Associate Professor Mark Roth
BSc(Pharmacology) BAppSc(Optom) PGCertOcTher NEWENCO FAAO OAM
Associate Professor Graham A Lee
MD MBBS(Qld) FRANZCO
City Eye Centre, Brisbane; University of Queensland, Brisbane; International Ophthalmology Portal, Co-founder
Associate Professors Mark Roth and Graham Lee discuss the next generation in non-steroidal anti-inflammatory agents, nepafenac 0.3% suspension (Ilevro).
Roth: Dr Lee, thanks for taking your time to cover this important topic that affects all our patients undergoing cataract surgery. Most optometrists have never found a great use for non-steroidal anti-inflammatory drugs (NSAIDs) in primary eye care but they are important in surgical eye care.
Lee: In Australia, we have had access to ketorolac 0.5% (Acular, Allergan) and diclofenac 0.1% (Voltaren Ophtha, Novartis Ophthalmics) for many years (Table 1). I agree they have not been used in primary eye care widely and are contraindicated in cases of epithelial defects and keratitis or ulceration due to the risks of corneal melting. They may have a role as steroid-sparing agents in allergic conjunctivitis and episcleritis. Their most useful role is in the prevention of intra-operative miosis, reduction of post-operative inflammation and pain, and management of cystoid macular oedema (CME).
Table 1. Overview of NSAID treatments
Roth: NSAIDs are never a true substitute for steroids when topical drugs are required to treat inflammation; in fact they don’t directly reduce inflammation but rather inhibit an enzyme along the synthetic pathway to the production of prostaglandins. What is the mechanism that makes them so potentially effective for surgical eye care, such as the prevention of CME?
Lee: NSAIDs block prostaglandin synthesis by inhibiting the cyclo-oxgenase (COX) pathway (Figure 2). Corticosteroids are more potent as they block prostaglandin synthesis by inhibiting both the COX and lipoxygenase (LOX) pathways of inflammation. By blocking prostaglandin synthesis, the inflammatory cascade is reduced, that is, leukocyte migration, vasodilatation, pain and vascular permeability. The topical NSAIDs have been proposed to have a synergistic effect with topical corticosteroids and this has been useful in treatment of CME.
Roth: I found the article by Kim et al in Ophthalmology 20151 to be a great review of NSAIDs and cataract surgery, but it left me wondering if there really is consensus for prophylactic use to reduce CME. Many people are debating the important points from this key review. What are your views?
Lee: The Kim et al article was a report from the American Academy of Ophthalmology. It was a review and meta-analysis of the literature on topical NSAIDs. The main messages I got from that study was the lack of Level 1 evidence for the long-term benefit of NSAID therapy in preventing vision loss from CME at three months or more after cataract surgery, but it did hasten visual recovery in the first three months. Therefore, it is more useful in the early post-operative period but doesn’t provide superior outcomes. There is good collective evidence that topical NSAIDs used three days prior to surgery reduces CME. This is not necessarily important for routine cataract patients; however, for those at greater risk of CME, such as a previous history of CME or an epiretinal membrane, this may be useful.
Roth: Is the evidence stronger for a combination of NSAIDs and topical steroid?
Lee: The Kim et al article reported the evidence for synergistic action of NSAIDs and corticosteroid is not supported by the literature; however, it is common practice to use both in conjunction and although the Level 1 evidence is lacking, clinically there appears to be an advantage in concurrent use.
Roth: Does the whole paradigm change when we split diabetic from non-diabetic patients?
Lee: For straightforward cases, topical NSAIDs are not necessary, although some of my colleagues routinely use them in conjunction with topical corticosteroids. I consider their use for at-risk patients.
Roth: Glaucoma and cataract surgery is a huge topic on its own, but specifically: how do you manage glaucoma patients prior to cataract surgery if they are on a prostaglandin analogue for primary open angle glaucoma (POAG)? Exogenous prostaglandin analogue use has been linked to CME.
Lee: I tend to stop the prostaglandin analogue one day post cataract surgery to reduce the risk of CME. This gives patients a trial off the medication to see how much pressure-lowering effect was obtained from the cataract surgery and/or stent insertion. If needed, I will restart the prostaglandin analogue at three weeks post cataract surgery. This practice varies among different surgeons. Some cease a week prior to surgery and don’t restart until one month post-surgery as required. Others continue the prostaglandin analogues as usual, without a period of cessation.
Figure 1. Inhibition of PG synthesis. Nepafenac inhibits all prostanoid production by the iris/ciliary body excised 60 minutes following dosing.
Roth: Nepafenac 0.3% (Ilevro, Novartis Ophthalmics) is the new non-steroidal anti-inflammatory agent for cataract surgery. What are its main features that differentiate it from the other NSAIDs available?
Lee: The advantages of nepafenac 0.3% suspension is that it is once-daily as opposed to ketorolac 0.5%, dosed at four times a day. It stings much less than the other NSAIDs drops. Ilevro uses pro-drug technology. It enters the cornea as nepafenac, and hydrolysis in various ocular tissues converts the molecule into amfenac, the more potent form of the molecule (Figure 1). This provides maximal efficacy at target sites including the iris and ciliary body.
Roth: As a suspension there is greater contact time with the ocular surface. Is that how once-a-day dosing is achieved or are there other mechanisms in play?
Lee: The 0.3% suspension provides a higher concentration of active molecule (compared to the 0.1% solution; not available in Australia), reduced particle size, increasing surface area for dissolution and other additives including carboxymethylcellulose sodium (milling agent) and guar (retention agent).
Roth: Apart from a hypersensitivity to NSAIDs, including asthma, this drug is pretty well tolerated, including less stinging. Are there any other significant precautions?
Lee: As mentioned earlier, in cases of epithelial defects, keratitis or ulceration, there are risks of corneal melting. Diabetic patients, patients with rheumatoid arthritis and other collagen vascular diseases, rosacea, chemical or thermal burns, neuropathic corneas, graft vs host disease, dry eye, herpetic disease either zoster or simplex and a history of LASIK flaps are at higher risk of corneal and scleral complications. Any condition where the ocular surface is compromised is potentially at risk. It also should be avoided in patients with a bleeding tendency, pregnancy, breast-feeding, children and adolescents under 18 years, and not used with soft contact lenses.
Roth: Does hypersensitivity or allergy to oral NSAIDs necessarily translate to topical NSAIDs?
Lee: I would avoid due to the risk for potential systemic absorption.
Roth: Less stinging and less frequent dosing logically seem better for compliance, but has that actually been your experience? It’s a big challenge.
Lee: Once-daily dosing is definitely better for compliance and the reduced stinging is also important. Patients have reported more blurring with initial instillation as it is yellow, opaque and thicker than the usual eye-drop solutions. If patients have reduced vision from CME, they will be motivated to take medications to hasten their recovery.
Roth: I think optometrists should play a greater role in helping with education and compliance pre- and post-surgically. What’s your opinion?
Lee: Patients find access to their optometrist easier and often the first port of call, particularly if their ophthalmologist is not available. Optometrists need to be familiar with the appearance of the eye post-surgery to detect what is normal recovery versus a complication. If they know the how and why of post-operative management, they can reinforce what the ophthalmologist has instructed and overall this will be of benefit to patient outcomes.
Roth: My first two patients using this drug all came back with the same complaint: ‘It’s hard to get the drop out of the bottle.’ I had no idea, so it was difficult for me to discuss the issue with them. I had to go away and try the bottle for myself. I must admit, it’s more difficult to get the drop out compared to other topicals. If patients are informed beforehand, it’s less of a surprise. Your views?
Lee: The drop is a 0.3% suspension so will be more viscous and harder to squeeze out of the bottle. Shaking the bottle to mix the contents thoroughly may be helpful before opening. It should be stored under 25 degrees, but if it is refrigerated, it may be more difficult to squeeze the bottle. Patients with weakness of their fingers, for example, those who have arthritis or carpal tunnel syndrome, may need to have someone administer the drops for them.
Roth: Ilevro is approved and indicated for ocular pain and inflammation. The recommended regimen is one drop the day before cataract surgery, two drops on the day of surgery and once daily for 14 days, for a total of 17 drops. What would be your suggested regimen for cataract surgery including steroids?
Lee: For my routine cataract patients, the cost-benefit ratio for using NSAIDs is not warranted. For medium-risk patients, I would use it once a day from day one post-operation in conjunction with the topical corticosteroids and antibiotics for four weeks.
Figure 2. Inflammation cascade
Roth: Are there circumstances in which you would vary that regimen? For example, a patient with recurrent uveitis or perhaps CME in the first cataract operated eye?
Lee: For higher risk patients, I would consider commencing three days pre-operatively and continue up to eight weeks post-operatively, depending on evidence of CME on OCT in the first eye. Of course, it’s important to note that the use of topical NSAIDS for prevention or treatment of cystoid macular oedema is an off-label indication, despite their widespread use.
Roth: I’m going to take my eye physician hat off and put my well-informed, anxious patient hat on. Isn’t all cataract surgery a risk factor for CME? If it were my eye having cataract surgery, I would be keen on the NSAIDs before, during and after surgery (LOL!).
Lee: For routine cataract surgery, I do not feel the risk/cost-benefit ratio is in favour of the use of topical NSAIDs. However, if there are no contraindications as outlined previously and the patient was concerned regarding CME, it would be reasonable to use NSAIDs.
Roth: We have focused on NSAIDs and the prevention of CME but if a patient post-operatively developed CME, then would an NSAID become an integral part of the treatment regimen together with corticosteroids?
Lee: Management of CME is whole topic in itself. It is most important to identify the cause and address the underlying factors. For example, there may be a vitreous strand causing retinal traction, an epiretinal membrane, prostaglandin analogue use and so on. Once causes of the CME are resolved, my pharmacological management of visually-significant CME is commencement of topical steroid such as prednisolone acetate 1% four times a day and an NSAID such as nepafenac 0.3% daily or ketorolac 0.5% four times a day. If after two months there is limited response, intravitreal triamcinolone (40 mg/ml) can be useful. Oral acetazolamide has also been used; however, side-effects limit its use.
Roth: Is a drop-less approach to cataract surgery with intracameral injection of antibiotic and anti-inflammatory the future?
Lee: ‘No drops’ post surgery would be a revolution. Whether it is a depot of medication variously intracameral, via a trabecular stent, intracorneal, subconjunctival, subtenons, punctal plug, forniceal and so on, it will take out the compliance factor. However, there is this issue: if the patient has an adverse reaction, a depot is difficult to remove. The Holy Grail will be maximally effective surgery, with minimal invasion resulting in no significant inflammation or risk of infection. Now that would be a grand future.
1. Kim SJ, Schoenberger SD, Thorne JE, Ehlers JP, Yeh S, Bakri SJ. Topical nonsteroidal anti-inflammatory drugs and cataract surgery: A report by the American Academy of Ophthalmology. Ophthalmology 2015; 122: 11: 2159-2168. doi: 10.1016/j.ophtha.2015.05.014.