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Editors Selection IGR 7-3

Medical treatment: Treatment variations

Carl Camras

Comment by Carl Camras on:

12989 The influence of diclofenac ophthalmic solution on the intraocular pressure-lowering effect of topical 0.5% timolol and 0.005% latanoprost in primary open-angle glaucoma patients, Costagliola C; Parmeggiani F; Antinozzi PP et al., Experimental Eye Research, 2005; 81: 610-615


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A well-written publication by Costagliola et al. (1031) describes a well-designed study with very interesting findings. The study demonstrates that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), enhances the ocular hypotensive effect of latanoprost (LP). The mechanism proposed for this finding is that, by inhibiting the production of prostaglandins (PGs), NSAIDs up-regulate the expression of prostanoid receptors that might respond to LP to further reduce intraocular pressure (IOP).

Many studies have evaluated the role of NSAIDs in INHIBITING (not enhancing) the hypotensive effect of other modalities of glaucoma therapy. A review from 19891 summarizes some of these studies performed over 15 years ago. Since PGs are potent ocular hypotensive agents, stimulation of their endogenous ocular synthesis to account for the IOP reduction produced by various modalities of glaucoma therapy has been suggested2,1 The ability of NSAIDs to inhibit the ocular hypotensive effect of these therapeutic modalities supports the role of endogenous PGs. NSAIDs have been demonstrated to at least partially inhibit the ocular hypotensive effect of epinephrine,3 argon laser trabeculoplasty, and ciliodestructive procedures.1 In addition, some studies suggest that they also might partially inhibit the hypotensive effect of apraclonidine,4 brimonidine,5 and topically-applied carbonic anhydrase inhibitors,1 although other studies fail to demonstrate inhibition.6,7

Diclofenac enhances the ocular hypotensive effect of latanoprost
Some have hypothesized that NSAIDs might inhibit the hypotensive effect of PG analogs. This speculation might arise from a misunderstanding about the mechanism of action of NSAIDs, which are not PG antagonists. Instead of inhibiting the action of PGs or their analogs at prostanoid receptors, NSAIDs inhibit the endogenous synthesis of PGs from their precursor, arachidonic acid, by blocking cyclooxygenase, the enzyme responsible for the conversion of arachidonic acid to PGs. Therefore, NSAIDs are expected to inhibit the effect of a therapeutic modality that reduces IOP by stimulating the endogenous synthesis of PGs from their precursor, arachidonic acid. However, they should not block the effect of a PG analog that acts directly on prostanoid receptors to reduce IOP.

Some relatively minor weaknesses of the current study8 include its small size (16 patients in each group), failure to delineate in detail the demographics of each of the two groups (i.e., any possible differences in systemic medications, systemic diseases, or other ocular parameters such as central corneal thickness), variable duration of treatment of the NSAID with each of the ocular hypotensive drugs (one week with timolol and four weeks with LP), variable duration of observed treatment with each of the ocular hypotensive drugs (two weeks with timolol and eight weeks with LP), and lack of a diclofenac washout assessment with timolol.

Although the findings by Costagliola et al.8 are impressive, they must be considered relative to the pre-existing literature. The effect of NSAIDs on the ocular hypotensive effect of PGs has been reported since 1977, when PGs initially were found to reduce IOP after topical application.2 This initial study demonstrated very slight enhancement of the hypotensive effect of PGF-2α in rabbits with systemic indomethacin. The effect was considerably smaller than that observed in the recent study8 currently being discussed. Since this initial study in 1977, the interaction between NSAIDs and PGs has been evaluated in many other studies. Almost all of these studies have demonstrated no significant effect.1,5,9 One study demonstrated a slight, but significant NSAID-induced INHIBITION of the hypotensive effect of LP.10 Only a single more recent study carried out by the same group11 has confirmed the findings of the study currently being discussed. Only 16 patients were evaluated for this interaction in each of these two latter studies, whereas some of the previous studies failing to demonstrate an enhancing effect included more patients.

Nevertheless, despite the preponderance of evidence failing to demonstrate potentiation of the PG-induced IOP reduction by NSAIDs, these recent studies indicate that more studies are required to determine whether inhibition, potentiation, or no effect occurs when NSAIDs and PG analogs are used in combination. This is especially important since none of the studies reported in the current literature were ideally designed to conclusively evaluate the possibility of an interaction.

References

  1. Camras CB, Podos SM: The role of endogenous prostaglandins in clinically-used and investigational glaucoma therapy. In: Bito LZ, Stjernschantz (eds), The ocular effects of prostaglandins and other eicosanoids. New York 1989: 459-475.
  2. Camras CB, Bito LZ, Eakins KE. Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Invest Ophthalmol Vis Sci 1977;16:1125-1134.
  3. Camras CB, Feldman SG, Podos SM, Christensen RE, Gardner SK, Fazio DT. Inhibition of the epinephrine-induced reduction of intraocular pressure by systemic indomethacin in humans. Am J Ophthalmol. 1985;100:169-75.
  4. Wang R-F, Camras CB, Podos SM, et al. The role of prostaglandins in the para-aminoclonidine-induced reduction of intraocular pressure. Trans Am Ophthalmol Soc 1989; 87: 94-106
  5. Sponsel WE, Paris G, Trigo Y, Pena M, Weber A, Sanford K, McKinnon S. Latanoprost and brimonidine: therapeutic and physiologic assessment before and after oral nonsteroidal anti-inflammatory therapy. Am J Ophthalmol. 2002; 133: 11-18.
  6. Siegel MJ, Camras CB, Lustgarten JS, et al. Effect of flurbiprofen on the reduction of intraocular pressure after administration of 1% apraclonidine in patients with glaucoma. Arch Ophthalmol 1992; 110: 598-599.
  7. Sulewski ME, Robin AL, Cummings HL, et al. Effects of topical flurbiprofen on the intraocular pressure lowering effects of apraclonidine and timolol. Arch Ophthalmol 1991; 109: 807-809.
  8. Costagliola C, Parmeggiani F, Antinozzi PP, et al. The influence of diclofenac ophthalmic solution on the intraocular pressure-lowering effect of topical 0.5% timolol and 0.005% latanoprost in primary open-angle glaucoma patients. Exp Eye Res 2005; 81: 610-615.
  9. Miyake K, Ota I, Maekubo K, et al. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol 1999; 117: 34-40.
  10. Kashiwagi K,Tsukahara S. Effect of non-steroidal anti-inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost. Br J Ophthalmol 2003; 87: 297-301
  11. Costagliola C, Parmeggiani F, Caccavale A, et al. Nimesulide oral administration increases the intraocular pressure-lowering effect of latanoprost in patients with primary open-angle glaucoma. Am J Ophthalmol 2006; 141: 379-381.

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