New drugs, protocols reduce pain and inflammation associated with cataract surgery

Drugs, better surgical techniques and new technologies can limit the amount of pain and inflammation a patient experiences after undergoing cataract surgery.

Ophthalmologists and patients have different views about what constitutes a successful cataract surgery. Ophthalmologists generally view visual acuity outcomes as the most important concept in cataract and ophthalmic surgery, but patients perceive pain as equally important, OSN Cornea/External Disease Board Member Eric D. Donnenfeld, MD, said. If patients associate pain with the procedure, they may be left with negative feelings about the practice, no matter how much their vision improves.

“Pain and inflammation are two of the more important concepts we need to embrace and manage for patients undergoing ophthalmic surgery,” he said. “A procedure that ends with a patient having 20/20 vision but experiencing pain during and after the procedure will leave them with a bad experience. We consider pain and inflammation as being extremely important in our patients,” Donnenfeld said.

Source: Eric D. Donnenfeld, MD

The two main classifications of medications surgeons use to control postoperative pain and inflammation are NSAIDs for reducing pain and steroids for reducing postoperative inflammation.

A 2016 review by Hoffman and colleagues groups the commercially available NSAIDs into six major classifications: salicylates, fenamates, indoles, phenylalkanoic acids, phenylacetic acids and pyrazolones. Each works the same way, by blocking cyclooxygenase enzymes and hindering production of prostaglandins.

Even though NSAIDs work by inhibiting prostaglandin production, they do not influence preformed prostaglandin, according to Donnenfeld. Therefore, pretreatment with an NSAID is an important step in a surgeon’s protocol to limit postoperative pain.

NSAID pretreatment

“The NSAIDs that we use today are much better than they were in the past. Bromfenac and nepafenac are both excellent NSAIDs. The delivery systems have improved, specifically with nepafenac available as Ilevro 0.3% from Alcon, which is once-a-day dosing, and bromfenac available as Prolensa 0.07% from Bausch + Lomb or as BromSite 0.075% (Sun Ophthalmics),” Donnenfeld said.

BromSite was approved by the FDA in 2016 to prevent pain and treat inflammation in cataract surgery and is delivered via the DuraSite vehicle, which is a polymer-based formulation that increases the drug’s residence time on the ocular surface.

“All of these are excellent inhibitors of pain and inflammation. For cataract surgery, they all work extremely well once a day, and I’ll start them 3 days preoperatively,” Donnenfeld said.

The goal of preoperative treatment with an NSAID is to manage inflammation and pain before the procedure, OSN Cornea/External Disease Board Member Marjan Farid, MD, said.

On the day of surgery, Farid gives patients topical proparacaine eye drops before dilation, as well as topical TetraVisc (tetracaine 0.5%, OcuSoft) to manage intraoperative pain.

“I am also very aware that ocular surface desiccation occurs during the preoperative setting when patients are numb and not blinking well. I ask patients to keep their eyes closed between drops preoperatively. Intraoperatively, I make sure that the ocular surface is well lubricated to minimize postoperative punctate keratitis from dryness. This is a major cause of postoperative pain,” Farid said.

Postoperative NSAID use

Donnenfeld said he continues NSAIDs for 4 weeks postoperatively in his cataract patients but may extend NSAID use to 2 or 3 months for patients who experience extreme inflammation or those with inflammatory diseases, uveitis or diabetes.

“As far as other nonsteroidals, we routinely use Omidria at the time of cataract surgery,” Donnenfeld said. “In addition to maintaining pupil size and preventing inflammation that causes miosis, we find that patients’ eyes are optimal with the use of Omidria, and it’s very effective in patients with floppy iris syndrome. Patients also have quieter eyes, which I believe is due to the intracameral use of the ketorolac.”

Omidria (phenylephrine 1% and ketorolac 0.3% intraocular solution, Omeros) is the only FDA-approved intracameral NSAID-containing injection that reduces inflammation and maintains mydriasis, according to Farid. As well, its intraoperative use aids with postoperative inflammation.

“Use of good topical analgesics intraoperatively will also aid with immediate postoperative discomfort,” she said.

Reducing inflammation with steroids

Pre- and postop topical steroids reduce inflammation and are helpful at reducing corneal swelling. There are a variety of topical steroids available, and each has its own benefits. When using a steroid and NSAID in combination, it is possible to use a topical steroid at a lower frequency per day as compared with using a topical steroid without an NSAID, OSN Technology Section Editor William B. Trattler, MD, said.

“In my practice, I typically prescribe either Durezol (difluprednate ophthalmic emulsion 0.05%, Novartis) or Lotemax gel (loteprednol etabonate ophthalmic gel 0.5%, Bausch + Lomb) twice a day postoperatively for a month,” he said.

According to a 2011 study published in Clinical Ophthalmology, Durezol is a more potent steroid to use after cataract surgery compared with the previous gold standard prednisolone acetate. Patients dosed either once a day or twice a day for a median of 27.1 days experienced reduced inflammation compared with patients treated with prednisolone acetate.

In a separate 2011 study in the American Journal of Ophthalmology, patients treated with Durezol experienced less corneal edema than those treated with prednisolone acetate. In the 52-patient cohort, 62% of eyes treated with Durezol were without corneal edema compared with 38% of eyes treated with prednisolone acetate.

For patients with minor swelling, Durezol may not be necessary. Inveltys (loteprednol etabonate ophthalmic suspension 1%, Kala Pharmaceuticals) is an effective, safe steroid to treat inflammation after cataract surgery, and it should become widely available in 2019, Donnenfeld said. Inveltys was FDA approved in 2018 and is the only twice-daily corticosteroid for the treatment of postoperative inflammation and pain after ocular surgery.

“It has excellent anti-inflammatory properties with an unparalleled level of safety,” he said. The nanoparticle formulation is delivered via Kala’s mucus-penetrating technology. “[It] will be an excellent corticosteroid for cataract surgery and dry eye.”

Lotemax gel, a topical corticosteroid, was FDA approved in 2012 for the treatment of postoperative inflammation and pain after ocular surgery. The FDA accepted a new drug application for a lower concentration formulation — submicron loteprednol etabonate ophthalmic gel 0.38% — intended for less frequent dosing, and a PDUFA decision is pending Feb. 25.

A 0.5 mg to 1 mg preservative-free intracameral dose of triamcinolone can also provide a patient with a good steroid response for a few days before it is washed out. The triamcinolone gives the eye a “little extra boost” and helps quiet the eye almost immediately, OSN Healio.com Section Editor Uday Devgan, MD, said.

New drug delivery routes

The FDA approved Dextenza (dexamethasone ophthalmic insert 0.4 mg, Ocular Therapeutix), the first intracanalicular insert to deliver dexamethasone to treat postoperative ocular pain for up to 30 days, in December.

Dextenza demonstrated efficacy in two randomized, vehicle-controlled phase 3 studies in which a statistically significant number of patients who received the insert were free of pain 8 days after cataract surgery compared with patients in the vehicle control group.

Dextenza’s approval is another positive addition to a surgeon’s armamentarium to limit pain and inflammation after cataract surgery. Dextenza could possibly lead to less reliance on postoperative anti-inflammatory drops, Farid said.

“Cataract surgeons will be very happy with the approval of Dextenza for the treatment of postoperative pain. We are looking forward to having less reliance on topical postoperative anti-inflammatory drops that can cause secondary ocular surface dryness and irritation. This easily placed slow-release medication with minimal potential of side effects has the potential to significantly change our postoperative medication landscape,” she said.

New routes for administration of steroids can increase postoperative efficacy. Injectable steroids under the conjunctiva, such as subconjunctival dexamethasone or a sub-Tenon’s injection of triamcinolone, or intracamerally with appropriate medications can result in a better anti-inflammatory response after cataract surgery, according to Devgan.

“That’s what I’m doing postop,” he said, referring to the preservative-free triamcinolone in the anterior chamber.

Regarding slow-release intracanalicular delivery of dexamethasone, Devgan still has questions: “How much of that is going to get to the eye? Is there a cheaper, easier way to do this? Can I just inject steroid conjunctival or sub-Tenon’s and have the same effect or a better effect?”

Keep patients comfortable

Aside from medication, patient comfort is also a factor in pain and inflammation associated with cataract surgery, OSN Refractive Surgery Board Member Jason P. Brinton, MD, said.

Brinton operates and examines patients in an office facility, an environment that is more conducive to patient comfort than an operating room, he said.

“From a comfort standpoint, we consider it a significant advantage to have an office facility in which we can perform vision correction surgery with refractive IOLs. Patients are more comfortable having already become familiar with our office staff and environment, as opposed to having to go to a hospital or ambulatory surgical center,” he said.

A patient who is familiar with the operating environment, the surgeon and the clinic staff can be more at ease during a procedure and experience less discomfort postoperatively, Brinton said.

“The other aspect of comfort that is underemphasized is ‘vocal local’ anesthesia. Patients want to hear the doctor’s voice and want staff to tell them what to expect next through the process. We allow patients to listen to the music of their choice and, with certain guidelines, allow family members to suit up and sit next to their loved one, holding their hand during the treatment,” he said.

Cost-to-benefit ratio

Cost needs to be considered when deciding on a protocol to manage pain and inflammation. The three most typical postoperative classes of medication — antibiotic, steroid and NSAID — can cost more than the surgeon’s fee for cataract surgery if they are the retail brand name medications, Devgan said.

The medications can cost as much as $200 each, he said.

“It makes you wonder, is there a role for lower costs? I want to keep pace with innovation, new techniques and new technologies, but if you’re going to come out with a new product that’s hundreds of dollars, I have to ask myself, does that patient really need it or is there another alternative that’s better or just as good? I’m all for more products and new products that work well, but we need to balance the cost-to-benefit ratio for our patients,” he said.

Intraoperative strategies

One of the more overlooked aspects of pain and inflammation management involves the intraoperative steps taken to decrease trauma to the eye and to make the procedure as minimally invasive as possible, Devgan said.

When beginning the procedure, the surgeon must respect the corneal epithelium and not inadvertently cause a corneal epithelium abrasion. A corneal epithelium abrasion will “hurt tremendously” and ensure increased pain and inflammation postoperatively, he said.

“When you’re doing the procedure, be very efficient in the eye. The more phaco energy you put in the eye, the more inflammation you’ll have postop. The more fluid you run through the eye, the more inflammation you’ll have postop. The more you manipulate the iris, the more postop inflammation you’ll see. The longer the surgery is in minutes, the more inflammation. If you’re an experienced surgeon, you can be very efficient and minimize the phaco energy by using the phaco chop technique, as well as phaco power modulation. Minimize the amount of fluid you run through the eye, minimize the total surgical time, and those eyes are virtually pain-free without drops,” Devgan said.

The use of the miLOOP (IanTECH/Zeiss) for a more dense cataract can help break the cataract into smaller pieces intraocularly and make it easier to remove. This also greatly reduces the energy being put into the eye and offers the potential for less corneal edema, Trattler said.

“I also use femtosecond laser cataract surgery. The laser can soften the cataract to make the cataract a little easier to emulsify. The laser has been shown to reduce the total amount of energy required to emulsify the nucleus during surgery,” he said.

Younger patients and highly myopic patients can be more sensitive to changes in anterior chamber fluid volume and IOP. Infusion that starts with a low bottle height, with the height gradually increased during the procedure, can help limit these changes if the patient is uncomfortable, Brinton said.

An intracameral mixture of lidocaine 1% and phenylephrine 1.5% in balanced salt solution can also improve outcomes.

“Buffered solutions with higher concentrations of lidocaine can also be used. To avoid ocular surface irritation and dryness in the early postoperative period, we avoid [balanced salt solution] irrigation of the eye and instead, at the beginning of the treatment, place a dispersive viscoelastic such as hydroxypropyl methylcellulose on the ocular surface for patient comfort,” Brinton said.

New drugs on the horizon

In addition to the newly approved Dextenza, new drugs and delivery systems are being developed to improve pain and inflammation management after ocular surgery. Dexycu (dexamethasone intraocular suspension, EyePoint Pharmaceuticals) was approved in February 2018 and will become available in 2019, Donnenfeld said.

The intraoperative, intracameral delivery of dexamethasone in the eye should provide “extremely high levels of anti-inflammatory therapies” and will absorb over 2 to 3 weeks, he said.

“It could eliminate the need for topical or clinical steroids in most patients after cataract surgery,” Donnenfeld said.

Mati Therapeutics announced interim phase 2 clinical trial results evaluating the efficacy of nepafenac delivered via sustained ocular drug delivery platform. A week after surgery, pain scores favored patients who received nepafenac over placebo, according to a Mati Therapeutics press release.

The interim data showed “extraordinary levels of pain control” with patients receiving the punctal plug NSAID, Donnenfeld said.

“The NSAID had five times less pain than the placebo group. That’s another drug coming down the line, a punctal plug NSAID drug delivery. Pain is an important concept of patients having surgery. I’m very excited about the new drug delivery platforms, either punctal plug drug delivery or intracameral drug delivery. Drug delivery systems are the future of pharmaceuticals in ophthalmology,” he said.

A shift to intracameral or intracanalicular slow-release pharmacological agents to aid in reducing inflammation and pain will become increasingly popular, Farid said.

“These techniques minimize the issue of noncompliance and trauma from medication bottle tips hitting the ocular surface postoperatively. Furthermore, less topical postoperative medications will improve the state of the ocular surface and associated preservative-related ocular surface disease from topical medications,” she said.

When surgeons are determining the protocol for patients to follow after cataract surgery, they should remember to tailor their postoperative regimen to their specific patient population in their specific clinic, Devgan said.

Not all patient populations are the same, not all cataracts are the same, and not all surgeons have the same experience. Strategies for treatment and removal need to be carefully considered, he said.

“A Beverly Hills cataract is removed pretty easily because the modest nuclear sclerosis means that it’s not dense. It’s removed fast and easily. In the charity clinic with my UCLA residents, this is the home of the brunescent and white cataract. What works well in my hands in a Beverly Hills setting may not work the same, even if it’s my own hand, in this underserved part of Los Angeles at our county teaching hospital. You must tailor your treatment to your patient. You know your patient and your population, your nuances, better than everyone else. It’s certainly not one size fits all,” he said. – by Robert Linnehan

• References:
• Brinton JP, et al. Patient communication during cataract surgery. www.eyerounds.org/tutorials/Communication-Cataract-Surgery.htm. Published July 28, 2011.
• Donnenfeld ED, et al. Am J Ophthalmol. 2011;doi:10.1016/j.ajo.2011.03.018.
• Donnenfeld ED. Clin Ophthalmol. 2011;doi:10.2147/OPTH.S6541.
• Donnenfeld ED, et al. J Cataract Refract Surg. 2018;doi:10.1016/j.jcrs.2018.07.015.
• FDA approves Inveltys for treatment of inflammation, pain after ocular surgery. https://www.healio.com/news/ophthalmology/20180823/fda-approves-inveltys-for-treatment-of-inflammation-pain-after-ocular-surgery. Published Aug. 23, 2018. Accessed Nov. 19, 2018.
• Hoffman RS, et al. J Cataract Refract Surg. 2016;doi:10.1016/j.jcrs.2016.06.006.
• Mati Therapeutics interim phase II nepafenac clinical trial results signal significant post-op pain reduction in cataract surgery patients. www.businesswire.com/news/home/20180904005058/en/Mati-Therapeutics-Interim-Phase-II-Nepafenac-Clinical. Published Sept. 4, 2018. Accessed Nov. 19, 2018.
• Ocular Therapeutix announces FDA approval of Dextenza for the treatment of ocular pain following ophthalmic surgery. Published Dec. 3, 2018. Accessed Dec. 3, 2018.

• For more information:
• Jason P. Brinton, MD, can be reached at Brinton Vision, 555 N. New Ballas Road, Suite 310, Saint Louis, MO 63141-6896; email: jbrinton@brintonvision.com.
• Uday Devgan, MD, can be reached at Devgan Eye Surgery, 11600 Wilshire Blvd. #200, Los Angeles, CA 90025; email: devgan@gmail.com.
• Eric D. Donnenfeld, MD, can be reached at Ophthalmic Consultants of Long Island, 711 Stewart Ave., Suite 160, Garden City, NY 11530; email: ericdonnenfeld@gmail.com.
• Marjan Farid, MD, can be reached at Gavin Herbert Eye Institute at the University of California, Irvine, 850 Health Sciences Road, Irvine, CA 92697; email: mfarid@uci.edu.
• William B. Trattler, MD, can be reached at Baptist Medical Arts Building, 8940 N. Kendall Drive, Suite 400-E, Miami, FL 33176; email: wtrattler@gmail.com.

Disclosures: Brinton reports he is a consultant for STAAR Surgical, Johnson & Johnson, Nidek and Zeiss. Devgan reports no relevant financial disclosures. Donnenfeld reports he is consultant for Alcon, Allergan, Bausch + Lomb, Kala Pharmaceuticals, Mati Therapeutics, Ocular Therapeutix and Omeros. Farid reports she is a consultant for Johnson & Johnson, Allergan, Shire Pharmaceuticals, EyePoint Pharmaceuticals, Kala Pharmaceuticals, CorneaGen and Bio-Tissue. Trattler reports he is a consultant for Bausch + Lomb, EyePoint Pharmaceuticals, Ocular Therapeutix, Sun Pharmaceuticals, IanTECH, Lensar and Novartis.

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