NSAIDs
(Non-Steroidal Anti-inflammatory Drugs)
A New Look at NSAIDs
There are now four star players in the field of nonsteroidal
anti-inflammatory drugs. Older drugs have been reformulated
and new drugs have come to market.
While oral NSAIDs are heavily used in systemic medicine, topical
ophthalmic NSAID use is relatively limited within eye care. The
foundational perspective on this class of drugs is the acknowledgement
that steroids reign supreme in inflammation control. Topical
NSAIDs are never an appropriate substitute when the clinical
condition merits a potent topical corticosteroid.
NSAID use has much more applicability in perioperative care than
in primary eye care. However, there are several clinical circumstances
in which patient care can be enhanced through the use of such
a drug.
Pharmacology of NSAIDs
Let’s first understand the pharmacology of NSAIDs. First of all,
they have no direct anti-inflammatory properties. They simply
inhibit an enzyme along the synthetic pathway to the production
of prostaglandins, which are powerful mediators of inflammation.
As doctors, it is vital that we have knowledge of this particular
pathway. It is known as the arachidonic acid cascade. As you
can see in the diagram (“The Arachidonic Acid Pathway,” at right),
the origin substrate is phospholipids released from cell membranes
as a generic response to multiple causes of cellular microtrauma.
Corticosteroids inhibit the conversion of these phospholipids
to arachidonic acid by inhibiting the catalytic enzyme phospholipase
A early in this synthetic cascade.
Once arachidonic acid (AA) is formed, two different enzymes convert
it ultimately to either prostaglandin formation or leukotriene
formation. Cyclooxygenase converts AA to prostaglandins, and
lipoxygenase converts AA to leukotrienes. The key point: while
NSAIDs inhibit the enzymatic activity of cyclooxygenase, they
have no effect on lipoxygenase, thereby allowing the production
of leukotrienes to go unchecked.
For clinical perspective, remember the early days of photorefractive
keratectomy where NSAIDs were initially used postoperatively?
Patients experienced problems with white blood cell corneal infiltrates
until it was realized that steroids prevented their formation.
Why? Leukotrienes are chemotactic for leukocytes for which NSAIDs
do nothing, since NSAIDs only inhibit the synthesis of prostaglandins
and have no activity against lipoxygenase-catalyzed production
of leukotrienes. Since steroids work higher up in the AA synthetic
pathway, they inhibit both cyclooxygenase and lipoxygenase, thus
inhibiting production of both prostaglandins and leukotrienes.
All this may sound like gibberish to some. The AA pathway is
more easily grasped by studying the diagram, which illustrates
the processes just described. Once you have a clear understanding
of the AA pathway, then you can begin to prescribe with enhanced
clinical authority and precision.
It is generally thought that steroids and NSAIDs may demonstrate
some synergy and therefore might be beneficial if used concurrently.
For example, standard-of-care treatment of postoperative cystoid
macular edema (CME) is usually treated with Pred Forte (prednisolone
acetate 1%, Allergan) and a topical NSAID (dosed at its FDA-approved
dosing frequency). This synergy is difficult to reconcile based
on the dynamics of the AA previously discussed. Perhaps the rapidity
of onset and/or the degree of enzymatic inhibition may be considerations
for explanation. Contrarily, we find no literature supporting
the use of both drug groups in the standard initial treatment
of anterior uveitis. There is still a lot to be learned in how
these drug classes modify tissue responses.
Compared to topical corticosteroids, NSAIDs have a limited role
in primary eye care. Nonetheless, there are several situations
where NSAIDs can be beneficial. There is a partial disconnect
between topical and systemic administration. Systemic NSAIDs
are true to their name and do indeed render a marked anti-inflammatory
effect, whereas topical NSAIDs mainly ameliorate pain while
providing some limited activity against inflammation.
The most common conditions for which topical NSAIDs can play
a beneficial role are
- Corneal abrasions
- Just before, and just after, in-office 5% Betadine Sterile
Ophthalmic Prep Solution treatment for highly symptomatic EKC
- Post foreign body removal
- Post anterior stromal puncture procedure
- Post penetrating keratoplasty, or any surface disruptive laser
procedure
- Treating and/or preventing cystoid macular edema
- Allergic conjunctivitis
- Supplemental to steroids in treating recalcitrant uveitis
- Some cases of photophobia
- Post cataract surgery care
- Supplemental to oral NSAIDs in treating scleritis
- Treating and/or preventing inflamed pterygia and pingueculae
 Voltaren
(diclofenac, Novartis) and Acular LS (ketorolac, Allergan)
have been the standard bearers of topical NSAID care over the
past decade. Both are used q.i.d. and are largely clinical
equivalents. One study compared ketorolac and diclofenac head-to-head.1
Its conclusion: “The decrease in corneal sensitivity in normal
human corneas is more pronounced and longer lasting with diclofenac
than with ketorolac.”
The original formulation of Acular was a 0.5% solution, but
marked stinging upon instillation was its Achilles’ heel.
The drug’s recent reformulation to a 0.4% solution (Acular
LS) is now quite tolerable; a very nice upgrade.
 The
big news within this drug class is the recent introduction
of two more NSAIDs: Xibrom (bromfenac, Ista) and Nevanac
(nepafenac, Alcon). Both of these drugs claim enhanced ocular
penetration, and exact in vivo quantification of this claim
continues to be defined.
 Xibrom’s
uniqueness is that it is dosed twice daily, and is well-tolerated.
Nevanac is unique in that it is the first available pro-drug.
Nevanac is enzymatically converted to amfenac sodium which,
like all NSAIDs, inhibits cyclooxygenase. It is dosed three
times a day.
All these drugs are approved by the FDA for treating postoperative
inflammation (Acular LS is also approved to treat ocular
allergy), and as such, they are used much more in a surgical
context. There are, however, a number of applicable uses
relevant to primary eye care, as enumerated above.
Because of the rare, but real, potential for corneal toxicity
and melting, use these drugs cautiously when there is preexisting
corneal epithelial compromise. As a rule, we never prescribe
any topical NSAID for use beyond one week—with an exception
for CME, which we treat with a topical NSAID for a month.
While steroids are often initially dosed as frequently as
hourly for a few days, we strongly urge that NSAID use not
exceed the FDA-approved dosing frequency.
In summary, there are several off-label uses for NSAIDs within
the context of primary eye care. Their main use is in the
prevention or treatment of cataract surgery-related cystoid
macular edema concurrent with a potent corticosteroid.
1 Seitz B, Sorken K, LaBree LD, et al. Corneal sensitivity
and burning sensation. Comparing topical ketorolac and diclofenac.
Arch Ophthalmol 1996 Aug;114(8):921-4.
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