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November 21, 2025
5 min read
Once upon a time, dry eye disease was simple.
Like a desert, an eye with dry eye disease (DED) simply had too little water to get the job done. It makes me chuckle when I see modern medications that have little or nothing to do with tear volume evaluated in clinical trials named after famous deserts.
If you are an eye doctor of a certain age, a moniker that I wear with a wary degree of honor, you remember the ubiquitous archetype of a DED patient created by Allergan (RIP) that defined the dry eye world in the ’90s and ’00s: a 35- to 65-year-old woman, married, three children, 3 years of postsecondary education, part-time employed with a family income of $75,000.
We called her “Linda Blair.” You know, after The Exorcist. You could spot her as she walked through the lobby to the front desk. “My eyes burn. Fix me!” Woe be unto s/he who failed to succeed in that task.
Every contemporary talk on DED begins with a review of the mechanisms underlying what we see on the surface of our patients’ eyes and what they experience out in the wild. Where once every patient was a figurative nail, there to be pounded with the only hammer available (Restasis), we now recognize a world in which the inflammation underlying DED has multiple effects on every part of the lacrimal functional unit. Roughly 50% of patients with dry eye have a pure evaporative DED; they have a normal tear volume. Thirty-five percent have both evaporation and low tear volume. Only 15% or so have a pure aqueous deficiency.
Still, if you do the math, you have to give some thought to increasing the effective volume of tears for half of the patients who cross your threshold, whether or not they are possessed.
This is about as basic as things get in eye care: If it is dry, wet it. There are only two ways to accomplish this. Either you make more tears, or you keep the tears you make in contact with the surface of the eye for a longer period of time. Or both. For the purposes of this “DED 101” update, we can leave aside addressing any underlying medical problems that led to the aqueous deficiency in the first place and concentrate on potentially high-yield interventions we can institute without the assistance of our medical colleagues. Unless you are addressing high tear osmolarity with a hypotonic artificial tear, can we not talk about over-the-counter tears as therapy? Please and thank you.
Perhaps the oldest effective therapeutic intervention for DED is reducing tear outflow by occluding puncta. If you think of the eye as a sink with one faucet and two drains, blocking one of the drains will slow the egress of liquid from the sink. Every eye doctor learns this in training. If nothing is done to inflow, you are unlikely to cause the sink to overflow.
Over the years, there have been various iterations of plugs for the drain, beginning with the parasol “manhole cover.” Called “permanent plugs,” they are notable for dislodging, either partially (ouch!) or completely, as well as stimulating all manner of inflammation, scar formation and even infection. More modern “temporary plugs” are made of collagen that dissolves over a period of 3 to 4 months. They are inserted more deeply into the punctum and need to be “replaced” repeatedly. Inflammatory and infectious complications are less common but can be more serious.
New to this arena is what should more accurately be described as lacrimal or canalicular occlusion achieved with the injection of cross-linked hyaluronic acid under the brand Lacrifill (Nordic Pharma). Unlike plugs, Lacrifill is injected into the canalicular system much more deeply. Indeed, in some instances, both the upper and lower halves of the system can be occluded with a single injection in either the upper or lower punctum. Unlike plugs of any type, the trial submitted to the FDA resulting in approval of the device demonstrated a statistically significant reduction in inflammation manifested as corneal staining. We know that Lacrifill lasts at least 6 months (the FDA required flushing it out at that point), and in our hands, it seems to last longer.
What about increasing tear production? Does anyone remember the singular phase 3 study finding that resulted in FDA approval for Restasis (cyclosporine ophthalmic emulsion 0.05%, AbbVie)? If you guessed increased tear production, you are correct. Indeed, all the other findings notwithstanding, all the newer FDA-approved immunomodulators — Xiidra (lifitegrast ophthalmic solution 5%, Bausch + Lomb), Cequa (cyclosporine ophthalmic solution 0.09%, Sun Ophthalmics) and Vevye (cyclosporine ophthalmic solution 0.1%, Harrow) — also had to demonstrate increased tear production. Despite this, none of the medications in the category can compete on tear production with the newer entrants to the game, Tyrvaya (varenicline solution, Viatris) and Tryptyr (acoltremon ophthalmic solution 0.003%, Alcon).
Tyrvaya, a nasal spray, is a nicotinic acetylcholine agonist that stimulates the first division of the trigeminal nerve as it passes just beneath the mucosal surface of the nasal lining. Tryptyr is a TRPM8 receptor agonist that stimulates temperature-sensitive nerves in the cornea. Both create amazing tear production. In their respective phase 3 trials, each demonstrated an increase in non-anesthetized Schirmer scores of greater than 10 mm in nearly 50% of subjects, far surpassing their respective vehicles. Both maintained their efficacy over the entirety of the trials. In real-world experience, both at SkyVision Centers and in the clinics of my closest colleagues, there does not appear to be any diminution of this effect over time.
Data for symptom relief are a bit of a mixed bag, though. Both Tyrvaya and Tryptyr failed to meet their symptom endpoint on one of their two phase 3 trials. Where they did demonstrate a statistically significant difference between drug and vehicle, the numerical difference was underwhelming: 5 to 9 points on a 100-point scale. As a secondary medication, we can report a meaningful decrease in patient symptoms with Tyrvaya. In the wild, colleagues who are early adopters of Tryptyr report beneficial effects and reduced symptoms that exceed those found in the trials. Neither drug has any direct effect on ocular surface inflammation, and unlike Lacrifill, there is no evidence that I can find for a reduction in surface inflammation (eg, corneal staining) without an inherent anti-inflammatory mechanism of action.
All the medications and devices I have mentioned have an Achilles’ heel. Legacy plugs suffer from frequent complications, none more annoying than their tendency to fall out. Newer dissolvable plugs, while quite friendly to a practice’s bottom line, require multiple applications per year, necessitating more frequent office visits and higher patient costs. Lacrifill may last much longer than 6 months, reducing both of these problems, but is much more expensive and therefore poses a greater financial burden on a practice.
Both drugs are saddled with a significant side effect, which makes prescribing them something less than a slam dunk. Have you tried Tyrvaya? You sneeze like Wile E. Coyote going over a cliff in his Acme truck, losing the wheels, roof, mirrors and doors on the way down. Make sure you warn every patient to use Tyrvaya in the privacy of home. How about Tryptyr? If you want a laugh, Google “Tryptyr first drop” and watch patients’ reactions to the initial “minty cool” sensation. To be fair, in our in-office first application trials with the staff, both the sneezing and the application site discomfort were tolerable and short-lived. (I will report on our Tryptyr experience at SkyVision Centers in an upcoming blog post.)
Tryptyr, Tyrvaya, Lacrifill and the various and sundry plugs are all appropriate first-line therapies in pure aqueous-deficient DED. In those cases in which the primary symptom driver is evaporation and a tear deficiency is also present, all the tear volume enhancers fit into our new world of “and” as secondary or supplemental treatments when the direct anti-inflammatory or anti-evaporative treatment only provides partial relief for your patient.
For more information:
Darrell E. White, MD, of SkyVision Centers in Westlake, Ohio, can be reached at dwhite@healio.com.
Sources/Disclosures
Source:
Expert Submission
Disclosures:
White reports speaking and consulting for Allergan, Bausch + Lomb, Sun, Tarsus and Viatris, consulting for Aldeyra, Bruder, Nordic Pharma and Thea, and consulting for and being an investor in Orasis and SpyGlass.
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