SQU Med J, April 2010, Vol. 10, Iss. 1, pp. 57-63, Epub. 17th Apr 10 Submitted -10th July 09 Revision Req. 23rd Nov 09. Revision Recd. 9th Dec 09 Accepted - 6th Jan 10 Department of Ophthalmology, Al-Assad Hospital, Tishreen University, Latakia, Syria * To whom correspondence should be addressed. Email: aksam.ahmad@yahoo.com مقارنة بني كيتوروالك تروميثامني وأسيتات الربيدنيزولون يف منع تقلص احلدقة احملّفز باجلراحة أثناء جراحة الساد أكسم جودت أحمد، يوسف محمد سليمان، جنوى فايز كردغلي امللخ�ص: الهدف: مقارنة فعالية و�شالمة ا�شتعمال اأ�شيتات الربيدنيزول�ن 1% والكيت�روالك تروميتامني 0.5% م��شعيًا للمحافظة على ت��ّشع احلدقة خالل جراحة ال�شاد. الطريقة: �شملت هذه الدرا�شة اال�شتباقية الع�ش�ائية املقّنعة جزئيًا خم�شني مري�شًاً، حيث مت تطبيق معاجلة م��شعية بالطريقة �ش�اء ال�شاد، ا�شتخراج قبل �شاعة من 24 بدءاً مري�شا( 25 ( تروميتامني بالكيت�روالك اأو مري�شا( 25 ( اأ�شيتات بالربيدنيزول�ن تعادل 4 كلية جرعة اإىل ال��ش�ل وحتى دواء كل من �شاعات كل 6 قطرة ُتعطى كانت الَعَد�َشة(. با�ْشِتْحاَلُب اأو العد�شة با�شتخراج التقليدية املر�شى �شالمة من وللتاأكد اجلراحي، العمل اأثناء اأوقات ثالثة يف احلدقة قطر قيا�س مت االإيبنفرين. من خاليًا االإرواء �شائل وكان قطرات، مت مراقبتهم عرب التنظري املجهري احلي�ي وتنظري قعر العني وال�شغط داخل املقلة واالآثاٌر ال�شاِئَرة وحدة االإب�شار. النتائج: كان مت��شط تغري قطر احلدقة من مرحلة ما قبل ال�شق اإىل مرحلة ما بعد اإرواء وغ�شل الق�رسة وال�شفط وزرع العد�شة اأقل وب�شكل ج�هري مع الكيت�روالك منه مع الربيدنيزول�ن)P=0.003 (. وبالنتيجة كان مت��شط قطر احلدقة بعد غ�شل الق�رسة وال�شفط وزرع العد�شة اأكرب وب�شكل ج�هري مع الكيت�روالك ،)P=0.244( مل تالحظ اأية فروق ج�هرية بني املجم�عتني يف قطر احلدقة �ش�اء قبل ال�شق االأول .)P>0.0001(مقارنة مع الربيدنيزول�ن الدوائني. لكال �شاِئَرة اآثاٌر ت�شجل ومل املجم�عتني بني متقاربة كانت فقد االأمان متغريات اأما .)P=0.505( احلدقة مقّب�س اإعطاء بعد اأو اخلال�صة: كان حتّمل املر�شى للكيت�روالك تروميثامني والأ�شيتات الربيدنيزول�ن جيدا وب�شكل مت�شاوي وبدون اآثاٌر �شاِئَرة، لكن الكيت�روالك تروميثامني كان اأف�شل يف منع تقل�س احلدقة الناجت عن اجلراحة. مفتاح الكلمات: كيت�روالك تروميتامني، اأ�شيتات الربيدنيزول�ن، ا�شتخراج ال�شاد، تقل�س احلدقة، ت��شع احلدقة. abstract: Objectives: The aim of this study was to compare the efficacy and safety of topical prednisolone acetate 1% and topical ketorolac tromethamine 0.5% in the maintenance of pupillary mydriasis during cataract surgery. Methods: Fifty patients were enrolled in this prospective, partially masked and randomised study. They were assigned to receive topical treatment with either prednisolone acetate (n = 25) or ketorolac tromethamine (n = 25), starting 24 hours before cataract extraction (either routine extracapsular cataract extraction or phacoemulsification). One drop of the study medication was instilled every 6 hours for a total of 4 drops. No epinephrine was used in the intraoperative irrigation solution. Pupil diameter was measured three different times during surgery. To ensure participant safety, biomicroscopy, ophthalmoscopy, intraocular pressure, adverse events and visual acuity were also monitored. Results: The mean pupil diameter change from the time of the pre-incision until after cortical irrigation and aspiration and lens implantation was significantly less with ketorolac than with prednisolone (P = 0.003). Consequently, mean pupil diameter after cortical irrigation and aspiration and lens implantation was significantly greater with ketorolac than with prednisolone (P <0.0001). No significant differences between groups were observed in the pupil diameter before the first incision (P = 0.244), nor after administration of a miotic agent (P = 0.505). Safety variables were comparable and no drug-related adverse events were reported. Conclusion: Ketorolac tromethamine 0.5% and prednisolone acetate 1% solutions were equally well tolerated without related adverse events, but ketorolac was better in preventing surgically induced miosis. Keywords: Ketorolac tromethamine; Prednisolone acetate; Cataract extraction; Miosis; Mydriasis. Comparison of Ketorolac Tromethamine and Prednisolone Acetate in Preventing Surgically Induced Miosis during Cataract Surgery Yusuf M Suleiman, Najwa F Krdoghli, *Aksam J Ahmad clinical & basic research Advances in Knowledge 1. Ketorolac tromethamine and prednisolone acetate are well tolerated when applied topically before cataract extraction. 2. Ketorolac tromethamine is very effective in preventing surgically induced miosis, while prednisolone acetate is not, despite the fact that both drugs inhibit the liberation of prostaglandins which are believed to be the main cause of surgically induced miosis and postoperative inflammation during cataract surgery. 3. Many previous studies have demonstrated that both drugs are equally effective in preventing and treating postoperative inflammation. Comparison of Ketorolac Tromethamine and Prednisolone Acetate in Preventing Surgically Induced Miosis during Cataract Surgery 58 | SQU Medical Journal, April 2010, Volume 10, Issue 1 Techniques for extracapsular cataract extraction (ECCE) have improved tremendously in the past few decades, with small-incision surgery nowadays being the standard treatment. Nevertheless, ocular tissue is traumatised during surgery leading to the activation of phospholipase A2,1 and the liberation of two groups of lipid molecules: arachidonic acid (AA) metabolites, and platelet-activating factors (PAFs).2 Arachidonic acid forms the substrate for further reactions mainly by the cyclo-oxygenase and the lipoxygenase pathways. The main products of the cyclo-oxygenase pathway are prostaglandins (PGs), and the main products of the lipoxygenase pathway are leukotrienes (LTs). Endogenous PGs produce many effects such as: miosis during surgery, postoperative inflammation, increased permeability of the blood-ocular barriers, conjunctival hyperaemia and change in intraocular pressure.1-3 Platelet-activating factors induce an impressive repertoire of responses in vitro and seem to be a major regulator of cell adhesion and vascular permeability in many forms of acute inflammation, trauma, shock, and ischaemia, but their precise role is still under investigation.2 The decrease in pupil diameter can make cataract removal more difficult and increases the risk of surgical trauma, postoperative ocular inflammation,4 and posterior capsule rupture.5 Thus, maintaining adequate pupil dilation is considered an important part of ensuring that cataract removal proceeds smoothly. Inhibition of PGs’ biosynthesis inhibits intraoperative miosis during cataract surgery, reduces the vascular permeability of the blood- ocular barrier, and modifies inflammation.3 Non-steroid anti inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase enzyme, so inhibiting the biosynthesis of PGs but not LTs.2-3 Topical ophthalmic NSAIDs have been shown to be effective in treating a variety of conditions in which prostaglandins are believed to play a causative role,3 including surgically induced miosis,6-7 postoperative inflammation,8-9 treatment and prevention of cystoid macular oedema (CME),3-10 and control the pain of refractive surgery.11 The NSAID ketorolac tromethamine has demonstrated efficacy in the prevention of surgically induced miosis,12 in the treatment of postoperative ocular pain,13 in the treatment of chronic aphakic and pseudophakic CME14 and in the prevention and suppression of ocular inflammation after cataract surgery.15 Glucocorticoids inhibit the phospholipase A2 enzyme and consequently inhibit the biosynthesis of both platelet-activating factors and arachidonic acide.2 This results in the inhibition of the biosynthesis of both PGs and LTs.3 Topical steroids like prednisolone acetate have been the standard regimen postoperatively for many years and are known to prevent inflammatory reactions after cataract extraction. Previous studies have not mentioned the role of corticosteroids in preventing surgically induced miosis, despite that corticosteroids inhibit PGs liberation. However, important side effects of topical steroids are increased intraocular pressure (IOP), impairment of wound healing and postoperative ocular infection.16-17 The present study compared the efficacy and safety profile of ketorolac tromethamine 0.5% ophthalmic solution with that of prednisolone acetate 1% ophthalmic solution in maintaining the pupillary mydriasis during cataract surgery. The primary efficacy variable was the change in pupil diameter during surgery. Methods This prospective, partially masked and randomised study was performed in the Ophthalmology Department, Al-Assad Hospital, Tishreen University, Latakia, Syria during the period March 2008 to March 2009. Patients who were scheduled to undergo unilateral cataract surgery (either routine ECCE or phacoemulsification) and posterior Therefore, these findings suggest that there are other factors, rather than prostaglandins, that interfere in surgically induced miosis. application to patient care 1. Ketorolac has many advantages over prednisolone, such as preventing surgically induced miosis and its complications, avoiding the possible steroid-induced pressure increase, and avoiding other steroid-related side effects. These advantages, together with the good efficacy in controlling postoperative inflammation and lowering costs, may make ketorolac a good choice before and after cataract extraction, especially if a patient is a known steroid responder. Yusuf M Suleiman, Najwa F Krdoghli, and Aksam J Ahmad Clinical and Basic Research | 59 chamber-intraocular lens (PC-IOL) implantation were enrolled in the study. The study protocol was approved by the appropriate institutional review board and written informed consent was obtained from all patients before enrollment in the study. Some cases were excluded according to the study protocol. Patients were not enrolled if they had any of the following features: were pregnant or lactating; only one eye with good visual acuity; any uncontrolled systemic or ocular disease; a history of uveitis or glaucoma; pseudoexfoliation syndrome; a history of any ocular disorder or surgery that might interfere with the surgical procedure or interpretation of the study results; a known sensitivity to any of the components of the study medication; use of systemic steroids or NSAIDs within 2 weeks before study entry, or topical ophthalmic drugs in the eye to be operated within 1 month before study entry. After this process, fifty patients were enrolled in the study. Randomly, 25 patients were given ketorolac tromethamine 0.5% and 25 patients were given prednisolone acetate 1% by the study executor, while the surgeon was masked to patient randomisation. Patient characteristics of the two groups are shown in Table 1. No significant differences in age, sex, pre-surgery IOP, operated eye or procedure were observed between the two groups (P ≥ 0.076). All patients in the two groups completed the study and were included in the efficacy and safety analysis. Patients were assigned to receive either ketorolac tromethamine 0.5% solution (ROLAC® Oubari Pharma, Aleppo, Syria) or prednisolone acetate 1% solution (PRED-ALPHA-FORT® ALPHA- Ind., Aleppo, Syria) according to a randomisation schedule, starting 24 hours before surgery. One drop of study medication was instilled every 6 hours, for a total of 4 drops. Topical pupillary dilating agents (tropicamide 0.5% and phenylephrine 10 %) were used, starting one hour before surgery, to induce operative mydriasis. Antimicrobial agents were used starting 24 hours before surgery, and retrobulbar anaesthesia was used in all patients. The intraocular irrigating solutions did not contain epinephrine, rather viscoelastics were used by all surgeons. A miotic agent (carbachol) was used after intraocular lens (IOL) implantation, only when the pupil was still markedly dilated, to study the effect of ketorolac and prednisolone on the carbachol efficacy. Any non-study medications that could interfere with interpretation of the study results (e.g. affect pupil diameter) were specifically prohibited by the study protocol. The surgery then proceeded as scheduled and all patients received a subconjunctival dexamethasone plus gentamycin injection at the end of the surgery. Intraoperative pupil diameter was measured at three different times during surgery using a Castroviejo caliper and standard microscope at 10x magnification under full illumination. The first measurement (preincision [pre-I]) provided the baseline value and was taken immediately before the first incision. The second measurement was Table 1: Patients characteristics of the two study groups Prednisolone group n = 25 Ketorolac group n = 25 P value Age by year Mean ± SD 70.56 ± 8.39 65.68 ± 10.52 0.076* Range 47-84 42-80 Sex Female 13 (52%) 14 (56%) > 0.1** Male 12 (48%) 11 (44 %) Pre-surgery IoP (mmHg) Mean ± SD 13.88 ± 3.47 13.49 ± 5.20 0.752* operated eye Right 14 (56%) 14 (56%) 1** Left 11 (44%) 11 (44%) Procedure ECCE 15 (60%) 15 (60%) 1** 10 (40%) 10 (40%)Phaco Legend: * = Analysis of variance test; ** = χ2 test.; IOP = intraocular pressure; ECCE = extra capsular cataract extraction; Phaco = phacoemulsification Comparison of Ketorolac Tromethamine and Prednisolone Acetate in Preventing Surgically Induced Miosis during Cataract Surgery 60 | SQU Medical Journal, April 2010, Volume 10, Issue 1 taken at the end of surgery, after cortical irrigation and aspiration, and PC-IOL implantation, before postoperative administration of a miotic agent (post-irrigation and aspiration [post-I/A]). The final measurement was taken at the end of surgery, but only for the patients who had postoperative administration of a miotic agent (postmiotic [post-M]). Care was taken to avoid the presence of viscoelastic in the anterior chamber prior to measurements. The change in pupil diameter during the most traumatic part of the surgical procedure was determined by subtracting the post-I/A value from the pre-I value. The change in pupil diameter caused by the postoperative use of a miotic agent was determined by subtracting the post-M value from the post-I/A value. The safety variables included the results of slit-lamp biomicroscopy and ophthalmoscopy, intraocular pressure, and visual acuity (Snellen chart). Adverse events were recorded and graded for severity. Microsoft Excel (2003 Version) was simply used to manipulate the data and the available analysis of variance test was used to analyse the continuous variables (such as pupil diameter, changes in pupil diameter, intraocular pressure and age). Treatment differences in nominal categorical variables (such as sex, operated eye and surgical procedure) were analysed using (χ 2) test. All tests were two sided, and the probability values of ≤0.05 were considered as statistically significant. Results The efficacy analysis revealed the following results with the mean pupil diameter during the three stages and the changes in pupil diameter shown in Table 2. The (mean ± SD) pre-I pupil diameter was (7.72 ± 0.54 mm) in the ketorolac group and (7.52 ± 0.65 mm) in the prednisolone group. No significant differences in pre-I pupil diameter were observed between the two groups (P = 0.244). The (mean ± SD) Post I/A pupil diameter was greater in the ketorolac group (6.28 ± 0.74 mm) than in the prednisolone group (5.34 ± 0.72 mm) and the difference was statistically significant(P < 0.0001). The mean pupil diameter change from pre-I to post I/A and PC-IOL implantation was significantly less (P = 0.003) in the ketorolac group (1.44 ± 0.96 mm) than in the prednisolone group (2.18 ± 0.70 mm). The number of patients requiring additional mydriatic medication during surgery was significantly greater (P < 0.005) in the prednisolone group (n = 14) than in the ketorolac group (n = 4). The number of patients who received a miotic agent at the end of surgery was significantly greater (P < 0.025) in the ketorolac group (21) than in the prednisolone group (13). The (mean ± SD) post-M pupil diameter was (3.76 ± 0.77 mm) in the ketorolac group and (3.92 ± 0.49 mm) in the prednisolone group. The difference was not significant (P = 0.505). The mean change in the pupil diameter from post I/A to post-M was significantly greater (P = 0.014) in the ketorolac group (2.55 ± 1.18 mm) than in the prednisolone group (1.61 ± 0.96 mm). The safety analysis revealed no significant differences between groups in slit-lamp biomicroscopy and ophthalmoscopy results, intraocular pressure or visual acuity. In addition, no Table 2: Angiographic characteristics of both groups Ketorolac group n = 25 Prednisolone group n = 25 P value Pre-I pupil diameter (Mean ± SD) 7.72 ± 0.54 7.52 ± 0.65 0.244* Post I/A pupil diameter (Mean ± SD) 6.28 ± 0.74 5.34 ± 0.72 < 0.0001* Change in pupil diameter from pre-I to post I/A (Mean ± SD) 1.44 ± 0.96 2.18 ± 0.70 0.003* Patients needing mydriatic agent during surgery 4 (16%) 14 (56%) < 0.005** Patients who received carbachol 21 (84%) 13 (52%) < 0.025** Post M pupil diameter (Mean ± SD) 3.76 ± 0.77 3.92 ± 0.49 0.505* Change in pupil diameter from post I/A to Post M (Mean ± SD) 2.55 ± 1.18 1.61 ± 0.96 0.014* Legend: * = Analysis of variance test; ** = χ2 test; Pre-I = preincision; Post I/A = Post irrigation & aspiration; post M = post miotic Note: Post M pupil diameter and change in pupil diameter from post I/A to Post M concerns only the eyes which received carbachol at the end of surgery. Yusuf M Suleiman, Najwa F Krdoghli, and Aksam J Ahmad Clinical and Basic Research | 61 treatment-related adverse events occurred. Adverse events occurred in 12% of patients in each group, but no event was considered to be related to the study medication. Discussion Surgically induced miosis is a well known event during cataract surgery and believed to be related to the stimulation of PGs release following surgical trauma. The first NSAIDs approved by the FDA for use as intraoperative inhibitors of miosis during cataract surgery were 0.03% flurbiprofen and 1% suprofen. They decrease the synthesis of PGs in the ocular tissues by inhibiting the cyclo-oxygenase pathway, thus reducing miosis. All commercially available topical NSAIDs appear to share this therapeutic benefit.1 One previous study has demonstrated the efficacy and safety profile of 0.5% ketorolac compared with its vehicle on maintaining intraoperative mydriasis.18 The results showed that the mean pupil diameter after cortical irrigation and aspiration was significantly greater (P = 0.03) with 0.5% ketorolac than with its vehicle. Many other previous studies have demonstrated the efficacy of ketorolac in preventing surgically induced miosis.12-19 In addition, many previous studies have compared the efficacy of NSAIDs and corticoids in ocular inflammation after cataract surgery, 8,9, 20-23 but the role of cocorticoids, which inhibit the biosynthesis of both PGs and LTs, in preventing surgically induced miosis seems not to have been investigated. Our study demonstrated that ketorolac was significantly better than prednisolone in maintaining mydriasis during surgery. Patients in the ketorolac group had smaller mean decreases in pupil diameter than did patients in the prednisolone group. Many previous studies have demonstrated no significant differences between ketorolac and prednisolone in controlling postoperative inflammation. These findings, considering the fact that both study medications inhibit the biosynthesis of PGs, can probably be attributed to a diminished role of PGs in surgically induced miosis. This suggests that the ketorolac-treated eyes were less susceptible to prostaglandin-independent factors contributing to surgically induced miosis. Our study also demonstrated no significant differences between ketorolac and prednisolone in the response to the mydriatic agents applied preoperatively, or to the miotic agent applied at the end of surgery. Previous studies have demonstrated that no differences between ketorolac and its vehicle were observed in the response to miotic agents administered at the end of surgery, or in the response to the mydriatic agents applied preoperatively,18 suggesting that neither ketorolac nor prednisolone has direct antimiotic or mydriatic properties. In our study, the number of patients requiring additional mydriatics was significantly greater in the prednisolone group (P < 0.025) compared to the ketorolac group, while others demonstrated that no differences between ketorolac and its vehicle were observed in the need for additional mydriatics during surgery.18 This means that patients in the prednisolone group in our study required more additional mydriatics than patients in ketorolac vehicle group in the other comparable study. These findings support more the hypothesis that there are other factors responsible for reducing miosis which are altered by prednisolone, and that ketorolac decreases surgically induced miosis through inhibition of routes other than inhibition of prostaglandin synthesis. A previous study showed that ketorolac had significantly greater efficacy than the glucocorticoids against blood-aqueous barrier breakdown at day 5 and week 2, as demonstrated by the difference in fluorescein concentration between the operated and nonoperated eyes. That is the median fluorescein concentration in the anterior chamber in the gluococorticoid-treated eyes was significantly elevated during the first two weeks after surgery and then began to decrease.20 Another previous study also demonstrated comparable results.24 That is during the first two postoperative weeks, the fluorescein leakage was significantly greater in the steroid- treated eyes than in the indomethacin+steroid- treated eyes. After the second postoperative week, the fluorescein leakage in the steroid-treated eyes continued to decrease. These findings suggest that prednisolone takes more time to act than ketorolac thereby having less efficacy in the intraoperative period. However, these two studies, and others,21,22 have demonstrated that prednisolone and ketorolac were equally effective in regard of cells and flare in the anterior chamber during the early postoperative period. Another previous study demonstrated Comparison of Ketorolac Tromethamine and Prednisolone Acetate in Preventing Surgically Induced Miosis during Cataract Surgery 62 | SQU Medical Journal, April 2010, Volume 10, Issue 1 that fluorescein concentration in placebo-treated eyes was significantly elevated during the first two postoperative weeks (comparable to fluorescein concentration in prednisolone-treated eyes in other studies) then began to decrease and the anterior chamber reaction (cells and flare) was also intensive.25 This means that prednisolone seems to be similar to the placebo regarding the effect on fluorescein leakage. Moreover the decrease in fluorescein concentration after the second postoperative week in the prednisolone-treated eyes seems not to be related to a delayed prednisolone efficacy. This means that prednisolone is also effective in the early postoperative period as regards the clinical anterior chamber reaction. It appears that although fluorescein is the most sensitive technique for demonstrating breakdown of blood-aqueous barrier (BAB), it may not always be an indicator of large molecule permeability.26 These findings disprove the hypothesis that prednisolone takes more time to act than ketorolac and suggest that ketorolac is effective against even small-molecule permeability (fluorescein) while prednisolone is effective only against large molecule permeability (cells, protein). The differences in the efficacy between ketorolac and prednisolone may be due to their differing effects on platelet activating factors, which are inhibited by glucocorticoids, but not by NSAIDs; however, this hypothesis needs to be verified. In the present study, the use of ketorolac and prednisolone was not associated with any significant adverse effects. This is consistent with previous studies that have documented the comparable tolerability of ketorolac and prednisolone in the treatment of postoperative ocular inflammation.20- 22 Conclusion Ketorolac tromethamine 0.5% ophthalmic solution seems to be more effective in preventing surgically induced miosis during cataract surgery compared to prednisolone acetate 1% ophthalmic solution. Consequently, topical ketorolac administered 24 hour before cataract surgery, reduces the complications of miosis during surgery and the need for intraoperative epinephrine which has been linked to CME.27-28 We therefore advise to apply ketorolac 24 hours before cataract surgery. a c k n o w l e d g e m e n t s The authors would like to thank Tishreen University, Faculty of Medicine and Al-Assad Hospital administrations and staff for the help provided during various stages of this work. s o u r c e o f f u n d i n g This research was performed in the Department of Ophthalmology, Al-Assad Hospital, Tishreen University, Latakia, Syria, during the period March 2008 to March 2009. It was financed by Al-Assad Hospital and Tishreen University. c o n f l i c t o f i n t e r e s t The authors report no conflict of interest. References 1. Colin J. The Role of NSAIDs in the Management of postoperative ophthalmic Inflammation. Drugs 2007; 67:1291–308. 2. Moorthy RS, Davis J, Foster CS, Lowder CY, Vitale AT, Lopatynsky M, et al. Intraocular inflammation and uveitis. In: American Academy of Ophthalmology. Basic and Clinical Science Course, 2007-2008. Singapore: AAO, 2007. pp.77–9. 3. Koay P. The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology. Br J Ophthalmol 1996; 80:480–5. 4. Drolsum L, Davanger M, Haaskjold E. Risk factors for an inflammatory response after extracapsular cataract extraction and posterior chamber IOL. Acta Ophthalmol (Copenh) 1994; 72:21–6. 5. Goodman DF, Stark WJ, Gottsch JD. Complication of cataract extraction with intraocular lens implantation. Ophthalmic Surg 1989; 20:132–40. 6. Cillino S, Casanova F, Cucco F, Ponte F. Topical flurbiprofen in extracapsular cataract surgery: Effect on pupillary diameter and iris fluorescein leakage. J Cataract Refract Surg 1993; 19:622–5. 7. Stark WJ, Fagadu WR, Stewart RH. Reduction of pupillary constriction during cataract surgery using suprofen. Arch Ophthalmol 1986; 104:364–6. 8. Demco TA, Sutton H, Demco CJ, Raj PS. Topical diclofenac sodium compared with prednisolone acetate after phacoemulsification–lens implant surgery. Eur J Ophthalmol 1997; 7:236–40. 9. Solomon KD, Vroman DT, Barker D. Comparison of ketorolac tromethamine 0.5% and rimexolone 1% to control inflammation after cataract extraction. Prospective randomized double-masked study. J Cataract Refract Surg 2001; 27:1232–7. 10. Sivaprasad S, Bunce C, Wormald R. Non-steroidal Yusuf M Suleiman, Najwa F Krdoghli, and Aksam J Ahmad Clinical and Basic Research | 63 anti-inflammatory agents for cystoid macular oedema following cataract surgery: A systematic Review. Br J Ophthalmol 2005; 89:1420–2. 11. Gwon A, Vaughan ER, Cheetham JK, DeGryse R. Ocufen (Flurbiprofen) in the treatment of ocular pain after radial keratotomy. CLAO J 1994; 20:131–8. 12. Solomon KD, Turkalj JW, Whiteside SB, Stewart JA, Apple DJ. Topical 0.5% Ketorolac vs 0.03% Flurbiprofen for inhibition of miosis during cataract surgery. Arch Ophthalmol 1997; 115:1119–22. 13. Epstein RL, Laurence EP. Relative effectiveness of topical ketorolac and topical diclofenac on discomfort after radial keratotomy. J Cataract Refract Surg 1995; 21:156–9. 14. Flach AJ, Jampol LM, Weinberg D, Kraff MC, Yannuzzi LA, Campo RV et al. Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine. Am J Ophthalmol 1991; 112:514–9. 15. Flach AJ, Graham J, Kruger LP, Stegman RC, Tanenbaum L. Quantitative assessment of postsurgical breakdown of the blood aqueous barrier following administration of 0.5% ketorolac tromethamine solution. A double-masked, paired comparison vehicle placebo solution study. Arch Ophthalmol 1988; 106:344–7. 16. Bron A, Denis P, Hoang-Xuan TC, Boureau- Andrieux C, Crozafon P, Hachet E, et al. The effects of rimexolone 1% in postoperative inflammation after cataract extraction. A double-masked placebo- controlled study. Eur J Ophthalmol 1998; 8:16–21. 17. Heier J, Cheetham JK, Degryse R, Dirks MS, Caldwell DR, Silverstone DE, et al. Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: A randomized, vehicle-controlled clinical trial. Am J Ophthalmol 1999; 127:253–9. 18. Stewart R, Grosserode R, Cheetham J K, Rosenthal A. Efficacy and safety profile of ketorolac 0.5% ophthalmic solution in the prevention of surgically induced miosis during cataract surgery. Clin Ther 1999; 21:723–32. 19. Snyder RW, Siekert RW, Schwiegerling J, Donnenfeld E, Thompson P. Acular as a single agent for use as an antimiotic and anti-inflammatory in cataract surgery. J Cataract Refract Surg 2000; 26:1225–7. 20. Ostrov CS, Sirkin SR, Deutsch WE, Masi RJ, Chandler JW, Lindquist TD. Ketorolac, prednisolone, and dexamethasone for postoperative inflammation. Clin Ther 1997; 9:259–72. 21. Hirneiß C, Neubauer AS, Kampik A, Schönfeld C. Comparison of prednisolone 1%, rimexolone1% and ketorolac tromethamine 0.5% after cataract extraction. Graefes Arch Clin Exp Ophthalmol 2005; 243:768–73. 22. Simone JM, Pendelton RA, Jenkins JE. Comparison of the efficacy and safety of ketorolac tromethamine 0.5% and prednisolone acetate 1% after cataract surgery. J Cataract Refract Surg 1999; 25:699–704. 23. El-Harazi SM, Ruis RS, Feldman RM, Villanueva G, Chuang AZ. A randomized double-masked trial comparing ketorolac tromethamine 0.5%, diclofenac sodium 0.1%, and prednisolone acetate 1% in reducing post-phacoemulsification flare and cells. Ophthalmic Surg Lasers 1998; 29:539–44. 24. Donald RS, Manus CK, Howard LL, Gholam AP, Samih T. Breakdown and reestablishment of blood-aqueous barrier with implant surgery. Arch Ophthalmol 1982; 100:588–90. 25. Donald RS, Manus K. Steroidal and nonsteroidal anti-inflammatory agents: effect on postsurgical inflammation and blood-aqueous humor barrier breakdown. Arch Ophthalmol 1984; 102:1453–6. 26. Donald RS, Alan S, Colman K, Parashos L, Bruce G, Gholam AP. Quantitative assessment of postsurgical breakdown of the blood-aqueous arrier. Arch Ophthalmol 1983; 101:131–3. 27. Mackool RJ, Muldoon T, Fortier A, Nelson D. Epinephrine-induced cystoid macular edema in aphakic eyes. Arch Ophthalmol 1977; 95:791–3. 28. Obstbaum SA, Galin MA, Poole TA. Topical epinephrine and cystoid macular edema. Am J Ophthalmol 1976; 8:455–8.