Stimulating Natural Tear Production

It is tempting to imagine the lacrimal gland as a little tap above the eye. Dry eye means the tap is not producing enough water, and therefore treatment should simply make the tap work harder. But tear production is much more complicated.

The lacrimal gland is part of a connected system often called the lacrimal functional unit. It involves:

• •the ocular surface
• •corneal and conjunctival sensory nerves
• •the nervous system
• •the lacrimal glands
• •meibomian glands
• •goblet cells
• •and the eyelids and blinking system

These structures continually communicate with one another. The eye senses what is happening on its surface and sends sensory information through neural pathways. The nervous system can then send signals back to structures involved in tear secretion. In simplified form:

ocular-surface sensation→sensory nerves→brainstem pathways→secretory signals→tears

This is why tear production is partly a neural reflex.

Where Tears Come From

Corneal Nerves

A tiny piece of dust lands on your cornea. Almost immediately, your eye waters. You did not consciously tell your lacrimal gland to produce tears. The ocular surface detected the stimulus. Sensory nerves carried that information. A reflex response was activated. The lacrimal system responded.

That same biological principle can be used therapeutically.

We often talk about “tear production” as though it were one constant process. It is not. The amount and composition of tears can change depending on stimulation. There is ongoing secretion associated with maintaining the ocular surface, and there can be much stronger reflex secretion triggered by sensory input.

This distinction also helps explain why someone can have aqueous-deficient dry eye and still cry, or why an irritated dry eye may sometimes water excessively. The ability to generate reflex tears does not necessarily mean that everyday tear availability is adequate.

There are several approaches. Some treatments stimulate the neural pathways involved in tear secretion. Others act pharmacologically on receptors involved in secretion from ocular-surface tissues. And some drugs influence not only aqueous fluid but also mucin secretion.

So “tear stimulation” is actually a group of different strategies rather than one treatment.

This one sounds strange the first time you hear about it.

Because the nose contains sensory nerves that can activate the same broader reflex pathways involved in tear production. Varenicline nasal spray is designed to stimulate the trigeminal parasympathetic pathway. Instead of putting medication directly onto the ocular surface, the drug is administered intranasally. The nasal sensory pathway is stimulated, and that neural signal can then activate natural tear secretion.

So the treatment is essentially using a reflex that already exists.

Yes, clinical trials have demonstrated increased tear production. In the phase 3 ONSET-2 randomized controlled trial, 758 adults with dry eye disease were treated with varenicline nasal spray or vehicle for four weeks. Participants had baseline Schirmer scores of 10 mm or less. A significantly larger proportion of patients receiving varenicline achieved at least a 10-mm increase in Schirmer score compared with vehicle.

That is important because the treatment is not simply making the eye feel wetter. It can measurably increase tear production.

One advantage is obvious: nothing has to be placed directly onto an already irritated ocular surface. For someone whose eyes sting with almost every drop, that can be attractive.

But there is another conceptual advantage. Instead of replacing one component of the tear film externally, neural stimulation attempts to recruit the body’s own secretory system. TFOS DEWS III includes nasal neurostimulation among neuromodulatory approaches to dry-eye management.

No. This distinction matters enormously. Stimulating a system is not the same as repairing it.

Imagine a gland that is capable of producing more tears but is not receiving enough stimulation. Increasing the signal may produce a substantial response. But imagine another lacrimal gland whose secretory tissue has been severely damaged. Sending a stronger signal does not necessarily recreate tissue that is no longer functional.

So the effect of stimulation depends partly on how much functional secretory capacity remains.

At least part of the relevant pathway must remain functional. Depending on the treatment, that may include:

• •sensory neural pathways
• •parasympathetic signaling
• •lacrimal gland tissue
• •and/or ocular-surface secretory cells

This is one reason two people who both have “aqueous-deficient dry eye” may respond very differently. The final symptom may look similar (not enough tears), but the biological reason may not be the same. One person’s system may be under-stimulated. Another person’s gland may have reduced secretory capacity. Another may have inflammation interfering with lacrimal function. Another may have a systemic autoimmune disease affecting the gland. And another may have several of these simultaneously.

This is particularly interesting. The ocular surface normally provides sensory input that helps regulate tear secretion. If corneal sensation is substantially reduced, that feedback system may become impaired.

In other words, the problem may not necessarily begin with “my lacrimal gland cannot make tears.” It could partly involve “the normal sensory signal that tells the system to make tears has changed.”

That is one reason corneal nerves matter so much in dry eye. They are not only responsible for feeling pain or discomfort. They participate in maintaining ocular-surface homeostasis.

Neural Dysfunction in Dry Eye

To some extent, that is part of the rationale. Intranasal neurostimulation activates sensory input through the nasal trigeminal pathway rather than relying solely on stimulation of the ocular surface. But it still requires downstream neural and secretory machinery capable of responding.

So it would be too simplistic to say “If your corneal nerves do not work properly, nasal stimulation will fix tear production.” The system is more complicated than that.

Diquafosol works differently. It is a P2Y2 receptor agonist. Rather than primarily stimulating tears through a nasal neural reflex, it acts on purinergic receptors involved in secretion at the ocular surface. Diquafosol can promote fluid secretion and mucin secretion.

This is an important distinction. Dry eye is not simply a water-deficiency disease. The ocular surface needs an appropriate interaction between aqueous fluid, lipids, mucins, epithelial cells and the glycocalyx. So increasing secretion at the ocular surface can potentially affect more than tear volume alone.

There is a substantial clinical literature. A systematic review of eight randomized trials involving 1,516 patients found improvements in several dry-eye outcomes, although the studies were heterogeneous. Ocular-surface staining improved consistently across the included trials, while improvements in Schirmer testing, tear-breakup time and symptoms varied between studies.

A later meta-analysis of nine randomized trials involving 1,295 patients found that 3% diquafosol produced greater improvements than 0.1% hyaluronic acid in several outcomes, including Schirmer score, TBUT, OSDI and ocular-surface staining, although adverse events were somewhat more frequent.

So diquafosol is not simply another artificial tear. It is a secretagogue, a drug intended to stimulate secretion.

This is important for patients reading about treatments online. Diquafosol has been used clinically in several Asian countries and has long been approved for dry eye in markets including Japan and South Korea. Its availability varies considerably by country.

So seeing a treatment repeatedly discussed in research papers does not necessarily mean your local ophthalmologist can prescribe it.

Rebamipide is another drug frequently encountered in the Asian dry-eye literature. Its main interest is not simply “making more watery tears.” It is particularly associated with mucin-related effects and ocular-surface protection.

A randomized, double-masked, placebo-controlled trial involving 308 patients evaluated 1% and 2% rebamipide for dry eye, and subsequent research has continued to investigate its effects on dry-eye signs, symptoms and mucin biology. Again, availability is geographically limited.

Because water alone cannot create a healthy tear film. Remember what we discussed earlier in this Guide. The ocular surface is coated by a glycocalyx containing membrane-associated mucins, while secreted mucins, particularly from conjunctival goblet cells, contribute to the tear environment. These components help the tear film interact properly with the ocular surface.

So there is an important conceptual difference between adding water and supporting the biological secretion system that helps create a functional tear film. That is one reason drugs such as diquafosol and rebamipide are scientifically interesting.

The Tear Film

Yes, but in a different context. Pilocarpine and cevimeline are systemic cholinergic agonists that stimulate exocrine secretion. They are particularly familiar in conditions such as Sjögren disease, where patients may have both severe dry mouth and dry eyes. These drugs can increase salivary secretion and may also increase tear production in some patients.

But because they act systemically, their effects are not limited to the eye. They can cause adverse effects such as:

• •sweating
• •flushing
• •gastrointestinal symptoms
• •and other cholinergic effects

The evidence specifically for dry-eye outcomes is also much less extensive than the evidence for some other approaches. A recent systematic review found insufficient comparable trial data for pilocarpine and cevimeline to include them in its quantitative analysis of secretagogues.

Sjögren's Disease and Dry Eye

Medications and Dry Eye

That is probably the wrong comparison. They are different tools.

• •Artificial tears add material to the ocular surface from outside.
• •Punctal plugs reduce the loss of tears through drainage.
• •Secretagogues and neurostimulation attempt to increase secretion from the patient’s own system.

Someone might benefit from one. Someone might benefit from several. And the correct choice depends on why tear availability is inadequate in the first place.

Artificial Tears & Lubricating Eye Drops

Potentially, yes. Conceptually these treatments act at different points:

• •stimulation: make more tears
• •punctal occlusion: retain tears longer

There is no universal rule that only one strategy can be used. But combining treatments should still have a reason. If tear volume is already adequate, simply increasing production and blocking drainage may lead to excessive tearing rather than meaningful improvement. Again, treatment should follow the target.

Punctal Plugs & Tear Conservation

No, and this is worth emphasizing. A Schirmer strip measures wetting. It does not tell us everything about:

• •tear composition
• •lipid quality
• •mucin function
• •tear-film stability
• •ocular-surface health
• •or how comfortable the patient feels

A treatment can produce a measurable increase in Schirmer score without completely normalizing the tear film. Conversely, clinically meaningful improvement does not always require a dramatic Schirmer increase. This is why treatment studies usually examine several outcomes rather than only one test.

The Schirmer Test

Not directly. Increasing aqueous or mucin secretion does not automatically:

• •open obstructed meibomian glands
• •normalize abnormal meibum
• •or restore damaged glands

But someone with MGD may simultaneously have insufficient aqueous tears. That person may need treatment directed at both components.

Dry eye does not respect our article headings. A real patient can have MGD, aqueous deficiency, inflammation and incomplete blinking all at the same time.

Dry Eye Is Often Mixed

That does not necessarily mean “My lacrimal glands are dead.” There are many possible explanations. The particular treatment may not have targeted the relevant mechanism. The neural pathway may respond differently. Secretory capacity may be limited. Inflammation or ocular-surface disease may still be active. Or inadequate aqueous production may simply not be the dominant cause of symptoms.

One failed treatment cannot tell us the entire state of the lacrimal functional unit.

That is interesting information too. If stimulating the system produces a substantial increase in tears and meaningful improvement, it demonstrates that at least part of the secretory pathway retains functional capacity.

But again, response to treatment is not the same as identifying the original cause. A therapy can compensate for a dysfunctional system without explaining why that dysfunction developed.

How to Choose a Dry Eye Treatment