  complications  stem  from  risks  such  as  small  pupils, 
shallow  anterior  chambers,  pos-  terior  vitreous  pressure, vitreous prolapse, zonular dialysis, and capsule fragility.71 
Many of the risks 
Universal Versus Selective Nonsteroidal Antiinflammatory Drugs 
There are 2 basic approaches to the use of NSAIDs in patients having cataract surgery. The universal approach uses 
NSAIDs in combination with steroids in all patients, whereas the selective method reserves NSAIDs for high-risk 
cases only. High-risk cases include patients more likely to develop macular edema following surgery such as 
individuals with diabetes,78 uveitis,79 radiation retinopathy, vascular occlusions,27 epiretinal membranes,27 or 
retinitis pigmentosa80 or individuals who developed CME in their fellow eye. The selective approach would also be 
reserved for routine patients who developed CME following sur- gery or had excessive iris manipulation during 
surgery. The selective method is designed to prevent potential NSAID adverse side effects in eyes at low risk for the 
development of CME and also to lower the financial burden of expensive topical NSAIDs. Both universal and 
selective approaches to incorporating NSAIDs have validity, and neither should be considered a stan- dard of care in 
modern cataract surgery. and the underlying pathology of PXF syndrome with an altered BAB can lead to 
significant postoperative inflammation in the early postoperative period.72,73 
ADVERSE EFFECTS OF TOPICAL NONSTEROIDAL ANTIINFLAMMATORY DRUGS Eyes with an altered 
BAB would be expected to have 
Systemic absorption of most topical NSAIDs is 
mini- a greater incidence of CME.74 In addition, iris trauma, 
mal. Consequently, topical administration is seldom 
which is more likely to occur in eyes with PXF 
associated with the same side effects as oral 
 
1375 REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 
administration. Nevertheless, documented NSAID al- 
rosacea, keratitis sicca, complex or repeat 
ophthalmic lergies, cross-reactions, and intolerances require 
surgeries, and concomitant use of other medications 
consideration and discussion with the patient if topical 
that inhibit healing or are toxic to the epithelium.91 
equivalents are to be used. There are many reports of 
Frequent or prolonged dosing, even in low-risk 
eyes, re- NSAIDs worsening asthma, but almost all were in pre- 
quires a careful history, examination, and moni- 
existing asthmatics.81–83 
toring.91,101,103 Continued misuse of topical 
NSAIDs Burning, stinging, conjunctival injection, and con- 
may contribute to continued adverse events.21 tact 
dermatitis are the most commonly reported 
The most worrisome side effects of topical 
steroids adverse side effects of NSAIDs.84,85 Most topical 
in cataract surgery would be steroid-induced glau- 
NSAIDs are weakly acidic to improve corneal penetra- 
coma first, followed by delayed wound healing, 
ocular tion. As such, they are naturally more irritating than 
rebound inflammation, and opportunistic infections 
more neutral topical medications. 
including fungi and herpes simplex virus. 
Nonsteroidal antiinflammatory drugs have been re- ported to cause superficial punctate keratitis,86 subepi- thelial 
infiltrates and immune rings,87 stromal 
CONCLUSION infiltrates,88 and epithelial 
defects.89 In 1999, the 
Since the approval of flurbiprofen by the FDA in 
1988, American Society of Cataract and Refractive Surgery 
ophthalmic NSAIDs have enjoyed an almost 
30-year received several reports of corneal stromal ulcers in 
history of significant safety and demonstrable effec- 
patients using topical NSAIDs. In response, a generic 
tiveness. Any medication can place patients at risk 
form of diclofenac (Falcon Pharmaceuticals) was with- 
for side effects. However, given the extraordinary 
drawn from the market even though several of the 
number of annual doses of topical NSAIDs, the fre- 
published early cases also implicated nongeneric Vol- 
quency of adverse events appears to be 
exceptionally taren.21 Shortly thereafter, a retrospective review of 
low and acceptable. several cases suggested that 
coexistent ocular 
Topical NSAIDs have been useful in preventing 
in- morbidity was more to blame than simple drug 
traoperative miosis, postoperative inflammation, 
and toxicity.90 However, after withdrawal of the Falcon 
the development of CME. In addition, they may 
product, reports to the U.S. Food and Drug Adminis- 
modulate postoperative pain and inhibit the 
prolifera- tration (FDA) of severe corneal events associated 
tion of LECs that are responsible for PCO. Nonste- 
with NSAID use markedly declined.91 One group sug- 
roidal antiinflammatory drugs have a synergistic 
gested the inactive ingredients of the generic product 
effect with steroids on the development of CME but 
(which were different from those of Voltaren) as 
may be used alone in high-risk eyes in which 
topical possible etiologic factors.92 Recently, a comparative 
steroid use may be detrimental. effectiveness 
retrospective study of over 4500 eyes 
Whether used solely in eyes at increased risk for 
the that received generic diclofenac, flurbiprofen, or ketor- 
development of CME or universally in all patients 
hav- olac revealed no corneal melts or other significant 
ing cataract surgery, the benefits of these topical 
med- corneal events other than 1 instance of temporary 
ications should be assessed by each clinician as 
mild corneal thinning in an eye treated with predniso- 
appropriate for their particular practice or patient 
pop- lone alone in a patient with rheumatoid arthritis.49 
ulation. This is especially true for many glaucoma pa- 
Every topical NSAID has been implicated in severe 
tients who may be using PGAs at the time of 
cataract corneal events.90,93–100 The common denominator in 
surgery or who may be prone to CME due to 
compli- almost all cases was a preexisting epithelial defect.101 
cated surgery from PXF syndrome. A thorough 
under- Topical NSAIDs may be an additional trigger 
standing of the potency, approaches for avoiding 
and following cataract surgery that turns an epithelial 
treating CME, and adverse reactions and 
contraindica- defect into a melt in eyes that are at risk for ulcera- 
tions of these medications should help surgeons 
maxi- tion.97 The role of NSAIDs in wound healing is still 
mize their benefits and improve surgical outcomes 
to be elucidated. Of particular concern is diclofenac 
and patient satisfaction. blockage of lipoxygenase 
enzymes since this can indi- rectly inhibit the keratocyte proliferation that is neces- sary for wound healing.102 
Due to the potential local side effects of topical 
J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 
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Financial Disclosure 
99. Lin JC, Rapuano CJ, Laibson PR, Eagle RC Jr, Cohen EJ. 
Drs. Braga-Mele, Donaldson, Henderson, and Kahook are 
con- Corneal melting associated with use of topical nonsteroidal 
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Henderson, anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 
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Allergan, Inc. None of the other authors has a financial or 
proprietary Rev Ophthalmol 1996; 14:124–128. Available at: http://www. 
interest in any material or method mentioned. 
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