Ketorolac tromethamine, also known as ophthalmic ketorolac (Acuvail®), is a first-generation non-steroidal anti-inflammatory (NSAID) widely used in ophthalmology, prescribed over 3 million times in 2018 alone (1). A racemic mixture of R-(+) and S-(−)- ketorolac tromethamine, it exerts anti-inflammatory, analgesic, and anti-pyretic actions. Many of ketorolac’s effects are associated with the inhibition of ocular prostaglandin synthesis by the competitive blocking of cyclooxygenase 1 and 2 (2), which has been shown to be stimulated by trauma to the eye and contribute to ocular inflammation (3).

Ketorolac was patented in 1976 and approved for medical use in 1989 (4). Ketorolac tromethamine 0.4% (Acular® LS, Allergan, Inc, Irvine, CA, USA) was introduced after ketorolac tromethamine 0.5% in the United States in 2003 (5). Though containing 20% less active ingredient than ketorolac tromethamine 0.5%, ketorolac tromethamine 0.4% has been proven to be equally effective in the reduction of ocular pain and burning or stinging. Ketorolac can be administered orally, intranasally, intravenously, intramuscularly, or topically as eye drops.

Studies have found ketorolac tromethamine to be effective in reducing pain and inflammation across a range of pre-, intra-, and postoperative contexts. Intraoperatively, it can maintain pupil size, improve visual outcomes, and reduce patient complaints. Postoperatively, multiple large, randomized, double-masked studies demonstrated significantly less inflammation and pain after cataract surgery with ketorolac tromethamine (6–8). Clinical trials have also shown it to be highly effective in also relieving pain after radial keratotomy (RK) (9), photorefractive keratectomy (PRK) (10), and laser in situ keratomileusis (LASIK) (11). It also helps prevent the post-operative complications of pseudophakic and cystoid macular edema (12). Overall, patients receiving a topical NSAID such as ketorolac tromethamine have been found to require significantly fewer additional oral analgesics and resumed normal activities sooner (13,14). Beyond the operating theatre, it also relieves pain associated with allergic conjunctivitis (15) and can be used as an efficient adjuvant in the initial treatment phase of chronic dry eye (16).

Ketorolac tromethamine incurs rare adverse side effects; the federal drug administration (FDA) safety sheet data documents transient discomfort on instillation of ketorolac tromethamine 0.4% in 40% of subjects participating in clinical trials. With regard to alternatives, the effects of ketorolac tromethamine have been compared with the efficacy of topical steroids after extra-capsular cataract extraction (17) and phacoemulsification (18). Another study showed that both ketorolac tromethamine and diclofenac sodium were more effective than moist drops at reducing discomfort post-PRK, although only ketorolac tromethamine resulted in improved foreign-body sensation, functionality, and compliance scores (9). Therefore, despite contextual side effects and alternatives, there is a clear role for ketorolac tromethamine in the context of ocular surgery.

Overall, in light of its favourable safety profile, ketorolac is an important tool to alleviate postoperative ocular pain and help surgeons meet the high expectations of today’s cataract and refractive surgery patients.

References

1. Ketorolac Tromethamine – Drug Usage Statistics, ClinCalc DrugStats Database [Internet]. Available from: https://clincalc.com/DrugStats/Drugs/KetorolacTromethamine

2. Litvak KM, McEvoy GK. Ketorolac, an injectable nonnarcotic analgesic. Clinical Pharmacy. 1990.

3. Keulen De Vos HCJ, Van Rij G, Renardel de Lavalette JCG, Jansen JTG. Effect of indomethacin in preventing surgically induced miosis. Br J Ophthalmol. 1983.

4. Ketorolac (Systemic) Monograph for Professionals – Drugs.com [Internet]. Available from: https://www.drugs.com/monograph/ketorolac-systemic.html

5. Sandoval HP, Fernández De Castro LE, Vroman DT, Solomon KD. A review of the use of ketorolac tromethamine 0.4% in the treatment of post-surgical inflammation following cataract and refractive surgery Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit production of prostaglandins (PG) by inhibiting cyclo-oxygenase (COX). Vol. 1, Clinical Ophthalmology. Dove Press; 2007.

6. Kim S. Critical appraisal of ophthalmic ketorolac in treatment of pain and inflammation following cataract surgery. Clin Ophthalmol. 2011 Jun;5:751.

7. Price MO, Price FW. Efficacy of topical ketorolac tromethamine 0.4% for control of pain or discomfort associated with cataract surgery. Curr Med Res Opin. 2004.

8. Solomon KD, Vroman DT, Barker D, Gehlken J. 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(8):1232–7.

9. McDonald MB, Brint SF, Caplan DI, Bourque LB, Shoaf K. Comparison of ketorolac tromethamine, diclofenac sodium, and moist drops for ocular pain after radial keratotomy. J Cataract Refract Surg. 1999 Aug;25(8):1097–108.

10. Rajpal RK, Cooperman BB, Cheetham JK. Analgesic efficacy and safety of ketorolac after photorefractive keratectomy. J Refract Surg. 1999 Nov 1;15(6):661–7.

11. Kosrirukvongs P, Srivannaboon S, Prabhasawat P, Pornpanich K. Topical ketorolac tromethamine in the reduction of adverse effects of laser in situ keratomileusis. In: Journal of the Medical Association of Thailand. 2001.

12. Flach AJ, Dolan BJ, Irvine AR. Effectiveness of ketorolac tromethamine 0.5% ophthalmic solution for chronic aphakic and pseudophakic cystoid macular edema. Am J Ophthalmol. 1987;103(4):479–86.

13. Kaiser PK, Pineda R, An B, Brun S, Burk S, Kim R, et al. A study of topical nonsteroidal anti-inflammatory drops and no pressure patching in the treatment of corneal abrasions. Ophthalmology. 1997.

14. Goyal R, Shankar J, Fone DL, Hughes DS. Randomised controlled trial of ketorolac in the management of corneal abrasions. Acta Ophthalmol Scand. 2001.

15. Yaylali V, Demirlenk I, Tatlipinar S, Özbay D, Esme A, Yildirim C, et al. Comparative study of 0.1% olopatadine hydrochloride and 0.5% ketorolac tromethamine in the treatment of seasonal allergic conjunctivitis. Acta Ophthalmol Scand. 2003;81(4):378–82.

16. Schechter BA. Ketorolac during the induction phase of cyclosporin-A therapy. J Ocul Pharmacol Ther. 2006 Apr;22(2):150–4.

17. Simone JN, 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 May;25(5):699–704.

18. Holzer MP, Solomon KD, Sandoval HP, Vroman DT. Comparison of ketorolac tromethamine 0.5% and loteprednol etabonate 0.5% for inflammation after phacoemulsification: Prospective randomized double-masked study. J Cataract Refract Surg. 2002;28(1):93–9.