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Cataract Surgery and Nonsteroidal Antiinflammatory Drugs

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Cataract Surgery and Nonsteroidal Antiinflammatory Drugs REVIEW/UPDATE 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- synergistically with corticosteroids, or for specific tated by the use of topical medications before and after high-risk eyes prone to the development of CME, the the surgical procedure. These topical medications may effectiveness of these medications is compelling. include antibiotics, steroids, nonsteroidal antiinflam- This paper reviews the literature on currently avail- matory drugs (NSAIDs), and the full array of glaucoma able topical and intracameral NSAIDs and their medications to modulate intraocular pressure (IOP) in various uses in cataract and lens surgery, with specific the perioperative period. Many surgeons have found attention to the prevention and treatment of pseudo- NSAIDs to be an indispensable tool for providing the phakic CME and to the assorted treatment paradigms best surgical outcomes in both routine and complicated for addressing both routine and high-risk cases. In cataract procedures. As a class of drugs, NSAIDs have addition, special consideration of patients with coexis- been proven to be a safe and effective alternative to cor- tent glaucoma having cataract surgery will focus on ticosteroids in the topical prevention and management the potential effectiveness and benefits of using of noninfectious ocular inflammation and cystoid mac- NSAIDs in these patients. Possible adverse reactions ular edema (CME).1,2 They have also been valued as a and contraindications will also be reviewed. means of maintaining intraoperative mydriasis and moderating postoperative pain. Whether used alone, Mechanism of Action Commercially available NSAIDs consist of a chemi- cally heterogeneous group of compounds that can be Submitted: October 26, 2015. grouped into 6 major classes: salicylates, fenamates, Final revision submitted: April 4, 2016. indoles, phenylalkanoic acids, phenyl acetic acids, 2,3 Accepted: April 11, 2016. and pyrazolones. Despite their chemical heterogene- ity, all NSAIDs act by blocking the cyclooxygenase Shan Lin, MD, and Louis R. Pasquale, MD, reviewed the final paper. (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: [email protected]. 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.2016.06.006 Published by Elsevier Inc. 0886-3350 REVIEW/UPDATE: CATARACT SURGERY AND NSAIDS 1369 inhibition of COX-2 tends to determine the clinical ef- Penetration and Efficacy of Topical Ophthalmic ficacy of the NSAID. Nonsteroidal Antiinflammatory Drugs Due to the physiologic barrier of the ocular surface Mode of Delivery 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 Bromfenac The bromfenac molecule has been altered mydriasis and reduce pain during surgery is available. to make it more lipophilic to improve corneal penetra- tion, increase duration of action, and enhance COX-2 CURRENTLY AVAILABLE TOPICAL OPHTHALMIC inhibition.8 It has good ocular penetration with insig- NONSTEROIDAL ANTIINFLAMMATORY DRUGS 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. Bottle USA/ Drug (Generic) Drug (Brand) Manufacturer Dosage Size (mL) Europe Indication Bromfenac Bromday Bausch & Lomb QD 1.7 USA Treatment of postop inflammation and 0.09% reduction of pain after cataract surgery Prolensa Bausch & Lomb QD 1.6, 3 USA 0.07% Xibrom 0.09% ISTA; now generic BID 2.5, 5 USA Yellox Croma BID 5 Europe 0.9% mg/mL Pharmaceuticals Indomethacin Indocollyre Bausch & Lomb QID 5 Europe Treatment of postop inflammation and 0.1% 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 2.5 USA/Europe Intraoperative mydriasis surgery Ketololac Ketorolac Generic QID 3, 5, 10 USA/Europe Treatment of pain and inflammation tromethamine 0.4%, 0.5% following cataract surgery Ketololac Acular 0.5% Allergan QID 3, 5, 10 USA/Europe Treatment of pain and inflammation tromethamine 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 Alcon/Novartis TID 3 USA/Europe Treatment of pain and inflammation 0.1% associated with cataract surgery Ilevro Alcon/Novartis QD 1.7 USA 0.3% BID Z twice daily; NSAID Z nonsteroidal anti-inflammatory drug; QD Z once daily; QID Z 4 times daily J CATARACT REFRACT SURG - VOL 42, SEPTEMBER 2016 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 Intracameral Ketoralac–Phenylephrine used in the sodium salt form to increase its solubility.13 Arecentlyapprovedcombination of phenylephrine Additionally, at the physiologic pH of the eye, diclofe- 1.0% and ketorolac 0.3% injectable solution, Omidria, nac has limited permeability and must be buffered to a was designed to prevent intraoperative miosis and lower pH (6.0) to increase corneal penetration.7 Howev- reduce intraoperative pain. It is added to the irrigating er, decreasing the pH of the solution results in precipi- solution used during cataract surgery and is thus deliv- tation, and thus stabilizers must be used.14 To improve ered throughout the surgical procedure. Since ketorolac the poor aqueous solubility and corneal penetration, an inhibits both COX enzymes (COX 1 and COX 2), it is able oily formulation (in sesame oil) was created. 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
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