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Diclofenac sodium 0.1% ophthalmic solution: Update on pharmacodynamics,

clinical interest and safety profile

Article  in  Expert Review of Ophthalmology · April 2008

DOI: 10.1586/17469899.3.2.139

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 Drug Profile

Diclofenac sodium 0.1%

ophthalmic solution: update on
pharmacodynamics, clinical
interest and safety profile
Expert Rev. Ophthalmol. 3(2), 139–148 (2008)

Bahram Bodaghi Diclofenac sodium 0.1% ophthalmic solution has a long, well-proven track record as a potent,
Service d’Ophtalmologie, efficacious, topical, ocular anti-inflammatory agent, especially in the control of miosis during
Hôpital Pitié-Salpétrière, surgery, postsurgical inflammation of the anterior segment, cystoid macular edema and
Paris, France inflammation owing to noninfectious conjunctivitis such as allergic conjunctivitis. Owing to its
Tel.: +33 142 163 211 analgesic properties, it is also widely used for short-duration treatment in pain associated with
Fax: +33 142 163 218 photorefractive keratectomy and corneal erosion. Therefore, it has been approved by health
bahram.bodaghi@psl.aphp.fr authorities for a wide range of indications, depending on each country. It has been shown to
be at least as effective as other nonsteroidal anti-inflammatory drugs and corticosteroids.
Diclofenac is a well-tolerated product and the few serious corneal adverse events that do
occur could be avoided by good prescriptive practice and careful follow-up of patients at-risk.
This review summarizes the available data on pharmacokinetics and pharmacodynamics, as
well as the efficacy, safety and regulatory aspects related to diclofenac.

KEYWORDS: analgesia • diclofenac • eye • ocular inflammation • preservative

Diclofenac sodium is a NSAID with well-estab-
lished medicinal uses, and recognized efficacy
and safety. It became available as an eye drop for-
mulation in the early 1990s. Since then, several
topical ophthalmic formulations have become
available worldwide with broad indications,
which can be classified into two main areas.
The first indication is the treatment of ocular
inflammation, including control of miosis dur-
ing surgery, postsurgical inflammation of the
anterior segment, cystoid macular edema (CME)
and inflammation due to noninfectious conjunc-
tivitis such as allergic conjunctivitis. If needed,
this anti-inflammatory treatment may be pro-
longed under strict supervision for several weeks.
The alternative treatments for inflammation
include the other NSAIDs, steroids and antialler-
gics. NSAIDs do not produce the classical
adverse effects associated with steroids, such as
elevation of intraocular pressure (IOP), cataract
and aggravation of ocular infection.
Treatment of ocular pain associated with
photorefractive keratectomy (PRK) and cor-
neal erosion is the other indication. Corneal
analgesia should be used only for few days.
There is no alternative therapy for analgesia
as misuse of anesthetics may lead to serious
neurotrophic keratitis.
Diclofenac has a well-studied history of effi-
cacy in both of these fields. Postmarketing sur-
veillance has highlighted that some changes in
ingredients may dramatically alter the safety
profile of generic formulations of topical oph-
thalmic diclofenac. It also shows the importance
of compliance to good prescribing practice.
Overview of the market
Diclofenac is widely distributed in Europe and
the USA under several brand names and in a
variety of formulations (TABLE 1).
Introduction to diclofenac
Diclofenac is a NSAID available in several topi-
cal ophthalmic formulations each including var-
ious excipients that play a major role in the
safety profile [1].

www.future-drugs.com 10.1586/17469899.3.2.139 © 2008 Future Drugs Ltd ISSN 1746-9899 139

 Drug Profile Bodaghi

Table 1. Formulations of diclofenac 0.1% ophthalmic solution registered by country.

Multidose preserved formulations
Country Thiomersal* Sorbic acid‡ BAK§ MD nonpreserved# UD nonpreserved¶
Austria – – Voltaren Ophtha – Voltaren Ophtha
Belgium Voltaren Ophta – – Dicloabak –
Denmark – – Voltaren Ophtha – Voltaren Ophtha
Diclofenacnatrium Stulln**
Finland – – Voltaren Ophtha – Voltaren Ophtha
France Voltarene – – Dicloced Voltarene
Germany – – Voltaren Ophtha – Voltaren
Ophtha-sine
Difen-Stulln UD**
Italy Diclotears – Voltaren Ofta Dicloabak Voltaren Ofta
Dropflam Diclocular‡‡ Diclocular§§
Dicloftil## Dicloftil
Diclotears¶¶
Luxembourg Voltaren Ophta – – Dicloabak –
Netherlands – – Naclof Dicloabak Naclof
Poland Naclof – Difadol*** Dicloabak
Portugal – – Voltaren Dicloabak –
Spain – – Voltaren Dicloabak Voltaren Colirio
Diclofenaco–lepori‡‡‡ Diclofenaco-Lepori§§
Sweden – – Voltaren ophtha – Voltaren ophtha
UK – – Voltarol ophtha – Voltarol ophtha
USA – Voltaren ophthalmic – – –
*
Thiomersal preserved: diclofenac sodium 0.1% preserved with thiomersal; excipients: macrogolglycerol ricinoleate, trometamol, boric acid and water.
‡
Sorbic acid preserved: diclofenac sodium 0.1% preserved with sorbic acid; excipients: polyoxyl 35 castor oil, boric acid, tromethamine, disodium edetate and water.
§
BAK preserved: diclofenac sodium 0.1% preserved with BAK; excipients: hydroxypropyl-y-cyclodextrin, hydrochloric acid, disodium edetate, propylene glycol,
trometamol, tyloxapol , and water.
#
Multidose nonpreserved diclofenac sodium 0.1% in Abak multidose container; excipients: macrogolglycerol ricinoleate, trometamol, boric acid and water. Approved
in Mutual Recognition Procedure in 2006.
¶
Unidose nonpreserved; diclofenac sodium 0.1%; excipients: macrogolglycerol ricinoleate, trometamol, boric acid and water for injections.
**
Diclofenac sodium 0.1%; excipients: macrogolglycerol ricinoleate, trometamol, boric acid, sodium hydroxide and water.
‡‡
Diclofenac sodium 0.1% preserved with BAK; excipients: lysine monohydrate, boric acid, sodium borate, macrogolglycerol ricinoleate, sodium chloride and water.
§§
Diclofenac sodium 0.1%; excipients: lysine monohydrate, boric acid, sodium borate, macrogolglycerol ricinoleate, sodium chloride, sodium edetate and water.
##
Diclofenac sodium 0.1% preserved with BAK; excipients: sodium edetate, boric acid, sodium borate, povidone, macrogolglycerol ricinoleate, arginine and water.
¶¶
Unidose formulations similar to the multidose with the same brand, except the preservative.
***
Diclofenac sodium 0.1% preserved with BAK; excipients: unknown list.
‡‡‡
Diclofenac sodium 0.1% preserved with BAK; excipients: L-lysine monohydrate, boric acid, sodium borate, macrogolglycerol ricinoleate, sodium chloride, sodium
edetate and water.
BAK: Benzalkonium chloride; MD: Multidose; UD: Unidose.

Diclofenac sodium is a white or slightly yellowish, slightly

Chemistry
Diclofenac sodium
Diclofenac sodium is a phenylacetic acid derivative and acts as an
inhibitor of prostaglandin (PG) synthetase. The chemical names
for diclofenac sodium are:
• 2-[(2,6 dichlorophenyl)amino] benzene acetic acid monosodium
• Sodium [2-[(2,6 dichlorophenyl)amino]phenyl] acetate
• 2 - [(2,6 dichloroanilino)phenyl] acetic acid sodium
It has an empirical formula of C14H10Cl2NNaO2 and a molecular
weight of 318.1 Da.
hygroscopic crystalline powder. It is sparingly soluble in water,
freely soluble in methanol, soluble in alcohol and slightly soluble
in acetone.
Available formulations
The first available diclofenac formulations used sorbic acid or
thiomersal, a mercury-containing preservative (TABLE 1). Currently,
another formulation is preserved with benzalkonium chloride with
hydroxypropylgamma cyclodextrin [2]. The DSOS formulation,
which contained another quaternary ammonium (polyquaternium)
and tocophersolan, was removed from the market in 1999 [3].

140 Expert Rev. Ophthalmol. 3(2), (2008)

 Diclofenac sodium 0.1% ophthalmic solution
All the preservative-free formulations
were firstly packaged in single-dose units, Table 2. In vitro human whole blood assays for inhibition of COX-2
but recently the ABAK® container has (endotoxin-induced PGE2 production) and COX-1 (thromboxan B2).
been developed that delivers eye drops NSAIDs
without preservatives from a multidose
Diclofenac
container [4,5]. All preservative-free formu-
lations contain the same ingredients as the Indomethacin
thiomersal-preserved reference product, Ketorolac
except the preservative.
Flurbiprofen
Naproxen
Pharmacodynamics
COX: Cyclooxygenase coenzyme; PG: Prostaglandin.
Anti-inflammatory effect Data from [13].
Prostaglandins are released by trauma-
tized tissue, increasing the permeability of the blood–aqueous
barrier so that proteins and inflammatory cells pass into the
aqueous humour, inducing postoperative inflammation [6–9].
Expansion of the process to the posterior segment may lead to
a disruption of the blood–retinal barrier, which results in
CME [10]. In addition, the vasodilatory effect of PG induces
hyperemia in the conjunctiva. PGs also cause the iris sphinc-
ter to constrict (miosis) [11]. The pharmacologic effect of most
NSAIDs is based on an inhibition of the cyclooxygenase
coenzyme (COX-1 and -2) activity on arachidonic acid,
which subsequently inhibits the formation of PGs.
COX-1 and -2 form PG from arachidonic acid at significantly
different rates and in response to different triggers. COX-1, a
physiological enzyme, is relatively constantly expressed in tissue.
It enables the production of PGE2, which regulates normal cell
activity and maintains physiological functions [12]; its role is
inflammation independent. Normally, little or no COX-2 is
found in resting cells but its expression can be increased dramat-
ically. Therefore, the control of COX-2 is of greater relevance
when attempting to control inflammation-induced PG produc-
tion [12]. In contrast to most other NSAIDs, diclofenac inhibits
COX-2 more selectively than COX-1, with a COX-2:COX-1
ratio of 0.36 (TABLE 2) [13]. It is thus well targeted to treat the
inflammatory response and has the additional benefits of leaving
the COX-1-controlled physiological functions relatively undis-
rupted [12]. Other topical NSAIDs, such as ketorolac, indometh-
acin and flurbiprofen, have an inhibition predominantly toward
COX-1 with a COX-2 /COX-1 ratio of 2.61, 2.9 and 14.6,
respectively (TABLE 2) [13].
The pharmacodynamic effects of diclofenac have mainly
been illustrated in the post-cataract surgery model of inflam-
mation in man. Diclofenac was initially shown to inhibit the
blood–aqueous barrier breakdown using fluorophotometry
[9,14] and more recently by laser flare meter [15,16]. There is sig-
nificantly less anterior chamber flare in patients who received
diclofenac both pre- and postsurgery than in those who only
received diclofenac after surgery [17,18]. A preservative-free for-
mulation was also evaluated by laser flare meter and unpre-
served diclofenac was shown to exert the same efficacy as the
preserved product [18].
www.future-drugs.com
Drug Profile
COX-2 COX-1 Ratio COX2:COX1
0.05 ± 0.01 0.14 ± 0.03 0.36
0.46 ± 0.06 0.16 ± 0.01 2.88
0.86 ± 0.14 0.33 ± 0.05 2.61
6.42 ± 0.16 0.44 ± 0.07 14.59
73.74 ± 3.12 7.76 ± 0.83 9.50
Analgesic effect
Although mechanisms of pain after corneal wound are not fully
understood, it is believed that PGs cause hyperalgesia by sensitizing
pain nerve endings. Diclofenac’s effects on decreased corneal sensa-
tion are the result of its combined indirect effect on decreasing PG
production and its direct effect on the corneal nociceptive fibers
themselves [19]. This analgesic effect on corneal sensitivity has been
shown in recent clinical trials using the sophisticated gas esthesi-
ometer developed by Belmonte. In young healthy subjects, one
drop of diclofenac rapidly reduced the magnitude of the sensations
evoked by mechanical, chemical and thermal stimulation of the
cornea, without significantly modifying the detection threshold of
the different stimuli [20]. A similar phenomenon was shown in 20
Sjogren’s syndrome patients with epithelial corneal defects treated
with indomethacin or diclofenac (one drop, three-times daily) [21].
Pharmacokinetics & metabolism
Diclofenac is quickly absorbed into the aqueous humor follow-
ing ocular instillation. After a single drop of 0.1% solution
instilled onto the cornea, Cmax is approximately 82 ng/ml, occur-
ring 2.4 h after instillation. The value was 60 ng/ml for flurbi-
profen. Concentrations remain above 20 ng/ml for over 4 h. The
mean residence time for the drug within the aqueous humor is
7.4 h [22]. This good ocular penetration could explain the potent
efficacy of diclofenac as an anti-inflammatory for the eye.
Metabolism and subsequent urinary and biliary excretion of glu-
curonide and sulphate conjugates are the main routes of diclofenac
elimination. The principal metabolite, 4´-hydroxy diclofenac,
comprises 20–30% of the dose recoverable in urine. A further
10–20% is accounted for by four other inactive metabolites and
5–10% by conjugates of unchanged diclofenac [23]. Like other
NSAIDs, diclofenac is 90–99% protein-bound and is, therefore,
easily recovered from ocular tissues after topical administration [24].
Clinical efficacy
Since its first authorized claim for inhibition of per-operative
miosis during cataract surgery, the indications of diclofenac
sodium 0.1% ophthalmic solution have been extensively
141
 Drug Profile Bodaghi

expanded to the treatment of various types of inflammation
and pain (TABLES 3 & 4). All indications approved in Europe and
the USA are presented in TABLE 4.
Miosis during cataract surgery
Diclofenac eye-drops are used as an adjunctive to standard pre-
operative dilating regimens, such as phenylephrine, tropica-
mide and adrenaline. During cataract surgery, onset of miosis
linked to the effect on the iris sphincter of PGs and other medi-
ators is effectively inhibited by diclofenac when administered
preoperatively [11,25,26].
Prevention of postoperative inflammation following
cataract surgery
Intraocular inflammation following cataract surgery must be
controlled in order to avoid complications such as anterior
segment uveitis with increased IOP, posterior synechia with
possible mechanical consequences on aqueous humor flow
and CME that can interfere with visual recovery. Numerous
clinical trials have been performed comparing diclofenac
with the range of corticosteroids that were traditionally the
drugs of choice to treat postoperative inflammation and the
results are unequivocal: diclofenac is as efficacious as corti-
costeroids in treating post operative inflammation [7,27–29], if
not more so [14,15,30]. Some examples of these results are
described here.
In a double-masked fluorophotometric study evaluating
124 patients undergoing cataract surgery, there was signifi-
cantly less leakage of the blood–aqueous barrier in patients
treated with diclofenac compared with those treated with pred-
nisolone acetate 1.0% [14]. In another double-masked study
with 116 patients undergoing phacoemulsification, there was
no statistically significant difference between the diclofenac and
prednisolone groups for anterior chamber cells and flare, as well
as conjunctival hyperemia; with similar tolerance for both study
medications [28].
The anti-inflammatory effect of diclofenac also compared
favorably with fluorometholone 0.1% in 106 patients under-
going phacoemulsification followed by implantation of a
foldable acrylic IOL [15]. The amount of anterior chamber
flare, as well as the incidence of CME, was significantly lower
with diclofenac than with fluorometholone.
When diclofenac was compared with dexamethasone phos-
phate 0.1% in a double-masked study, anterior chamber flare
values in the two groups did not significantly differ at any time.
However, aqueous cell counts were significantly lower in the
diclofenac group 30 days after cataract surgery [30].
Diclofenac is also one of the most effective post-cataract
surgery anti-inflammatories within the NSAID group [29]. In
a double-masked study in 117 patients undergoing phaco-
emulsification and IOL implantation, diclofenac was equally
as effective as indomethacin, and more effective than flurbi-
profen, at reducing anterior chamber flare. Furthermore,
patients in the diclofenac group had significantly less burning
and stinging than those in the flurbiprofen and indomethacin
groups [31]. The result was supported by a study in 65 eyes
that showed diclofenac to be a more effective anti-inflamma-
tory than flurbiprofen when both treatments were combined
with prednisolone [32]. Another double-masked study showed
that diclofenac sodium 0.1% was equally as effective as the
registered indomethacin 0.1% solution [33].
The anti-inflammatory effects of diclofenac were compared
with those of the ketorolac tromethamine 0.5%. In a study
with 58 patients undergoing phacoemulsification with poste-
rior chamber-IOL implantation, diclofenac and ketorolac were
equally as effective at reducing anterior chamber cells and flare.

Table 3. Recommended posology ranges by indication.

Indication Minimum recommended dose Maximum recommended dose
Cataract and anterior segment surgery
Preoperatively One or two drops in the 1 h before One drop five-times 1–2 h before
*
Immediate postoperation One drop three-times immediately after One drop three-times immediately after
Postoperatively One drop four-times daily for up to 28 days One drop three- to five-times daily for as long as necessary
Photorefractive keratectomy
Preoperatively One drop 30–60 min prior Two drops the 1 h before
Immediate postoperation Two drops in the 1 h after One drop twice, 5 min apart
Postoperatively One drop four times in the 24 h after One drop four-times daily for up to 3 days
‡
Conjunctival inflammation
One drop three- to five-times daily 1 drop five-times daily for as long as necessary
*When specified.
‡
Conjunctival inflammation is a generic term covering various etiologies such as conjunctival allergy and dry eye. For these pathologies,diclofenac without preservatives
should be used [60].
There is no recommended posology for children.

142 Expert Rev. Ophthalmol. 3(2), (2008)

 Diclofenac sodium 0.1% ophthalmic solution Drug Profile

Table 4. Indications approved by country.

Indication Country
AT BE DK FI FR DE IT LU NL Poland PT ES SE USA UK
Inhibition of miosis × × × × × × × × × × × × ×
* *
Postsurgical inflammation × × × × × × × × × × × × × × ×
Photorefractive keratectomy-related × × × ×‡ × × × × × × × × ×
pain and photophobia
Noninfectious inflammation of the × × × ×§ × × ×# ׶
anterior segment
*
Seasonal allergic conjunctivitis
Cystoid macular edema prevention × × × × × × × ×
Post-traumatic inflammation ×** × × ×‡‡ × ×** ׇ‡
General ocular pain and photophobia × ×
Trabeculoplasty and strabismus surgery ×
*
Cataract surgery only.
‡
But only for 24 h postoperation.
§
Including septic inflammation.
#
Only noninfectious chronic conjunctivitis.
¶
Seasonal allergic conjunctivitis only.
**
Penetrating and nonpenetrating.
‡‡
Nonpenetrating only.
AT: Austria; BE: Belgium; DK: Denmark; FI: Finland; FR: France; DE: Germany; IT: Italy; LU: Luxembourg; NL: Netherlands; PT: Portugal; ES: Spain; SE: Sweden.

Neither drug had any effect on IOP and no medication-related
complications were observed in either treatment group [31]. Very
similar findings were obtained in two other studies: diclofenac
and ketorolac were equally as effective and safe [29,34]. A recent,
prospective, double-masked study in 40 patients showed that
ophthalmic applications of piroxicam and diclofenac are com-
parable for post-cataract surgery inflammation treatment.
Mean postoperative anterior chamber flare and cell scores and
postoperative corneal edema and descemet membrane folds
were comparable in both groups at all follow-up times [35].
A double-masked trial in 328 patients comparing diclofenac
and naproxen 0.2% for post-cataract surgery inflammation con-
trol showed no difference in anterior chamber inflammation
between the two groups [36]. This trial also demonstrated that
NSAIDs can be used without concurrent corticosteroids to treat
patients with mild-to-moderate inflammation after uncompli-
cated cataract surgery.
Preservative suppression did not alter diclofenac efficacy. Pre-
servative-free diclofenac packaged in an ABAK® multidose con-
tainer was shown to be as effective as the sodium merthiolate-
preserved diclofenac in a randomized, single-masked study hav-
ing included 194 patients included visual acuity, objective toler-
ance by slit-lamp, flurescein test and subjective evaluation of
local tolerance [4].
Pre- & postoperative CME
Cystoid macular edema is closely related to the breakdown of the
blood–aqueous barrier (partially caused by COX-2-mediated PG
release) and is the most common cause of poor visual outcome
following cataract surgery. Effective CME prevention and treat-
ment is, therefore, particularly pertinent to those with a pre-
disposition to blood–retinal barrier disruption due to diabetes
mellitus, uveitis and other disorders [15]. Miyake et al. assessed
the incidence of CME after small incision cataract surgery by
fluorescein angiography and found that diclofenac effectively
prevented CME: 5 weeks after surgery the diclofenac-treated
eyes had a CME incidence of only 5.7% (three out of 53 eyes)
compared with 54.7% (29 out of 53 eyes) of those treated
with the steroid fluorometholone (p ≤ 0.001) [15].
Prevention of postoperative inflammation following
other ocular surgery
Five clinical trials have compared diclofenac to topical steroids
and topical anesthetics after strabismus surgery. Diclofenac was
shown to be as efficacious as dexamethasone [37], prednisolone [38],
betamethasone [39] and oxybuprocaine [40], and in one study more
efficacious than dexamethasone [41].
Diclofenac showed significantly less patient discomfort and
less conjunctival inflammation, edema, and conjunctival gap
than the dexamethasone in 40 patients, at postoperative
week 2. In the dexamethasone group, 38% of patients showed
an increase in IOP to more than 21 mmHg during the 4 post-
operative weeks [41]. Another trial including 58 patients com-
paring diclofenac with dexamethasone found no statistically
significant difference between treatment in the rate of resolu-
tion of the inflammation and conjunctival healing, but there
was an increase in IOP at week 4 in the dexamethasone group,
which was not seen with diclofenac [37].

www.future-drugs.com 143
 Drug Profile Bodaghi
A double-masked, randomized trial compared topical
diclofenac with prednisolone sodium phosphate 1% in 80 eyes
of 52 patients. On postoperative day 7, in eyes that received
prednisolone, the conjunctival defects were larger (p = 0.004)
and more frequent (p = 0.02). In the first week after strabismus
surgery, topical diclofenac proved at least as effective as pred-
nisolone in controlling inflammation and discomfort, with less
delay in wound healing [38].
A randomized, double-masked clinical trial of 25 children was
conducted where one eye received diclofenac–gentamicin and the
contralateral eye received betamethasone–neomycin. Diclofenac
was as effective as betamethasone in the rate of resolution of the
inflammatory response [39].
Diclofenac also appears to be an efficacious analgesic treat-
ment for children undergoing strabismus surgery: 40 chil-
dren were randomly allocated to receive oxybuprocaine
0.4% or diclofenac, both of which provided good-to-excellent
perioperative analgesia [40].
Diclofenac efficacy was also assessed in therapeutic interven-
tion for glaucoma. Diclofenac has also been shown to signifi-
cantly stabilize the disruption of the blood–aqueous barrier in
comparison with placebo after argon laser trabeculoplasty
(ALT) [42]. There has been no difference in postoperative
inflammatory response in two groups of 20 patients undergo-
ing ALT in immediate postoperative IOP, between diclofenac
0.1% and dexamethasone 0.1% [43].
Few data are available concerning filtration surgery. A small
study indicates that diclofenac sodium 0.1% may be substi-
tuted for prednisolone 1% acetate as an effective anti-inflam-
matory medication without reducing the IOP control at 6
months following trabeculectomy with per-operative adjunc-
tive mitomycin-C. Moreover, no additional postoperative use
of anti-inflammatory or antimetabolite medication was
required in the diclofenac group contrarily to the prednisolone
acetate group [44].
Topical diclofenac is, therefore, an efficacious treatment for
use after anterior segment surgery, with notable advantages over
topical steroids in terms of safety.
Analgesia following photorefractive surgery
Post-PRK pain has been described as severe, sometimes throb-
bing in nature, and similar to severe corneal abrasion or UV
keratitis [45]. Ocular pain may persist for 36–48 h, peaking
within the first 24 h. A few-day treatment (1–3 days; TABLE 3)
with topical diclofenac significantly reduces the ocular pain,
burning/stinging and light sensitivity after excimer PRK and
reduces the need for narcotics [46].
Since laser in situ keratomileusis (LASIK) does not lead to
such throbbing pain, treatment with ophthalmic NSAIDs fol-
lowing LASIK procedure has never been validated by health
authorities and this use is an off-label indication.
Studies on diclofenac use to relieve ocular pain after PRK are
described hereafter. A trial was conducted comparing ketorolac
to diclofenac in 102 patients. A standardized questionnaire was
144
used to assess the patient’s average and peak levels of discom-
fort. The overall level of discomfort was lower for diclofenac
(p = 0.004) [47].
When 86 PRK patients were treated with indomethacin or
diclofenac postoperatively, with pain intensity quantified
according to a visual analog scale, no significant difference in
pain was observed between the two groups concerning intensity,
associated medications or numbers of days of discomfort [48].
Similar results were obtained in a double-masked trial involv-
ing 61 PRK patients [49]. Both diclofenac and indomethacin
significantly reduced pain on the first day following excimer
laser PRK, and this activity was maintained until the end of
the observation period.
In a double-masked, study in 125 patients, four NSAIDs
(diclofenac, flurbiprofen, ketorolac and indomethacin) were
tested against a placebo (artificial tears) for the treatment of
post-PRK pain [46]. At 24 h after surgery, patients treated with
flurbiprofen, ketorolac and diclofenac had significantly lower
pain scores than those treated with indomethacin or placebo
(p < 0.001). The mean number of analgesic tablets used was
significantly higher in the placebo group than in any NSAID
group (p < 0.001). Flurbiprofen appeared to be the most effec-
tive treatment even at 24 h after surgery when pain was at a
maximum. Flurbiprofen was also rated as better than diclofenac
in a small study on post-PRK pain in 16 patients [50].
Furthermore diclofenac has been shown to be more effective
than the anesthetic tetracaine in reducing ocular pain and func-
tional symptoms following PRK. It should be stressed that pro-
longed misuse of anesthetics to relieve ocular pain may lead to
serious neurotrophic keratitis. A total of 74 patients were rand-
omized to receive either tetracaine 1% or diclofenac after
undergoing PRK. Tetracaine was instilled at 30 min intervals
for 24 h and diclofenac was instilled four times daily for 3 days.
Patients in the diclofenac group had significantly less pain [51].
Similar results were found by Cherry who conducted a trial
with 112 eyes. ‘Pain at its worst’ was measured using a visual
analog scale [52]. These results expanded and confirmed earlier
results by the same group [53].
Analgesia following traumatic corneal abrasion
Patients treated with diclofenac reported significantly less
pain 2- and 24 h after traumatic corneal abrasion (TCA). Two
meta-analyses concluded that topical NSAIDs including
diclofenac provide effective analgesia for patients with trau-
matic corneal abrasions [54,55]. The use of ophthalmic
NSAIDs may decrease the need for sedating analgesics [55].
Treatment of TCA with diclofenac, a contact lens and antibi-
otic drops without cycloplegia sufficiently reduced the pain to
allow 80% of 176 patients treated to return immediately to
their normal activities [56].
From the current literature it can be concluded that
diclofenac is as effective as other NSAIDs and topical anesthet-
ics for attenuating pain and discomfort after photorefractive
surgery and traumatic corneal abrasion.
Expert Rev. Ophthalmol. 3(2), (2008)
 Diclofenac sodium 0.1% ophthalmic solution
Symptomatic treatment of noninfectious conjunctivitis
Seasonal allergic conjunctivitis
Topical NSAIDs significantly reduce ocular itching and con-
junctival hyperemia associated with seasonal antigen-induced,
allergic conjunctivitis. Topical diclofenac may have similar fea-
tures in the treatment of this disease [57]. Diclofenac is superior
to placebo in treating seasonal allergic conjunctivitis (SAC) [58]
and a significantly greater proportion of patients were symp-
tom-free after 7 days of treatment with diclofenac compared
with ketorolac [59]. Use of preservative-free diclofenac helps
avoid toxic and allergic effects of preservatives, especially useful
when treating allergic ocular diseases.
Vernal keratoconjunctivitis
Vernal keratoconjunctivitis (VKC) is a chronic bilateral debil-
itating disease occurring in children which requires continu-
ous anti-inflammatory control. NSAIDs that have relatively
good long-term use safety profiles (e.g., diclofenac) are well
suited to treating VKC, whereas steroids can only be used in
acute phases due to the side effects of their long-term use.
Diclofenac reduces the itching, hyperemia and photophobia
related to VKC that may be due to its anti-inflammatory
properties decreasing PGs in the conjunctiva. Furthermore,
diclofenac’s ability to decrease ocular surface sensitivity could
explain the improvement in VKC patient comfort during
treatment [60].
Keratoconjuntivitis sicca
Keratoconjuntivitis sicca (KCS) is associated with inflamma-
tion of the ocular surface. This inflammation is either the ori-
gin of injury or can exacerbate an existing injury in eye with
KCS. Short-term topical use of preservative-free diclofenac
0.1% was effective in improving the symptoms and signs of
KCS [61]. Early testing suggests that diclofenac can reduce the
discomfort of KCS due to Sjogren’s syndrome by exerting its
analgesic effect [21,62]. However, they should be under close mon-
itoring, and discontinuation is mandatory if corneal epithelial
defects appear or worsen during treatment.
Adverse events due to chemotherapy
Cytarabine (Ara-C) is used widely in chemotherapy for the
treatment of a variety of hematological malignancies. Conjunc-
tivitis is commonly induced by high-dose Ara-C. Although not
the worst adverse event of Ara-C treatment, it is very uncom-
fortable particularly if associated with photophobia and ocular
pain requiring analgesia. The incidence and severity of high-
dose Ara-C-induced conjunctivitis are significantly reduced by
combined dexamethasone–diclofenac prophylaxis [63].
Safety & tolerability
In terms of safety, the major advantage of NSAIDs remains the
fact that they do not induce the classical steroid-induced compli-
cations (i.e., IOP increase with a potential risk of steroid-induced
www.future-drugs.com
Drug Profile
glaucoma, posterior subcapsular cataract, immuno-modula-
tion with risk of infection or rebound effect). However, like
steroids, the NSAID class may impair wound healing when
misused or not adequately supervised [1,64–72]. Matrix metallo-
proteinases [71] and inhibition of substance P [73] might be
involved in delayed wound closure. The most common cor-
neal adverse effect is occurrence of superficial punctate kerati-
tis, which usually resolves after treatment discontinuation.
Other corneal complications caused by NSAID use have been
uncommon despite the increased use of this class of drug after
cataract surgery [66]. Corneal thinning and corneal melts have
been described. Particularly, at the end of the 1990s, the
American Society of Cataract and Refractive Surgery issued an
alert, noting a dramatic increase in case reports of corneal
injury [1,3,68,69]. Most cases were related to a generic formula-
tion (DSOS) ultimately removed from the market in Septem-
ber 1999. Few other case reports were associated with branded
NSAIDs and were usually linked to risk factors such as high
doses/misuse, comorbidity (abnormalities of the ocular surface,
rheumatoid arthritis, dry eye, rosacea, corneal epithelial defects,
keratopathy, neurotrophic ulcer and diabetes) and concomitant
administration of other cytotoxic products (steroids, fluoroqui-
nolones [71,74,75], aminisodes [1,4,68,69] or preservatives [5]). Since
then, the frequency of published case reports has decreased.
Since 2002, three cases of corneal melting were described
concerning an off-label indication (LASIK); all of them had a
dislocated flap [68]. Another case occurred after PRK in a dia-
betic patient having received a 2-month treatment with
diclofenac [71]. The only case of corneal thinning associated
with use of preservative-free diclofenac occurred in a patient
with a Schirmer measured to be at 0 mm after misuse
(LASEK). A day after diclofenac discontinuation, the corneal
ulcer was resolved [76]. Regarding ocular surface safety, pre-
servatives combined with diclofenac may be a concern as
illustrated by the better safety profile of a preservative-free
formulation in healthy volunteers [5]. In a recent trial, non-
preserved diclofenac was better tolerated than the thiomersal
preserved diclofenac after 7 days of treatment in 40 subjects [5].
There was also less follicular papillary conjunctivitis and sig-
nificantly better lissamine green scores in the nonpreserved
group. This could be particularly beneficial for reducing the
risk of toxic effects in those with fragile ocular surfaces due to
PRK or other surgery and at risk groups such as those with dry
eye or diabetes.
The most common adverse event reported in diclofenac trials
(as with other NSAIDs) is transient burning and stinging upon
instillation. Other adverse events include hyperemia and, more
rarely, itching, photosensitivity and foreign body sensation [67].
Allergies and hypersensitivity reactions (e.g., contact dermati-
tis) have also been reported and preservatives may play a role
such as thiomersal, which known to cause contact eczema and
ocular allergies.
Systemic effects are very rare since topical diclofenac is only
slightly absorbed through the nasal mucosa [67].
145
 Drug Profile Bodaghi

As long as NSAIDs such as diclofenac remain potent anti-

Regulatory affairs inflammatory/analgesic drugs, they will remain a major part
The approved indications and available formulations by country of the pharmaceutical armamentarium.
(for Europe and the USA) are presented in TABLES 1 & 4.

Five-year view
Conclusion Diclofenac will remain an essential anti-inflammatory alterna-
Diclofenac sodium 0.1% ophthalmic solution is a potent anti- tive to steroids. As its safety profile becomes even better
inflammatory drug with a wide range of indications. It has an understood, it will be possible to reduce serious corneal
advantageous benefit-risk ratio as long as responsible prescrib- adverse events.
ing practice is followed. Prolonged treatment at high dosage
must be avoided, patients with ocular surface disease must be
carefully followed-up, concurrent use of antibiotics or steroids Financial & competing interests disclosure
that may cause corneal risk must be carefully controlled and the Bahram Bodaghi participated as an investigator in a multicenter
most appropriate diclofenac formulation must be used. Preserv- French trial on Diclofenac sodium. He is also the first author of the
ative-free formulations should be preferred in case of ocular manuscript reporting on this trial and published in 2005. The author
surface disease or when combined with potentially cytotoxic has no other relevant affiliations or financial involvement with any
treatment [5]. organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
Expert commentary No writing assistance was utilized in the production of this manuscript.
Topical NSAIDs are widely used in the daily practice in oph-
thalmology. Their efficacy/safety profile is now well estab- Key issues
lished, as well as their precautions of use. Dosing and treat- • Diclofenac is equally effective in preventing inflammation as in
ment duration should be well-adapted to each indication on a corneal analgesia.
case-to-case basis. Corneal toxicity remains the major draw- • Diclofenac is an effective and well-tolerated product.
back and has been shown to be linked to different risk factors
• Nonpreserved diclofenac is better tolerated than
and misuses such as high daily frequency or long-term treat- preserved formulations.
ment. If prolonged use is needed, close monitoring is manda-
• Serious corneal adverse events can through avoided by good
tory, especially for patients with concomitant ocular surface prescriptive practice.
diseases or receiving additional topical cytotoxic compounds.
5 Chiambaretta F, Creuzot-Garcher C, 10 Miyake K. Ibaraki N. Prostaglandins and
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Affiliation
• Bahram Bodaghi
Service d’Ophtalmologie,
Hôpital Pitié-Salpétrière, Paris, France
Tel.: +33 142 163 211
Fax: +33 142 163 218
bahram.bodaghi@psl.aphp.fr
Expert Rev. Ophthalmol. 3(2), (2008)