ketorolac tromethamine 0.4% to relieve eye pain and inflammation following cataract extraction and...

$: Ketorolac tromethamine 0.4% to relieve eye pain and inflammation following cataract extraction and keratorefractive surgery$
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Drug Profile

The NSAID family of drugs are routinely used in ophthalmology to reduce postoperative inflam-mation and to prevent or treat cystoid macular edema (CME) postcataract extraction, to prevent intra operative miosis during cataract surgery, reduce pain and photophobia after keratorefrac-tive surgery, and provide relief of seasonal allergic conjunctivitis symptoms.

Overview of ocular inflammationThe eye’s response to chemical, mechanical and thermal stimuli has an extensive inflammatory range, most of which involves the formation of prostaglandins (PGs). Synthesis of PGs and leu-kotrienes (naturally produced eicosanoid lipid mediators) after surgical trauma have been described [1–3]. In brief, after inflammation has been triggered, the arachidonic acid cascade is activated, leading to the formation of PG that will lead to a breakdown in the blood aqueous barrier, a pain threshold decrease and photo-phobia increase. Additional signs of inflam-mation in the eye include hyperemia, swelling,

miosis and decreased vision. It is very impor-tant to control ocular inflammation in order to maintain ocular integrity and function. The inflammatory response can be blocked at differ-ent sites using various therapeutic agents, such as corticoids (e.g., by blocking phospholipase A activity, the release of arachidonic acid is impeded) and NSAIDs. NSAIDs are known to inhibit cyclooxygenase (COX), thus inhibiting the production of prostaglandins. COX-1 and -2 are isoforms described as having different physiological properties [4]. COX-1 is responsi-ble for the physiological production of prosta-noids, while COX-2 is related to inflammation and pathological function. Both isoforms are very similar in their amino acid composition, molecular mass, intracellular location and func-tion. Yet, there are differences, including differ-ent gene location and changes in amino acids, at specific positions. NSAIDs also suppress polymorphonuclear cell mobility and chemo-taxis, and decrease expression of inflammatory cytokines and degranulation of mast cells [5].

Helga P Sandoval† and Kerry D Solomon†Author for correspondenceMagill Research Center for Vision Correction, MUSC – Storm Eye Institute, 167 Ashley Avenue, Charleston, SC 29425, USA Tel.: +1 843 792 2305 Fax: +1 843 792 6347 [email protected]

Ketorolac tromethamine ophthalmic solution, a NSAID, demonstrated analgesic activity when administered systemically. The original 0.5% formulation was shown to reduce inflammation and pain, as well as general discomfort after cataract and keratorefractive surgery. A reformulation that contains 20% less active ingredient than the original was approved for the reduction of ocular pain and burning/stinging following corneal refractive surgery. Ketorolac tromethamine 0.4% is as effective as ketorolac tromethamine 0.5% to control inflammation after cataract surgery (including prevention of cystoid macular edema) as shown in different clinical trials. Comparisons to other NSAIDs for pain control after keratorefractive procedures, such as laser-assisted in situ keratomileusis and photorefractive keratectomy, have also been reported. The purpose of this study was to review the action of ketorolac tromethamine 0.4% in the relief of eye pain and inflammation after cataract extraction and keratorefractive surgery.

Keywords: eye • inflammation • ketorolac • NSAID • ocular • pain

Ketorolac tromethamine 0.4% to relieve eye pain and inflammation following cataract extraction and keratorefractive surgeryExpert Rev. Ophthalmol. 4(5), 461–468 (2009)

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Expert Rev. Ophthalmol. 4(5), (2009)462

Sandoval & SolomonDrug Profile

Overview of the marketThe gold standard for the treatment of ocular inflammation has been the use of corticosteroids; however, there is a higher risk of developing adverse events associated with its use (e.g., intra ocular pressure increase, cataract formation, wound healing delay, increased risk of infection and others). The prolonged use of corticoids has been associated with a higher risk of developing these complications.

Nonsteroidal anti-inflammatory drugs are a safe alternative to the use of corticoids and are now routinely used pre- and post-oper-atively. A number of NSAIDs are currently available in the USA with different indications for their use. Both flurbiprofen 0.03% (Ocufen®, Allergan, CA, USA) and suprofen 1% (Profenal®, Alcon, Switzerland) are approved for intraoperative use during cataract surgery to inhibit excessive miosis. Diclofenac sodium ophthalmic solution (Voltaren Ophthalmic, Novartis) is a NSAID indicated for treatment of inflammation after cataract surgery. The diclofenac indication also includes the temporary relief of photophobia and pain in refractive surgery patients. Bromfenac ophthalmic solution 0.09% (Xibrom, ISTA Pharmaceuticals, CA, USA) is approved for treating ocular inflammation after cataract surgery. This solution is the first, twice-daily ophthalmic NSAID to be approved in the USA. Nepafenac (Nevanac 0.1%, Alcon) is the first prodrug topical NSAID that has received US FDA approval. Nepafenac is used three-times daily to treat pain and inflammation associated with cataract surgery. Indomethacin 1% ophthalmic suspension is another NSAID for the inhibition of miosis and the prevention of ocular inflammation after cataract surgery, and for the treatment of pain after keratorefractive surgery; however, it is not available in the USA.

Ketorolac tromethamine 0.4%Ketorolac tromethamine, originally approved as 0.5% (Acular®; Allergan, UK), is indicated for the temporary relief of ocular itch-ing due to seasonal allergic conjunctivitis and for the treatment of postoperative inflammation in patients after cataract extraction. In 2003, a new formulation was introduced to the US market: ketorolac tromethamine 0.4% (Acular LS, Allergan) containing 20% less active ingredient than the original formulation. It is approved for the reduction of ocular pain and burning/stinging following corneal refractive surgery. One drop four-times daily in the operated eye as needed for up to 4 days following corneal refractive surgery is the recommended dose.

ChemistryKetorolac tromethamine is a part of the pyrrolo–pyrrole group of NSAIDs for ophthalmic use. Its official chemical name is 5-ben-zoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid:2-amino-2-(hydroxymethyl) propane-1,3-diol (1:1). The product is a racemic mixture of R- and S-isomers of ketorolac tromethamine that exists in three crystal forms, which are equally soluble in water. Additional characteristics include a pH of 7.4 and osmolality of 290 mOsmol/kg. Its pKa is 3.5 and its molecular weight is 376.41. Both ketorolac tromethamine 0.4 and 0.5% share these aforemen-tioned characteristics. Ketorolac 0.4% contains 20% less active ingredient than the original 0.5% formulation. Other differences

between the two solutions include the preservative concentration (ketorolac 0.5% contains 0.01% benzalkonium chloride, while ketorolac 0.4% contains 0.006%) and the concentration of the inactive ingredient edetate disodium (0.1 and 0.015% in ketorolac 0.5 and 0.4%, respectively).

PharmacodynamicsIt has been reported that when ketorolac tromethamine is used systemically it has an anti-inflammatory, analgesic and antipyretic action [6]. These activities seem to be due mainly to the inhibi-tion of the COX enzymatic system, thereby inhibiting the PG biosynthesis [6,7]. Similarly, the effect of ketorolac ophthalmic solution is believed to be due to the inhibition of PG synthesis in the eye [6,8–10].

Cyclooxygenase-1 and -2 are two of the three isoforms that have been described. Their expression in the eye has been described by Radi and Render [11]. They are similar, although it has been described that they have different physiological properties. COX-1 has been associated with the physiological production of prostaglandins, whereas COX-2 appears to be related to the pathological function and inflammatory response [4]. However, both isoforms are involved in multiple physiologic, as well as pathologic, processes [9,11–14].

The anti-inflammatory activity of ketorolac 0.4% and other NSAIDs was investigated using a rabbit model of ocular inflam-mation induced by injecting a lipopolysaccharide endotoxin iso-lated from Salmonella enterica intravenously, showing a nearly complete inhibition of PG synthesis in the aqueous humor com-pared with vehicle [15]. In addition, in a similar rabbit model, Waterbury and colleagues evaluated the COX activity and anti-inflammatory effect of ketorolac 0.4% [16]. They found that ketorolac 0.4% is a relatively COX-1-selective NSAID with potent ocular anti-inflammatory action producing almost complete inhi-bition of PG synthesis in aqueous humor in the treated eyes. These results are similar to previous reports of extraocular studies conducted in rats that have shown that ketorolac tromethamine is a potent inhibitor of COX-1 and -2 [17,18]. Although COX-2 has been associated with pathological processes, it can be found under normal conditions [12]. In addition, it has been shown that by inhibiting COX-1, flare could be reduced [9].

Pharmacokinetics & metabolismKetorolac 0.5% is distributed throughout all the ocular tissues in rabbit eyes [6,19]. Within 15 min after the topical application of ketorolac 0.5%, peak plasma levels were approximately 0.2 µg/ml [19]. In the FDA material-safety datasheet, after the application of one drop of ketorolac 0.5% three-times daily for 10 days, five out of 26 normal patients showed ketorolac plasma levels rang-ing between 10.7 and 22.5 ng/ml on day 10. When ketorolac tromethamine 10 mg is administered systemically every 6 h, peak plasma levels at steady state are approximately 960 ng/ml. When used systemically (intravenously or orally) 100% of ketorolac is absorbed and largely metabolized in the liver, while the main route of excretion of ketorolac and its metabolites is through the kidneys.

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Ketorolac tromethamine 0.4% following cataract extraction & keratorefractive surgery Drug Profile

Clinical efficacySeveral studies have been conducted to evaluate the anti-inflam-matory effect of ketorolac tromethamine 0.4% and pain relief after cataract and keratorefractive surgery. Ketorolac trometh-amine has been compared with other NSAIDs, placebo and ster-oids. Studies using animal models of ocular inflammation have been conducted as well. Overall, the results of these peer-reviewed published studies have shown that ketorolac tromethamine 0.4% ophthalmic solution is safe and efficacious in reducing pain and inflammation, postoperatively.

Ketorolac tromethamine 0.4% & cataract surgeryKetorolac tromethamine 0.4% versus placeboPrice and Price reported that ketorolac 0.4% patients complained of ocular pain significantly less often during 24 h after the pro-cedure than the control group (one vs nine eyes) [20]. No sig-nificant differences among the groups were detected in patient cooperation, ocular pain and discomfort during or immediately after surgery. The efficacy of ketorolac 0.4% to control pain and discomfort associated with cataract surgery was evaluated in this single-center, double-masked, randomized, fellow-eye, placebo-controlled trial that included 25 subjects undergoing bilateral cat-aract extraction. The first eye undergoing surgery was randomized to ketorolac 0.4% or artificial tears and the second eye received the alternate treatment. In this study, the assigned treatment was used four-times a day starting 3 days prior to and 1 day after surgery. The surgeon evaluated patient cooperation and ocular pain or discomfort during surgery, and each patient rated ocular pain and discomfort immediately and 24 h postoperatively. No adverse events occurred during this trial.

Ketorolac tromethamine 0.4% versus NSAIDsSandoval and coworkers compared the effectiveness and patient tolerance of ketorolac 0.4% (n = 20) to ketorolac 0.5% (n = 20) after routine phacoemulsification and lens implantation [21]. In this prospective, double-masked study that included 40 eyes of 40 patients, the assigned treatment was started 15 min prior to surgery and continued four-times a day after surgery for 1 week and twice a day for the following 3 weeks thereafter. Best-corrected visual acuity (BCVA), slit-lamp (SL) cell evaluation, intraocular pressure (IOP), laser cell and flare measurements, and subjective patient tolerance were assessed. The authors found that 1 day after surgery, 70% of patients in the ketorolac 0.5% group reported more symptoms – mainly foreign-body sensation and stinging/burning compared with 40% in the ketorolac 0.4% group. No significant differences were found in BCVA, slit-lamp cell evaluation, IOP or laser cell and flare measurements. The effectiveness of ketorolac tromethamine 0.4% to reduce anterior-segment inflammation after routine cataract surgery was similar to ketorolac 0.5% with less patient discomfort.

In a series of randomized, investigator-masked clinical studies, Bucci and colleagues compared the effectiveness of ketorolac 0.4% to other NSAIDs in reducing aqueous PGE

2

levels as a predictive determinant of clinical efficacy. In the first study, 132 patients received ketorolac 0.4% or nepafenac

0.1% four-times daily for 2 days before cataract extraction [22]. Aqueous samples obtained at surgery were analyzed for PGE

2 lev-

els and NSAID concentrations. Overall, aqueous concentration of ketorolac was significantly higher than amfenac, the active metabolite of nepafenac (1079.1 ± 881.5 vs 353.4 ± 126.0 ng/ml; p < 0.001). The mean aqueous PGE

2 levels in eyes treated with

ketorolac 0.4% were also lower than those treated with nepaf-enac 0.1% (159.5 ± 114.66 pg/ml and 322 ± 197.8 pg/l, respec-tively; p < 0.001). These findings demonstrated that ketorolac 0.4% penetrated into aqueous and inhibited PGE

2 synthesis

significantly more than nepafenac 0.1%.In the second study, 56 patients undergoing cataract surgery

received one drop of ketorolac 0.4% or bromfenac 0.09%, respec-tively, 6 and 12 h preoperatively consistent with on-label dosing schedules [23]. Similarly, aqueous humor was collected at the start of surgery and analyzed for NSAID concentrations and PGE

2 lev-

els. Ketorolac 0.4% reached aqueous at significantly higher con-centrations (130.5 ± 37.8 vs 6.2 ± 3.1 ng/ml; p = 0.004) and low-ered PGE

2 levels (204.2 ± 95.5 vs 263.7 ± 90.0 pg/ml; p = 0.020)

significantly more than bromfenac 0.09%. Although these find-ings suggest that ketorolac 0.4% administered four-times a day may provide superior control of prostaglandin-mediated inflam-mation compared with bromfenac 0.09% administered twice a day, this could be due to the difference between the two NSAIDs in concentration and/or dosing.

In another study, Duong and colleagues reported that ketorolac tromethamine 0.4% was significantly better than nepafenac 0.1% in patient satisfaction, compliance and postoperative pain control [24]. No differences between the two groups were found in regard to anterior segment inflammation after cataract extraction and IOL implantation. In this study, patients were randomized to ketorolac tromethamine 0.4% (n = 100 eyes of 94 patients) or nepafenac 0.1% (n = 93 eyes of 89 patients) starting 3 days prior to surgery and following the recommended dose for each NSAID, which was continued for 1 week after the surgical procedure. Additionally, patients in the ketorolac tromethamine 0.4% group received gatifloxacin 0.3% and prednisolone acetate 1%, while subjects in the nepafenac 0.1% group received moxifloxacin 0.5% and prednisolone acetate 1% four-times daily for 1 week; the antibiotic was then discontinued and the corticosteroid tapered.

Ketorolac tromethamine 0.4% & cystoid macular edemaPreoperative use of ketorolac has long been known to reduce the incidence of CME [25]. Several studies have demonstrated that ketorolac 0.5% effectively reduces macular thickness and improves visual acuity in patients with either acute or chronic pseudophakic CME [26–28]. A randomized, double-masked study evaluated the incidence of clinically significant CME in 100 patients under-going cataract surgery [29]. Patients received ketorolac 0.4% for 3 days, 1 day or 1 h, or a placebo before phacoemulsification. All treatment groups received ketorolac 0.4% for 3 weeks post-operatively; the placebo group received vehicle. This study dem-onstrated that patients receiving ketorolac 0.4% for 1 or 3 days did not develop CME, whereas 12% of patients in the placebo group and 4% of patients in the 1-h group developed CME.



In a prospective, randomized, investigator-masked, multicenter study, Wittpenn and colleagues recently evaluated whether adding perioperative ketorolac 0.4% improves cataract surgery outcomes relative to topical steroids alone in patients without known risk fac-tors for CME [30]. Patients with no recognized CME risks (diabetic retinopathy, retinal vascular disease or macular abnormality) who were scheduled to undergo phacoemulsification were randomized to receive either prednisolone acetate 1% four-times daily alone (steroid group; n = 278), or prednisolone 1% four-times daily plus ketorolac 0.4% four-times daily (steroid/ketorolac group; n = 268) for approximately 4 weeks postoperatively. Preoperatively, in the steroid/ketorolac group, patients also received topical ketorolac 0.4% four-times daily for 3 days. Overall, no patients in the ster-oid/ketorolac group and five patients in the steroid group had clinically apparent CME (p = 0.032). Based on optical coherence tomography, no steroid/ketorolac patient had definite or probable CME, compared with six (p = 0.003), and fewer patients had retinal thickening of more than 10 µm compared with the steroid group (26 vs 51%; p < 0.001). These findings suggest that adding perioperative ketorolac to postoperative prednisolone significantly reduces the incidences of CME and macular thickening in cataract surgery patients already at low risk for this condition.

Ketorolac tromethamine 0.4% after corneal refractive surgeryTo evaluate the safety and analgesic efficacy of ketorolac 0.4% after photorefractive keratectomy (PRK), two multicenter, randomized, double-masked studies that included 313 eyes from 313 subjects were conducted. Patients were treated with one drop of ketorolac 0.4% (n = 156) or its vehicle (n = 157), four-times daily for up to 4 days. Pain intensity, pain relief, use of escape medication and severity of ocular symptoms were the measured outcomes. In this study, it was shown that a significantly higher percentage of patients in the ketorolac 0.4% group complained less of ocular symptoms (burning/stinging vs control: 75 vs 52.2%; foreign-body sensation 63.5 vs 41.1%; photophobia 50.6 vs 26.1%; and tearing 50.6 vs 28.7%, respectively). Furthermore, during the first 12 h after surgery, fewer patients in the ketorolac 0.4% group had severe-to-intolerable pain (41.6 vs 84.4% control) and required less oral ‘escape’ pain medication (45.5 vs 90.4%). These results were statistically significant (p < 0.05). There were no significant dif-ferences among the two groups for any reported adverse events [31].

In a prospective, double-masked, randomized study, the effect ketorolac tromethamine 0.4% (n = 16 eyes), nepafenac 0.1% (n = 30 eyes) and bromfenac 0.09% (n = 12 eyes) on corneal wound heal-ing (time to total re-epithelialization), as well as pain control, were compared after PRK. Although described as a randomized study, the first 15 patients (30 eyes) were assigned to receive nepafenac and moxifloxacin 0.5% to determine the safety of this combination. After safety was demonstrated, the remaining subjects were then randomized to either ketorolac 0.4% or bromfenac 0.09%. Pain relief was defined as pain assessment before the NSAID eye-drop minus pain assessment after the NSAID eye-drop at days 1 and 3 after surgery. Subjects in the nepafenac group used moxifloxacin 0.5%, while subjects in the ketorolac tromethamine 0.4% and bromfenac 0.09% groups were instructed to use gatifloxacin 0.3%.

Antibiotic drops, as well as NSAID drops, were used three-times daily for a week. All patients used prednisolone acetate 1% four-times daily for a week. Subjects were provided with preservative-free artificial tears and hydro codone 5-mg/acetaminophen 500-mg tablets to use as needed. The results showed that eyes treated with ketorolac 0.4% or nepafenac 0.1% healed completely and signifi-cantly faster (mean: 5.5 days) than eyes treated with bromfenac 0.09% (mean: 7.3 days). In addition, there was a decrease in the pain score in all groups at day 1, but significantly decreased only in the nepafenac group. This decrease was significant in all groups at day 3. The use of oral medication was not addressed; therefore, it is unknown how this might impact the differences in pain outcomes. No adverse events were seen in any of the groups [32].

Sher and coworkers compared the efficacy to control pain, burning, photophobia, foreign-body sensation and epithelial heal-ing rates of ketorolac 0.4% and bromfenac 0.09% [33]. A total of 199 eyes undergoing PRK were included for analysis. Eyes were randomized to either of the NSAIDs. Subjects undergo-ing bilateral surgery received ketorolac tromethamine 0.4% in one eye and bromfenac 0.09% in the fellow eye. Patients were excluded if they used any postoperative oral analgesic or anti-inflammatory. Postoperatively, all patients received gatifloxacin 0.3%, prednisolone acetate 1.0% and artificial tears. Ketorolac tromethamine 0.4% (n = 102 eyes) was applied four-times daily, while bromfenac 0.09% (n = 97 eyes) was used twice a day. In addition, the use of mitomycin C 0.02% was optional, it was used in 82 and 88% of eyes in the ketorolac tromethamine 0.04% and bromfenac 0.09% groups, respectively. The results of this study showed that both NSAIDs were effective in controlling pain after PRK. No differences were found in burning, photophobia or foreign-body sensation. In addition, healing rates were similar in both groups with all eyes completely re-epithelialized by day 5. No NSAID-related adverse events were noted.

The use of ketorolac tromethamine 0.4% to control pain after laser in situ keratomileusis (LASIK) has also been evalu-ated. Dougherty conducted a double-masked study that included 60 eyes of 30 patients who were randomly assigned to instill ketorolac tromethamine 0.4% in one eye and artificial tears in the fellow eye starting 2 days before LASIK, and assessed the effect of ketorolac tromethamine 0.4% [34]. Pain was assessed immediately after flap creation (intraoperative), as well as 4, 6 and 24 h postoperatively. The mean overall pain score, although not significant, was lower in the ketorolac tromethamine 0.4% group, while the postoperative pain score was significantly lower (p < 0.05). No intraoperative complications were seen or adverse events reported.

A prospective, randomized, paired-eye comparison, double-masked study determined the degree of postoperative pain and rate of healing in eyes treated with either ketorolac 0.4% or nepa-fenac 0.1% after epi-LASIK [35]. Study medications were applied immediately after the procedure, before placement of the bandage contact lens. Although the original target population was 60 eyes of 30 patients, this study was halted after only 14 eyes of seven patients because most patients in the nepafenac 0.1% arm devel-oped haze. Eyes treated with nepafenac also healed at a slower rate



than eyes treated with ketorolac 0.4% in 57% of patients. Patients reported significantly more pain in nepafenac-treated eyes at day 3 when pain was at its peak (p = 0.046). Although this was a small sample size, these findings suggest that nepafenac 0.1% should be used with caution following epi-LASIK.

Other ketorolac tromethamine 0.4% surgical studiesKim and coworkers evaluating the effect of ketorolac trometh-amine 0.4% in patients having vitreoretinal surgery found that ketorolac tromethamine 0.4% was well tolerated and safely reduced postoperative pain and inflammation, thus improving visual recovery [36]. A total of 109 eyes of 109 patients were ran-domized to receive ketorolac tromethamine 0.4% or placebo. Assigned treatment was used four-times daily starting 3 days prior to surgery, and was continued for 1 month after surgery. Assessments included intraoperative pupil size, pain and inflam-mation on postoperative day 1 and postoperative best-corrected visual acuity at 1 month. Mild stinging and tearing was reported by five out of 55 patients (9%) in the ketorolac tromethamine 0.4% group, and two out of 54 patients (4%) in the control group.

In a prospective, double-masked study, patients were randomized to one of four groups of 25 subjects each, to assess the clinical benefit, relative efficacy and pharmacokinetic-response curve from data collected during the preoperative and postoperative use of ketorolac tromethamine 0.4% to evaluate cataract surgery out-come [29]. Group 1 received ketorolac 0.4% four-times daily for 3 days and three times (i.e., every 15 min) 1 h before surgery. Group 2 received ketorolac 0.4% four-times daily for 1 day prior to surgery and three times (i.e., every 15 min) 1 h before surgery. Group 3 received ketorolac 0.4% three times (i.e., every 15 min) 1 h before surgery. Group 4, had no predosing schedule and received only vehicle three times (i.e., every 15 min) 1 h before surgery. Postoperatively, subjects of groups 1–3 received ketorolac 0.4% for 3 weeks; and group 4 (placebo) received vehicle. Assessments included preservation of preoperative mydriasis, phacoemulsifica-tion time and energy, operative time, corneal clarity, endothelial cell counts, postoperative inflammation, intraoperative and post-operative discomfort, complications and incidence of clinically sig-nificant CME. Results showed that pupil size was maintained sig-nificantly better in groups 1 and 2 than in groups 3 and 4. Surgical time, phacoemulsification time and energy, and endothelial cell loss were decreased when using ketorolac 0.4% 1 and 3 days before surgery. Additionally, visual acuity outcomes were improved with its use. CME was not observed in any of the patients in groups 1 and 2, while 4 and 12% were noted in groups 3 and 4, respectively.

Safety & tolerabilityThe most frequent adverse event associated with the use of topical NSAIDs is transient stinging and burning after administration. A total of 40% of subjects participating in clinical trials reported transient stinging and burning after using ketorolac tromethamine 0.5% (FDA material-safety datasheet). These complaints decreased after use of ketorolac tromethamine 0.4%. Sandoval and colleagues reported that 30 and 45% of patients in the ketorolac 0.4% and ketorolac 0.5% group complained of burning and stinging after

routine cataract extraction, respectively [21]. In addition, 25% of subjects in the ketorolac 0.4% group and 47.8% in the vehicle group reported moderate-to-severe burning and stinging after PRK [31].

More-severe but less-frequent adverse events include kerati-tis, corneal subepithelial infiltrates, ulceration and corneal melt [5,37–46]. Different factors have been associated with the presence of these severe complications. The largest study included 140 eyes of 129 patients from 63 practices in the USA that had complications after using NSAIDs. The results are based on 117 eyes that could have the NSAID used confirmed. A lower number of eyes used ketorolac 0.5% or ketorolac 0.5% preservative-free 22 or 18.8%, the remaining eyes used Voltaren (27.4%) or generic diclofenac (53.8%). Eyes using ketorolac 0.5% tended to have more ocular comorbidities and drops were administered more often, having a higher total dosage. In addition, six out of the 22 cases using ketoro-lac 0.5% were severe; these cases did not use it in a surgical setting; and drops were used for a long period of time. They reported that presence of systemic diseases, such as diabetes, previous eye surgery in the affected eye and surgeries other than cataract (e.g., refractive surgery, penetrating keratoplasty, glaucoma and IOL exchange or secondary IOL implantation) were associated with higher risk of developing more-severe corneal complications. Nonsurgical cases were associated with higher doses and more comorbidities [37].

Other studies, including case series and case reports, have shown similar factors to be associated with the presence of cor-neal complications. The use of NSAIDs for long periods [40,42], as well as the use of doses higher than the recommended [44] and concomitant use with other topical agents, such as corticoids, and certain antibiotics, such as gentamicin [5,39], have been associated with corneal melt and perforation. In addition, the presence of certain systemic diseases, including diabetes, rheumatoid arthritis and Sjogren’s disease, and other corneal and ocular pathologies, have been also associated with these adverse events [39–41,43,45].

Although most of the studies have shown the benefit of using NSAIDs and their safety to prevent intraocular inflammation after cataract surgery, including CME, and pain after refractive surgery, certain severe adverse events can occur when used in the circumstances described previously.

Regulatory affairsKetorolac 0.4% is approved for use in the USA, Canada, Brazil, Mexico, Chile, Jordan, Colombia, Argentina and Venezuela for the reduction of ocular pain and burning/stinging following cor-neal refractive surgery. In India, ketorolac 0.4% is approved for the relief of ocular itching due to seasonal allergic conjunctivitis and for prophylaxis and relief of postoperative ocular inflammation.

Expert commentaryKetorolac tromethamine, has been widely used in ophthalmology. In reported clinical trials using ketorolac tromethamine 0.5%, it has been shown to be highly effective in relieving pain after radial keratotomy [47,48], PRK [49] and LASIK [50], and in treating allergic conjunctivitis [51]. Its efficacy in the reduction of inflammation after cataract surgery has been shown [52], and it has been successfully compared with the efficacy of topical steroids after extracapsular



cataract extraction [53,54] and phaco emulsification [55,56]. The effectiveness of ketorolac 0.5% in the treatment of aphakic and pseudophakic macular edema has also been described [26].

The reformulation of ketorolac tromethamine 0.4% (contain-ing 20% less active ingredient) is indicated for the reduction of ocular pain and burning/stinging following corneal refrac-tive surgery and has been proven in different studies to be as effective as the original 0.5% formulation in the reduction of anterior segment inflammation, as well as to prevent CME after routine cataract extraction. Reduction in patient complaints over-all, intraoperative maintenance of pupil size and postoperative improvement in visual outcome have all successfully been shown.

Five-year viewIn the past few years, interest in the use of perioperative NSAIDs has substantially increased, at least in part, to avoid steroid-related complications. Ketorolac is the most studied NSAID. Multiple clin-ical studies have demonstrated the safety and efficacy of ketorolac 0.4% for the alleviation of ocular inflammation and pain. Current data suggest that ketorolac 0.4% may be more effective than brom-fenac 0.09% and nepafenac 0.1%. Large, head-to-head clinical studies are warranted to compare the efficacy of NSAIDs for the treatment of inflammation and pain following ocular surgery.

Current evidence strongly supports the use of ketorolac 0.4% in combination with corticosteroids to decrease the incidence of postoperative CME. This potential benefit may soon be demon-strated more conclusively by other clinical trials. Further studies are, however, warranted to assess if the use of ketorolac 0.4% alone can provide comparable benefits to that of the combination of corti-costeroid and ketorolac 0.4%. Nevertheless, ketorolac appears to be safe and efficacious against a variety of ocular surgery complications.

Information resources

• Perry HD, Donnenfeld ED. An update on the use of ophthal-mic ketorolac tromethamine 0.4%. Expert Opin. Pharmacother. 7, 99–107 (2006).

• Sivaprasad S, Bunce C, Wormald R. Non-steroidal anti-inflam-matory agents for cystoid macular oedema following cataract surgery: a systematic review. Br. J. Ophthalmol. 89, 1420–1422 (2005).

Financial & competing interests disclosureThe authors have been supported in part by NIH/NEI EY-014793; and an unrestricted grant to MUSC-SEI from Research to Prevent Blindness, New York, NY, USA. The authors have no financial or proprietary interest in any product mentioned herein. Kerry D Solomon, MD, is a consultant for Alcon Laboratories and Allergan, Inc. The authors have no other relevant affiliations or financial involvement with any 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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Ketorolac 0.4% is comparable to ketorolac 0.5% to reduce intraocular inflammation after surgery.

• Ketorolac 0.4% is safe and effective to control pain after keratorefractive procedures.

• The use of ketorolac 0.4% in the preoperative as adjunct treatment with postoperative steroids prevents CME and macular thickening.

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Affiliations• Helga P Sandoval, MD MSCR

Magill Research Center for Vision Correction, MUSC – Storm Eye Institute, 167 Ashley Avenue, Charleston, SC 29425, USA Tel.: +1 843 792 2305 Fax: +1 843 792 6347 [email protected]

• Kerry D Solomon, MD Magill Research Center for Vision Correction, Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA

ketorolac tromethamine 0.4% to relieve eye pain and inflammation following cataract extraction and...

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