Dry Eye and Ocular Surface Disease Bonus Issue
October 2025
by Ellen Stodola
Editorial Co-Director
When treating dry eye patients, it’s possible to encounter patients who do not respond to treatment. Two experts discussed how to proceed with these patients and get them the care they need.
Dry eye is the number one reason for ophthalmology and optometry visits, said Eric Donnenfeld, MD. Unfortunately, many patients have decades of discomfort and loss of visual function and quality of life due to their dry eyes.
He noted that treatment for dry eye patients generally follows a pecking order. “There have been many different nomograms developed for managing dry eye,” he said, adding that the ASCRS Preoperative OSD Algorithm is a very good one. Essentially, you start with artificial tears as first-line therapy. “Probably my biggest complaint is people who complain of significant dry eye, they go to see an eye doctor, and the eye doctor’s knee-jerk response is to change the drops to a different artificial tear. Almost with 100% certainty, changing one tear to another is not going to resolve a patient’s dry eye problem,” Dr. Donnenfeld said. “If a patient is not getting the desired improvement with tears, we need to move on to more advanced therapy.”
After artificial tears, Dr. Donnenfeld said there are different classes of therapies to progress to—immunomodulators (like cyclosporine and lifitegrast), tear secretagogues, and tear film stabilizers.
Dr. Donnenfeld said he has been very impressed with XDEMVY (lotilaner, Tarsus) to treat Demodex blepharitis. “Demodex may be the missing link in the treatment of meibomian gland dysfunction,” he said.
Dr. Donnenfeld has found success in treating patients with an immunomodulator and a tear film stabilizer, noting that his go-to combination is lifitegrast and perfluorohexyloctane.
For patients who still aren’t getting relief fast enough, he is also a big believer in using low-dose corticosteroids. He noted EYSUVIS (loteprednol etabonate ophthalmic suspension, Alcon) and said loteprednol is a good way to manage these patients short term.
Alice Epitropoulos, MD, said it’s quite common for clinicians to see patients who do not respond to dry eye treatment. “I would estimate that 15–30% of patients with dry eye symptoms fall into a ‘non-responsive’ or ‘partial response’ category, though this varies depending on how treatment success is defined,” she said. “Many of these patients have chronic, multifactorial disease that progresses over time. Delayed treatment can lead to worsening symptoms, tear film instability, persistent inflammation, structural changes, and reduced quality of life.”
Reasons patients don’t respond
Dr. Epitropoulos explained that there are several potential reasons why some patients may not respond to treatment.
While many individuals experience relief from standard therapies like artificial tears, anti-inflammatory eye drops, or lifestyle modifications, a subset of patients continue to suffer from persistent symptoms. “This is especially true for those with neuropathic or chronic ocular surface pain, a subtype of dry eye where the discomfort is driven more by nerve dysfunction than by tear film deficiency or ocular surface disease.”
Dr. Epitropoulos said that neuropathic ocular pain is frequently underdiagnosed, and these patients may not respond to standard anti-inflammatory or tear-enhancing therapies.
She noted that patients with neuropathic pain often describe burning, stinging, or aching sensations that don’t correlate with clinical findings. Their symptoms often remain unresponsive to standard treatments for dry eye disease. “Unfortunately, effective treatment options for this group are limited, and managing their condition can be particularly challenging,” she said. “These patients may benefit from a multidisciplinary approach, including systemic medications like autologous serum, topical compounded morphine drops, neuromodulators, antidepressants, psychological support, or referrals to pain management specialists.”
Dr. Epitropoulos noted that EyeCool Therapeutics is working on technology aimed at improving or alleviating chronic ocular surface pain. This procedure involves delivering cold energy to the long ciliary nerves, temporarily disrupting the myelin sheath and inhibiting pain signaling. This approach is designed to reduce chronic ocular surface pain symptoms while preserving corneal sensitivity and the normal blink reflex. Earlier this year, the company announced positive results from a double-masked, randomized controlled trial demonstrating a favorable safety profile and a significant reduction in patient-reported ocular pain compared to the control group.
Dr. Epitropoulos said the unmet therapeutic needs of these patients underscore the critical need for ongoing research and innovation in the field of ocular surface disease, particularly for complex or treatment-resistant cases. She also shared a number of other reasons that patients may be non-responsive to dry eye treatments:
- Incorrect subtype identification: For instance, Demodex blepharitis, which can contribute to meibomian gland dysfunction and patient symptoms (itching, mattering), may not improve unless specifically addressed (lotilaner). Treating evaporative dry eye with aqueous-enhancing strategies, or vice versa, will naturally yield inadequate results.
- Incomplete treatment: Patients may discontinue medications early or use them inconsistently, especially if symptomatic relief is delayed, she said.
- Neurotrophic keratitis: This is another important consideration; patients with reduced corneal sensation may exhibit advanced ocular surface disease with minimal symptoms. These patients may not respond to conventional treatments due to impaired epithelial healing. Dr. Epitropoulos said that identifying neurotrophic components is crucial for directing appropriate therapies such as cenegermin (Oxervate, Dompe), serum tears, and/or amniotic membrane.
- Uncontrolled inflammation or meibomian gland dysfunction (MGD): Persistent subclinical inflammation, Demodex infestation, or gland dropout may not respond to conventional therapy.
- Systemic comorbidities: Autoimmune conditions, hormonal changes, sleep apnea, or polypharmacy (especially anticholinergics and antihistamines) can exacerbate symptoms.
- Environmental/lifestyle: Prolonged screen time, low humidity, infrequent or incomplete blinking, or poor sleep habits often play a role in treatment resistance.
Dr. Donnenfeld agreed that one of the main reasons patients may not respond to treatment is because of incorrect subtype identification. “When I evaluate a patient with dry eye who’s unhappy, I generally want to ascertain what the cause of the dry eye is,” he said, adding that certain therapies are good for aqueous deficient dry eye, and certain drugs are better for MGD. “A lot of times, when patients are not responding to one therapy, it’s because you’re treating the wrong disease.” For example, when cyclosporine was first approved by the FDA, that was the only therapy that was readily available for dry eye. “When all you have is a hammer, everything looks like a nail, and we treated a lot of patients who were not responding because they really had MGD and not aqueous deficient dry eye,” he said. “I like to find out what the cause of the problem is. Many times, patients need both treatments.”
Dr. Epitropoulos also noted that certain symptoms and conditions are more likely to be non-responsive to treatment. In particular, she said that neuropathic pain masquerading as dry eye tends to be especially difficult to manage. Key indicators include severe symptoms with minimal clinical signs, allodynia, and poor response to conventional treatments.
More advanced options
“Typically, I allow 6–8 weeks to evaluate the effectiveness of a new therapy, though some treatments, such as cyclosporine or lifitegrast, may need 3–6 months,” Dr. Epitropoulos said. “If a patient’s condition worsens or shows no improvement after 4 weeks, I begin adding or switching to other therapies, such as autologous serum or amniotic membrane. I also routinely reassess diagnostics, including osmolarity, MMP-9 and meibography, to better understand the underlying disease factors.”
When moving on to more advanced treatment options, Dr. Donnenfeld said punctal occlusion may be helpful for some dry eye patients. He noted Lacrifill (Nordic Pharma) being particularly effective at sealing the punctum. “The crosslinked hyaluronic acid in the punctum is released into the tear film and provides a sustained delivery of tears,” he said.
“For significant dry eye, I think that we underutilize serum tears,” he continued. “These are superb treatment for patients with recalcitrant dry eye.”
Along a similar line, he said amniotic membranes are often used for persistent epithelial defects. “For many patients with severe dry eyes, putting an amniotic membrane on for 3 or 4 days stabilizes the ocular surface, and that allows the other therapies to contribute to managing the dry eye,” he said. Amniotic membrane is not only a short-term treatment for dry eye but can be a long term as well.
Dr. Donnenfeld also thinks there is a significant role for oral doxycycline. A lot of doctors use too high a dose, he said. “All you need is 50 mg or less a day. I’ll keep them on that for sometimes months at a time.”
Dr. Epitropoulos said she will use a tiered approach to treatment in these patients. If a patient is not improving with baseline therapy (artificial tears, lid hygiene, prescription drops like cyclosporine or lifitegrast), she’ll consider:
- In-office procedures: Thermal pulsation (LipiFlow, Johnson & Johnson Vision, and iLux, Alcon) for MGD or intense pulsed light, especially for patients with rosacea
- Anti-inflammatory strategies: Short courses of corticosteroids or add-on agents like Tyrvaya (varenicline nasal spray, Viatris) or punctal occlusion (Lacrifill) can be used in aqueous deficient disease, she said.
- Autologous serum tears: These are especially helpful in severe or post-surgical dry eye and in cases of neurotrophic or neuropathic pathology.
- Amniotic membranes: These can be used for patients with epithelial compromise or severe keratitis, Dr. Epitropoulos said.
- Oxervate: This can be used in patients with NK.
- Neuropathic treatment: Gabapentin, pregabalin, or low-dose antidepressants can be used in select cases, Dr. Epitropoulos said, adding that a pain specialist referral is sometimes necessary.
Dr. Epitropoulos has found the Cedars Dry Eye Algorithm helpful for guiding treatment escalation in non-responders. “It incorporates the use of compounded medications, such as topical tacrolimus, doxycycline, testosterone drops, N-acetylcysteine drops, topical metronidazole, tailored to specific inflammatory or meibomian gland dysfunction,” she said. “These alternative therapies can be invaluable when conventional therapies have been exhausted.”
What’s next
Dr. Donnenfeld is excited for the developments being made in dry eye options. “Just like glaucoma, I think we’re going to have multiple therapies for dry eye that will work on different pathways,” he said.
“Empathy and education go a long way in maintaining patient engagement and adherence.”
Alice Epitropoulos, MD
He noted acoltremon ophthalmic solution 0.003% (TRYPTYR, Alcon), which works on the TRPM8 pathway to stimulate tear secretion, adding that trials were promising and showed rapid improvement in Schirmer scores and improvement in corneal staining.
Dr. Epitropoulos also noted several promising developments in this arena. One of the most exciting is the development of reactive aldehyde species (RASP) inhibitors like reproxalap (Aldeyra Therapeutics), she said, which target oxidative stress and inflammation high up on the inflammatory cascade. Data has shown promise in reducing both signs and symptoms of dry eye, particularly in patients with high inflammatory burden.
She also noted AZR-MD-001 (a selenium sulfide ophthalmic ointment, Azura Ophthalmics) as a novel therapeutic for MGD using a first-in-class ophthalmic keratolytic aimed at normalizing keratinization and lipid composition at the gland level by breaking apart disulfide bonds that bind keratin, addressing MGD more upstream than traditional therapies.
Dr. Epitropoulos stressed that managing non-responsive dry eye often requires a multidisciplinary, holistic approach. “In addition to pharmaceutical and procedural interventions, counseling on behavior modification—like blink training, ergonomic changes, diet, hydration, and sleep—is key,” she said. “Also, we should never underestimate the psychological impact of chronic ocular discomfort. Empathy and education go a long way in maintaining patient engagement and adherence.”
About the physicians
Eric Donnenfeld, MD
Ophthalmic Consultants of Long Island
Garden City, New York
Alice Epitropoulos, MD
Central Ohio Eye and Plastic Surgery
The Eye Center of Columbus
Columbus, Ohio
Relevant disclosures
Donnenfeld: AbbVie, Alcon, Azura, Bausch + Lomb, Nordic Pharma, Tarsus
Epitropoulos: AbbVie, Aerie Pharmaceuticals, Alcon, Aldeyra, Bausch + Lomb, BioTissue, Bruder Healthcare, Dompe, EyeCool Therapeutics, Harrow, Hilco Vision, Horizon, Johnson & Johnson Vision, OTX, Physician Recommended Nutriceuticals, Sun Ophthalmics, Tarsus, Trukera, Viatris
Contact
Donnenfeld: ericdonnenfeld@gmail.com
Epitropoulos: eyesmd33@gmail.com
