Use of topical bromfenac for treating ocular pain and inflammation beyond cataract surgery: a review of published studies

Figures & data

Figure 1 Cyclooxygenase pathway of prostaglandin production from membrane bound arachidonic acid and site of action of NSAIDs.

Adapted from Adv Ther, Voolume 27/ Edition 10, Schechter BA, Trattler W, Efficacy and safety of bromfenac for the treatment of corneal ulcer pain, 756–761, Copyright (2010), with permission from Adis, part of Springer Science+Business Media.¹

Table 1 Comparison of cyclooxygenase inhibitory activity of topical NSAIDs

Study	NSAID	COX-1 IC50 (μM)	COX-2 IC50 (μM)
Kida 2014^Citation42	Bromfenac	0.00556	0.00745
	Diclofenac	0.0555	0.0307
	Amfenac	0.0153	0.0204
Walters 2007^Citation43	Bromfenac	0.0864	0.0112
	Ketorolac	0.0139	0.0911
	Amfenac	0.138	0.00177
	Nepafenac	82.3	>1000
Waterbury 2006^Citation44	Bromfenac	0.210	0.0066
	Ketorolac	0.020	0.12
	Diclofenac	0.0079	NA

Notes: Reprinted from PLoS One, Volume 9/ Edition 5, Kida T, Kozai S, Takahashi H, Isaka M, Tokushige H, Sakamoto T, Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits, e96481, Copyright (2014), permission from Public Library of Science (PLoS) is not needed as this manuscript is an open-access article distributed under the terms of the Creative Commons Attributions License.⁴² Reprinted from J Cataract Refract Surg, Volume 33/ Edition 9, Walters T, Raizman M, Ernest P, Gayton J, Lehmann R, In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac, 1539–1545, Copyright (2007), with permission from Elsevier.⁴³ Reprinted from Curr Med Res Opin, Volume 22/ Edition 6, Waterbury LD, Silliman D, Jolas T, Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium, 1133–1140, Copyright (2006), with permission from Taylor & Francis Ltd (http://www.tandfonline.com).⁴⁴

Abbreviation: IC₅₀, half maximal inhibitory concentration; NA, not applicable.

Figure 2 Chemical structures of bromfenac and other ophthalmic NSAIDs.

Table 2 Summary of studies

Study	Study Design	Efficacy Findings	Safety Findings
Post-refractive eye surgery
Cleaveland 2017^Citation61	Prospective, double-masked, placebo-controlled, case series, post-LASIK	(i) Eye pain and the averaged all-symptoms ratings at 1-hour were reduced compared with baseline in the pre-bromfenac/post-AT group only (P=0.02).	No notable AEs.
	Bromfenac 0.07% vs AT	(ii) Patients in the pre-bromfenac/post-bromfenac group had no discomfort at 2-hours (P<0.001).
	Four groups: 1. presurgical bromfenac/ postsurgical bromfenac 2. presurgical bromfenac/ postsurgical AT 3. presurgical AT/postsurgical bromfenac 4. presurgical AT/postsurgical AT All treatments given as one drop immediately before/after surgery N=64 (120 eyes)	(iii) In the pre-bromfenac/post-AT group, patients had less tearing (P=0.02), foreign body sensation (P=0.01), photophobia (P<0.001), and discharge (P=0.01) at the 1-hour time-point.
		(iv) Subjects treated with pre-bromfenac-/post-bromfenac had less tearing (P=0.01), foreign body sensation (P=0.03), photophobia (P<0.001), discharge (P<0.001) and haziness (P=0.02) at the 2-hour time-point.
		(v) Incidence of DLK was 8.5% (7/82) eyes treated peri-op with bromfenac vs. 15.8% (6/38) eyes treated with AT (P>0.05).
		(vi) VA was similar between treatments at 1 day and 3 months postoperatively.
Chen 2015^Citation62	Open-label post LASEK surgery	(i) No significant difference between groups in corneal topography.	Cases of grade -0.5 haze in both groups (2-bromfenac; 2-FML) which disappeared 1 month after treatment ended and did not affect VA. Ocular turgidity and blurred vision in 1 bromfenac and 3 FML-treated eyes; all treated with IOP-lowering agents.
	Dexamethasone 0.1% QID for 7 days postsurgery, then 11 more weeks of either bromfenac 0.1% BID or FML 0.1% (tapered regimen)	(ii) Improved VA in bromfenac group compared to FML at one month (P<0.05). No significant difference at other time points.
	N=60 (120 eyes)	(iii) No significant difference in mean IOP between groups at all time points.
Dong 2015^Citation63	Prospective, randomized study in LASEK patients	(i) No significant difference in postoperative irritation symptoms between groups	Transient local discomfort including stabbing pain and burning sensation after instillation of ketorolac; no discomfort noted with bromfenac.
	Bromfenac 0.1% BID vs 0.5% ketorolac tromethamine QID, each given 3 days before and 1 day after surgery	(ii) Duration of postoperative irritation symptoms was shorter in the bromfenac group (median, 2.0 vs 14.0 days; P=0.004).
	N=64 patients/eyes	(iii) No significant difference in corneal healing time and VA between groups.
Durrie 2007^Citation64	Prospective, randomized, double-masked, post-PRK	(i) Reepithelialization occurred sooner with nepafenac and ketorolac compared to bromfenac (P<0.05).	No treatment-related AEs or evidence of corneal toxicity.
	Bromfenac 0.09% vs nepafenac 0.1% vs ketorolac 0.4% (each given TID beginning 1 day preoperatively and continuing for one week postoperatively)	(ii) Significant reductions in pain scores were observed with nepafenac 0.1% on day 1 (P=0.0146) and day 3 (P<0.0001), ketorolac 0.4% on day 3 (P=0.0341), and bromfenac 0.09% on day 3 (P=0.0386).
	N=29 (58 eyes)
Sher 2009^Citation65	Open label post-PRK study	(i) No significant difference between groups in pain, burning, photophobia, foreign body sensation over any of the days.	No treatment-related AEs.
	Bromfenac 0.09% BID vs ketorolac 0.4% QID; treatment continued until healing occurred	(ii) No significant difference in epithelial healing rate between groups.
	N=149 patients (212 eyes)
Wang 2011^Citation66	Prospective, randomized, post LASEK or Epi-LASIK	(i) Bromfenac-treated eyes had lower pain scores than ketorolac-treated eyes on the surgery day and through 4 days postoperatively (P<0.01).	Eight patients (20%) reported temporary dry eye and 2 (5%) reported temporary irritation in both eyes. No serious AEs noted.
	Bromfenac 0.09% in one eye vs ketorolac 0.5% in the other (15 minutes and one minute prior to surgery, 2 and 4 hours postoperatively and daily through day 4) N=40 (80 eyes)	(ii) No differences in blurriness between groups on day of surgery or postoperatively through day 4 (P>0.01). (iii) No difference in uncorrected VA between the two groups (P>0.01).
Xu 2013^Citation67	Prospective, case-controlled study in patients undergoing sub-Bowman’s keratomileusis	(i) Postoperatively, there was a significant difference in favor of bromfenac in low-moderate myopic patients for mean corneal curvature K2 at 1 and 3 months (P<0.05), and in high myopic patients for VA at 3 months (P=0.015).	In patients with low-moderate myopia, mean postoperative IOP at 1 month and 3 months was lower in bromfenac-treated patients as compared to FML-treated patients (7.8 vs 9.4 mm Hg and 8.1 vs 9.5 mm Hg, respectively; both P<0.05).
	Bromfenac 0.1% BID for 10-14 days (depending on myopic severity) vs FML 0.1% for 16 days postoperatively	(ii) No other postoperative differences between treatment groups.
	N=74 (140 eyes)
Macular Edema Associated with Uveitis, Diabetes, and RVO
Pinna 2017^Citation68	Open label pilot study in patients with newly diagnosed diabetic macular edema	(i) Mean CMT decreased from a baseline of 465.41 (118.47) µm to 388.88 (152.63) µm (P=0.02).	No AEs reported.
	Bromfenac 0.09% BID for 30 days	(ii) Mean macular volume decreased numerically, however the decrease did not reach significance (P=0.06).
	N=17	(iii) Best-corrected VA was unchanged (P=0.72).
Radwan 2013^Citation69	Retrospective, comparative case series, uveitic macular edema	(i) A decrease in CMT and improvement in VA was observed in the IVB/bromfenac and IVTA/bromfenac groups compared to baseline at 1 and 3 months (P≤0.031).	Safety outcomes not reported.
	Bromfenac^a BID monotherapy vs bromfenac BID+single IVB injection vs bromfenac plus single IVTA injection	(ii) CMT in the IVTA/bromfenac group was lower than in the IVB/bromfenac and bromfenac monotherapy groups at 1 month (P≤0.041).
	N=55 (67 eyes)	(iii) No significant effects on CMT or VA in the bromfenac monotherapy group at 1 or 3 months compared to baseline.
Shimura 2015^Citation70	Prospective, case-controlled, pilot study in patients with macular edema secondary to branch RVO	(i) No significant differences in foveal thickness or VA between bromfenac and AT-treated eyes.	No AEs related to the topical bromfenac.
	All patients received initial IVB injection, then randomized to bromfenac 0.1% QID or AT QID for 48 weeks; IVB repeated as necessary for recurrence of macular edema	(ii) Mean±SD number of IVB injections required was 3.8±1.1 for bromfenac vs 4.8±1.2 for control (P=0.014).
	N=44 (48 eyes)
Age Related Macular Degeneration
Grant 2008^Citation71	Retrospective case series in patients with wet AMD	(i) Patients treated with bromfenac/IVR required significantly fewer IVR injections (1.6±0.69^b) than patients receiving IVR alone (4.5±0.41; P=0.0002).	No AEs associated with topical bromfenac use.
	IVR vs IVR+bromfenac^a BID for 6 months	(ii) Improvement in VA was not significantly different between treatment regimens.
	N=30 IVR; N=30 IVR+bromfenac BID	(iii) Similar trends were observed for optical coherence tomography and fluorescein angiography data.
Flaxel 2012^Citation72	Prospective, randomized, open label comparative study in patients with wet AMD	(i) No statistically significant difference in the number of IVR injections received over 12 months.	No significant difference in AEs between groups.
	IVR monthly for 4 months, then monthly as needed, alone vs +bromfenac 0.09% BID for 12 months N=30	(ii) Greater reduction in mean 12-month change in CMT in the combination group vs monotherapy group (P=0.03). (iii) Proportion of eyes experiencing >50 μm decrease in CMT was higher in the combination therapy group (P=0.046).	Most common AEs in patients receiving bromfenac/IVR were burning/stinging (40% vs 20% with IVR alone), itchy eye (30% vs 50% with IVR alone), and headache (30% vs 40% with IVR alone). All AEs were mild.
Gomi 2012^Citation73	Single-center, double-masked, placebo-controlled study in patients with wet AMD	(i) Mean number of ranibizumab injections over 6 months was lower (P=0.0274) in the bromfenac group (2.2) compared to the control group (3.2).	No serious AEs or side effects attributed to bromfenac.
	Bromfenac 0.1% vs AT BID for 6 months N=16 bromfenac; N=22 AT	(ii) Change in VA did not differ between groups (P=0.314).
		(iii) Trend towards a reduction in CRT in the bromfenac group (P=0.060).
Wygledowska-Promienska 2014^Citation74	Prospective, open-label study in patients with AMD	(i) VA improved in the IVB/ bromfenac group at 6 months vs baseline (P=0.001) but not with IVB alone.	No significant difference in IOP between groups.
	IVB (3 injections then as needed)+bromfenac 0.09% for 3 months following first IVB injection vs IVB alone	(ii) Median height of subretinal fluid measured by OCT decreased significantly with IVB/ bromfenac but increased in the IVB only group.	No severe AEs.
	N=52 (26 in each group)	(iii) More IVB injections were required in the IVB alone group than in the IVB/ bromfenac group (5.8 vs 6.9).	No difference in ocular AEs between groups.
Wygledowska-Promienska 2015^Citation75	Prospective, open-label study in patients with AMD	(i) VA was improved in the IVA/ bromfenac group after 4 (P=0.001) and 6 months (P<0.001) while there was no significant improvement with aflibercept alone.	No AEs observed.
	IVA (3 injections per month then as needed)+bromfenac 0.09% for 3 months following first IVB injection vs IVB alone	(ii) CRT did not change significantly between visits in either group. (iii) Mean height of subretinal fluid decreased in both groups between baseline and 6 months but no significant difference between groups.
	N=54 (27 in each group)
Pain Related to Intravitreal Injections
Georgakopoulos 2017^Citation76	Single-center, prospective, randomized, double-blind, placebo-controlled crossover study in patients requiring intravitreal treatment with anti-VEGF agents (ranibizumab or aflibercept) for treatment of AMD, DME, macular edema secondary to central and branch RVO, or angiod streaks complicated by choroidal neovascularization Bromfenac 0.09% or placebo in one eye 30–45 minutes before IVA or IVR; treatment not received during first intravitreal injection was given during consecutive injection in study eye N=65 (each patient served as own control, bromfenac vs vehicle)	(i) Pain perception was significantly lower immediately after intravitreal injection when patients received pretreatment with bromfenac vs placebo as assessed by the VAS score (P=0.002) and the main component of the short form of the SF-MPQ (P=0.001). (ii) Six hours after intravitreal injection, pain was significantly lower with bromfenac versus vehicle pretreatment as assessed by the VAS score (P<0.001) and the SF-MPQ (P<0.001). (iii) The median present pain intensity score was significantly lower in patients pretreated with bromfenac vs placebo 6 hours post-intravitreal injection (P=0.001) but not immediately after intravitreal injection.	No AEs observed.
Anterior Segment/Ocular Surface Disorders
Sawa 1997^Citation30	Multicenter, randomized, double-blind, placebo-controlled study in patients with ocular surface inflammatory disorders (blepharitis, conjunctivitis, scleritis, and episcleritis)	(i) Ratings of very effective or effective established for both bromfenac (63.4%) and pranoprofen (54.7%), with no significant difference between treatment groups.	Bromfenac group: 4 patients with AEs (3.9%): increased eyelid inflammation, increased blepharitis, blood engorgement/follicle deterioration, sensitivity to infusion.
	Bromfenac 0.1% BID or panoprofen 0.1% QID for 2 weeks; placebo used for masking to maintain double-blind	(ii) Excellent rates of efficacy demonstrated for blepharitis, conjunctivitis, scleritis, and episcleritis.	Pranoprofen: 1 patient with an AE (1.0%): sensitivity to infusion.
	Safety: N=207 Efficacy: N=188		IOP decreased by 0.4 mm Hg in both groups but remained within normal limits.
Miyake-Kashima 2004^Citation77	Investigator-masked, randomized study in patients with SAC	(i) Subjective symptoms were not significantly improved in either group.	No serious AEs were observed.
	Bromfenac 0.1% BID in one eye vs pemirolast 0.1% BID in contralateral eye for 1 week	(ii) Bromfenac improved signs of conjunctival injection (P=0.002), papilla formation (P=0.03), edema (P=0.002), and swelling of eyelid (P=0.05).
	N=22	(iii) Pemirolast improved signs of conjunctival injection (P=0.0002), papilla formation (P=0.003), and edema (P=0.004).
		(iv) No significant differences between treatments for subjective or objective symptoms.
Fujishima 2009^Citation78	Multicenter, investigator-masked, randomized study	(i) All subjective symptom scores were significantly improved in both groups by 1 week (P<0.05).	No AEs reported and no reports of corneal epithelitis.
	Bromfenac 0.1% BID+DSCG 2% QID in one eye vs FML 0.02% QID+DSCG 2% QID in the contralateral eye	(ii) All objective signs and symptoms were significantly improved after 1-week treatment with concomitant use of bromfenac or FML with DSCG vs. baseline (P<0.05), with no differences between treatments.
	N=86	(iii) Patient-assessed global evaluation was equivalent between the treatment groups.
Uchio 2007^Citation79	Prospective, randomized, double-masked study in patients with vernal keratoconjunctivitis	The proportion of patients without recurrence (ie, “survival”) at 1 year was 90.9% in the bromfenac group compared with 56.3% in the placebo group and at 2 years was 90.9% in the bromfenac group compared with 11.3% in the placebo group; the difference in survival was statistically significant (P=0.01).	No clinically important side effects noted.
	Bromfenac 0.1% BID or saline eye drops; all patients received concomitant FML QID+tranilast QID vs placebo; mean follow-up=20.9 months
	N=22
Fujishima 2015^Citation80	Open-label, single-arm study in patients with dry eye disease who experienced no symptomatic improvement after 1 month of treatment with AT	(i) Dryness scores significantly improved from pre-bromfenac to the end of bromfenac treatment (P<0.001) and then worsened by 3 months after discontinuation of bromfenac vs the end of bromfenac treatment (P<0.001).	No AEs observed.
	Bromfenac 0.1% BID+AT QID for 1 month, followed by 3 months of treatment with AT QID alone N=26	(ii) No significant changes in Schirmer scores were observed during the study. (iii) Tear film breakup time significantly improved from before bromfenac to the end of bromfenac therapy (P<0.001) and then worsened from the end of bromfenac therapy to 3 months after bromfenac discontinuation (P<0.001). (iv). Superficial punctate keratopathy improved from pre-bromfenac to the end of bromfenac therapy (P<0.001) and then worsened by 3 months after discontinuation of bromfenac (P<0.001).
Usui 1997^Citation81	Multicenter, open-label study in patients with anterior uveitis	(i) Based on physician evaluation of anterior protein, the percentage of patients with a rating of effective or very effective was 62.5% for short-term treatment and 76.9% for long-term treatment.	AEs during short-term treatment: 1 case of superficial punctate keratitis and 2 cases of sensitivity to instillation.
	Bromfenac 0.1% BID for 2 weeks (short-term assessment) or up to 12 weeks (long-term assessment)	(ii) Based on evaluation of flare, the effectiveness rate was 51.9% for short-term treatment and 80.0% for long-term treatment.	No additional AEs occurred with long-term administration.
	Short-term evaluation: efficacy, n=40; safety, n=48 Long-term evaluation: efficacy, n=13; safety, n=17
Schechter 2010^Citation23	Prospective, non-randomized trial in patients with corneal ulcer pain whose eyes had bacterial or fungal infiltrates Bromfenac 0.9% BID (n=25 eyes) plus standard anti-infective agents or standard anti-infective agents alone (controls; n=10 eyes)	(i) Primary endpoint of time to healing did not differ significantly between treatment groups. (ii) Significantly more eyes treated with bromfenac had no pain by day 3 vs control eyes (52% versus 0%, P=0.023). (iii) By day 20, epithelial healing observed in 68% of bromfenac-treated eyes vs 10% of control eyes (P=0.040). (iv) Bromfenac treatment was associated with a shorter mean time to return to regular daily activities (3.2 days versus 25.8 days in controls, P<0.001) and a higher percentage of patients returning to normal activities within 2 days of starting treatment (71% vs 0% of controls, P=0.018).	No corneal AEs were observed.

Notes: ^aSource does not specify bromfenac concentration. ^bSource does not specify as standard deviation or standard error.

Abbreviations: AE, adverse event; AMD, age-related macular degeneration; AT, artificial tears; BID, twice-daily; CMT, central macular thickness; CRT, central retinal thickness; DLK, diffuse lamellar keratitis; DME, diabetic macular edema; DSCG, disodium cromoglicate; FML, fluorometholone; IVA, intravitreal aflibercept; IVB, intravitreal bevacizumab; IVR, intravitreal ranibizumab; IVTA, intravitreal triamcinolone acetonide; LASEK, laser epithelial keratomileusis; OCT, ocular coherence tomography; PRK, photorefractive keratectomy; QID, four times daily; RVO, retinal vein occlusion; SAC, seasonal allergic conjunctivitis; SF-MPQ, short form of the McGill Pain Questionnaire; TID, three times daily; VA, visual acuity; VEGF, vascular endothelial growth factor.

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