Ocular surface pain often hides behind the misnomer ‘dry eye.’ Dry eye disease (DED) is somewhat unique in that it is named after a single symptom—dryness—despite encompassing a wide spectrum of unpleasant sensations, many of which are more prominent and not perceived by patients as ‘dryness’ at all. Such symptoms may include burning, irritation, foreign body sensation, itchiness, photophobia, or even frank pain.1
What we call dry eye is rarely just dryness; it is a constellation of sensory disturbances, reflecting a spectrum of underlying mechanisms—from tear deficiency to nerve dysfunction.
“Labeling a patient’s complaint as ‘dry eye’ is easy; understanding the full scope of ocular surface pain is far more challenging—and far more important.”
Addressing the pain paradox
However, clinical experience reveals a persistent paradox: the severity of patient-reported symptoms frequently does not align with objective clinical findings.2
Some patients present with overt ocular surface disease (OSD) yet report minimal discomfort, while others experience severe pain despite relatively normal examinations. Furthermore, patients may report sensations—such as stabbing, aching, or extreme itchiness—that do not classically align with traditional dry eye symptomatology.3
Traditional objective dry eye testing measures including meibography, tear breakup time (TBUT), tear osmolarity, Schirmer testing, and corneal fluorescein staining, often fail to correlate with the intensity of symptoms.2 This disconnect highlights a critical gap in conventional OSD management and points toward mechanisms beyond simple tear film disruption.
Emerging research suggests that a subset of these patients may have dysfunction within the trigeminal sensory system that innervates the cornea and ocular surface.4 Ocular surface pain exists on a continuum of neurobiological mechanisms, including nociceptive pain (classically what we consider “dry eye”), neuropathic pain (arising from abnormal peripheral or central nerve signaling, sometimes following injury), or nociplastic pain (mediated by central nervous system hypersensitivity without clear tissue or nerve damage).4
This comprehensive guide integrates the latest neurobiological insights on corneal innervation with practical, evidence-based strategies, providing clinicians with the tools to recognize, assess, and manage the full spectrum of ocular surface pain.
Types of ocular surface pain
Chronic pain is pain that persists for longer than 12 weeks and affects more than 1 in 5 adults in America.5 Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”6 This definition highlights that pain is not solely a direct response to tissue injury but also reflects the complex processing of sensory signals within the nervous system.
In the context of this review, the term “ocular pain” is used broadly to include ocular dysesthesia, meaning any abnormal or unpleasant ocular sensation such as stinging, dryness, irritation, aching, pressure, foreign body sensation, photophobia, or wind sensitivity. Although often attributed to OSD, particularly DED, these sensations may arise from multiple pain mechanisms along the ocular surface and trigeminal sensory pathway.
For clinical and mechanistic purposes, it is generally categorized as:7
- Nociceptive
- Neuropathic
- Nociplastic pain
Nociceptive pain
Nociceptive pain arises from actual or threatened tissue damage and represents the normal protective response of the sensory nervous system. On the ocular surface, this occurs when peripheral nociceptors (sensory nerve endings that detect tissue-damaging or potentially harmful stimuli) within the cornea or conjunctiva are activated by environmental or inflammatory stimuli.7,8
Common triggers include tear film instability, desiccation, mechanical friction from eyelid abnormalities, infection, trauma, or inflammation of the ocular surface.7 Clinically, nociceptive ocular pain typically correlates with observable ocular surface pathology, such as punctate epithelial erosions, tear film abnormalities, or lid margin disease.
Symptoms tend to be relatively proportional to the degree of tissue injury and generally improve once the underlying ocular surface pathology is treated.7,8
Neuropathic pain
Neuropathic pain results from a lesion or disease affecting the somatosensory nervous system.9 In this form of pain, sensory nerves themselves become dysfunctional, generating abnormal or amplified pain signals even in the absence of ongoing tissue injury.8
Neuropathic pain may arise from direct injury to corneal or trigeminal nerves. Potential causes include refractive surgery, cataract surgery, herpetic infections, trauma, or chronic inflammatory conditions that alter nerve structure and function. These damaged nerves may exhibit abnormal excitability, spontaneous firing, or structural changes such as neuromas.7
When these abnormalities and hypersensitive nerves are present at the level of the corneal nerves, we refer to this as peripheral sensitization. When the nerve hypersensitivity originates further upstream along the trigeminal nerve (i.e., not in the eye itself but at the level of the brainstem and/or brain), we refer to this as central sensitization.7
Patients with neuropathic ocular pain frequently report symptoms that appear disproportionate to clinical findings, sometimes oversimplified when referred to as “pain without stain.” This is an oversimplification because even dry eye patients with surface staining may have neuropathic features to their dry eye, identified by symptoms far outweighing signs.
Want to learn more about neuropathic ocular pain? Check out the article Neuropathic Pain Management in Optometry!
Nociplastic pain
Nociplastic pain refers to pain arising from altered nociceptive processing within the central nervous system, occurring in the absence of clear tissue injury or identifiable damage to the somatosensory system.10
This form of pain is thought to result from central sensitization, a state in which neural circuits involved in pain processing become hyper-responsive. In this condition, excitatory pain pathways are amplified while inhibitory pathways that normally dampen pain signaling become less effective.10
Patients with nociplastic ocular pain often exhibit heightened systemic pain sensitivity rather than isolated ocular symptoms. Ocular discomfort may occur alongside other chronic pain conditions such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, or chronic migraine, suggesting that ocular symptoms may represent one manifestation of a broader disorder of pain regulation.10
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Clinical Guide to Ocular Surface Pain
Use this cheat sheet to review key concepts from the article on ocular surface pain, with IVCM imaging, treatment approaches, and more!
Understanding mixed pain mechanisms
Importantly, these mechanistic categories are not mutually exclusive; many conditions involve multiple pain mechanisms simultaneously.
For instance, chronic tear film instability or ocular surface inflammation may begin as pure nociceptive triggers, but over time, the constant bombardment of the nervous system can drive peripheral or central sensitization within the trigeminal pathway. Because eye pain can manifest from any location along this pathway, patients often demonstrate a "mixed" profile, showing features of both nociceptive stimulation and neuropathic amplification.
“Recognizing these mixed pain mechanisms is essential, as the dominant driver—whether it be the ocular surface environment or the nervous system itself—must dictate the diagnostic evaluation and treatment strategy.”
Furthermore, clinicians should remain aware of referred pain mechanisms, such as cervicogenic eye pain. In these cases, dysfunction in the upper cervical spine (C1 to C3) can trigger perceived ocular discomfort due to the convergence of cervical and trigeminal sensory inputs within the trigeminocervical complex.11
Ultimately, understanding that ocular pain is rarely a single-mechanism event allows for a more nuanced approach to the patient who feels "more" than what their clinical signs might suggest.
Table 1: Types of ocular surface pain.7-10
| Pain Type | Definition / Mechanism | Ocular Examples | Systemic Examples |
|---|---|---|---|
| Nociceptive Pain | Pain arising from actual or threatened tissue injury due to activation of corneal nerve nociceptors | Dry eye disease with ocular surface staining | Acute trauma |
| Corneal abrasion | Post-operative pain | ||
| Infectious keratitis | Inflammatory arthritis | ||
| Blepharitis | Tissue inflammation | ||
| Neuropathic Pain | Pain caused by a lesion or disease affecting the somatosensory nervous system, leading to abnormal nerve signaling and hypersensitivity | Post-LASIK neuralgia | Diabetic neuropathy |
| Symptoms often exceed observable tissue damage | Post-herpetic ocular pain | Post-herpetic neuralgia | |
| Trigeminal neuropathy | Trigeminal neuralgia | ||
| Persistent ocular pain with minimal surface findings | Chemotherapy-induced neuropathy | ||
| Nociplastic Pain | Pain arising from altered central nociceptive processing without clear tissue injury or somatosensory system damage | Ocular discomfort in patients with centralized pain syndromes | Fibromyalgia |
| Often associated with central sensitization and widespread pain disorders | Chronic fatigue syndrome | ||
| Irritable bowel syndrome | |||
| Chronic migraine |
Or…the absence of pain
While some patients with OSD experience symptoms that are disproportionate to clinical findings, the opposite pattern is also commonly encountered with neurotrophic keratitis (NK). These patients present with significant ocular surface findings but report minimal discomfort, often due to reduced corneal nerve sensation or impaired neural function that diminishes afferent signaling to the central nervous system.
Risk factors include:12
- Prior ocular surgery (e.g., PRK, LASIK, cataract surgery)
- Herpetic infections (HSV, HZO)
- Systemic neuropathies (e.g., diabetes)
- Chronic ocular surface inflammation
- Repeated epithelial injury
In such cases, corneal sensation testing (esthesiometry) is useful in deciphering if neurotrophic keratitis is present. This testing may be performed qualitatively using cotton-wisps, dental floss, or tissue paper.
It may also be done quantitatively using instruments such as the Cochet-Bonnet or Brill or Belmonte esthesiometer. Any reduction in corneal sensation—be it hypoesthesia or anesthesia—confirms a diagnosis of NK and guides intervention.13
A brief discussion of neurotrophic keratitis
Management of NK should focus on regenerative rather than supportive therapies encouraging epithelial healing and nerve support. Regenerative treatments include options such as autologous serum eye drops, platelet-rich plasma eye drops, amniotic membranes, and recombinant human nerve growth factor (cenegermin-bkbj ophthalmic solution, OXERVATE, Dompé).14
Supportive therapies, on the other hand, are options that indirectly support nerve healing by improving ocular surface health such as topical immunomodulators, bandage contact lenses, or scleral lenses. Importantly, NK can overlap with neuropathic pain, as some non-nociceptive fibers may acquire a nociceptive phenotype, contributing to paradoxical pain despite corneal nerve hypoesthesia.7
This article, however, focuses on ocular pain mechanisms, so a detailed discussion of NK is beyond its scope.
Interpreting symptoms and signs of OSD
Traditionally, clinicians have approached OSD in a relatively binary manner—patients either have “dry eye” or they do not. However, clinical experience and growing research in ocular pain suggest that the relationship between symptoms and ocular surface findings is often far more complex.
“Many patients do not fit neatly into a simple diagnostic category, and the degree of discomfort reported by a patient frequently does not correlate with the severity of observable clinical signs.”
For this reason, it can be helpful to conceptualize OSD using a framework that considers both symptom burden and objective ocular surface status simultaneously.
Figure 1: The conceptual diagram below illustrates this approach using a two-axis model. The vertical (Y) axis represents pain status, ranging from low pain or minimal symptoms at the bottom to high pain or severe symptoms at the top. The horizontal (X) axis represents ocular surface status, ranging from poor ocular surface health with significant clinical findings on the left to a relatively healthy ocular surface with minimal findings on the right.
In the figure, red indicators represent unfavorable states (more disease, more pathology), whereas green indicators represent favorable states (healthier tissue or fewer symptoms).
Figure 1: Courtesy of Kaleb Abbott, OD.
Using this framework, cases can be conceptualized as falling into four general regions:
- Upper left quadrant: “Dry eye”
- Patients exhibit both significant symptoms and objective ocular surface disease.
- Upper right quadrant: Neuropathic pain
- Patients report severe ocular discomfort despite relatively normal ocular surface findings.
- Lower left quadrant: Neurotrophic keratitis
- Patients demonstrate significant ocular surface pathology with minimal symptoms.
- Lower right quadrant: No “dry eye”
- Patients have minimal symptoms and minimal clinical findings.
Importantly, this framework should not be interpreted as a rigid classification system. OSD exists on a spectrum, and substantial overlap occurs between these categories. For example, patients with DED may develop secondary neuropathic pain, while individuals with NK may simultaneously exhibit features of DED. Similarly, patients with neuropathic pain may still have mild ocular surface abnormalities.
Therefore, the purpose of this model is not to assign patients to a single definitive category, but rather to provide clinicians with a conceptual starting point for interpreting the relationship between symptoms and clinical findings.
Predictors of DED symptoms
As previously mentioned, one of the most counterintuitive findings in DED research is that the presence or severity of OSD often fails to predict symptom burden.2 Instead, systemic and neurological factors are frequently stronger predictors of symptom severity than ocular surface metrics themselves.15 So if the ocular surface does not accurately predict the presence of ocular discomfort, what does?
Large observational studies have identified several factors associated with increased symptom reporting, including:15
- Chronic pain conditions
- Anxiety and depression
- Sleep disturbances
- Psychological stress
- Certain medications (e.g., antidepressants, antihistamines)
- Systemic inflammatory or atopic disease
Collectively, these findings highlight the role of central pain processing in shaping ocular discomfort.
Chronic overlapping pain conditions
Chronic overlapping pain conditions (COPCs)—such as fibromyalgia, migraine, small fiber neuropathy, temporomandibular disorder, and irritable bowel syndrome—are particularly relevant.7,16
These conditions are linked by central sensitization, a state in which pain-processing pathways become hyper-responsive, amplifying both noxious and non-noxious stimuli.17 When central sensitization occurs, sensory signals that would normally be interpreted as mild irritation—or even non-painful stimuli such as wind, light, or blinking—may be perceived as significant discomfort.18
Anxiety and depression
Psychological health further modulates symptom perception. Anxiety and depression are consistently associated with increased dry eye symptoms, reflecting the overlap between neural circuits governing pain and emotion, including limbic system involvement.19
These relationships are not merely coincidental; the neural networks responsible for processing pain overlap extensively with those involved in mood regulation and emotional processing.20 This may help explain why dry eye symptom severity correlates more strongly with chronic non-ocular pain, depression, and PTSD than with tear film parameters.21
Sleep disturbances
Sleep quality further influences ocular pain perception. Multiple studies demonstrate that poor sleep and insomnia are linked to worse ocular pain symptoms: patients with worse symptoms report significantly poorer sleep quality and higher rates of clinical insomnia.22,23 In short, insomnia can amplify perception of dry eye symptoms and eye pain.
Sleep deprivation impairs the brain’s descending inhibitory pain pathways, reducing the nervous system’s ability to dampen sensory signals.24 For this reason, patients with sleep disorders may experience heightened sensitivity to otherwise minor ocular surface stimuli.
“Taken together, the strongest predictors of dry eye symptoms often lie outside the eye.”
While ocular surface pathology may initiate nociceptive signaling, symptom severity is largely determined by central processing.15 Accordingly, also assessing systemic pain conditions, mental health, and sleep quality may be more informative than ocular surface testing alone.
Classic nociceptive pain (aka “dry eye”)
Despite the growing recognition of neuropathic and centrally mediated ocular pain, the most intuitive and historically recognized form of ocular discomfort remains nociceptive pain, which is the type of pain produced by actual or threatened tissue damage. In the context of the ocular surface, this represents what clinicians traditionally refer to as “dry eye.”
Nociceptive ocular pain originates from activation of sensory nerve endings within the cornea and conjunctiva. The cornea is the most densely innervated tissue in the human body and receives its sensory supply from the ophthalmic branch of the trigeminal nerve (V1).25 Estimates suggest that the cornea contains approximately 7,000 nociceptive nerve endings per square millimeter, making it roughly 300 to 600 times more sensitive than skin.25
Corneal sensory nerves originate from the nasociliary branch of the trigeminal nerve and enter the cornea radially through the limbus.25 These nerves lose their myelin sheaths shortly after entering the corneal stroma and continue anteriorly to form the subbasal nerve plexus, from which numerous free nerve endings extend into the corneal epithelium. These terminal nerve endings function as nociceptors, specialized sensory receptors designed to detect mechanical, thermal, and chemical threats to tissue integrity.7
Figure 2: Graphical representation of the trigeminal nerve pathway starting from activation of corneal nerve nociceptors by ion channels (right) to the somatosensory cortex (left).
Figure 2: Courtesy of Kaleb Abbott, OD.
Corneal nociceptors detect environmental stress via specialized ion channels on their nerve endings. When these channels open, positively charged ions enter, depolarizing the membrane and generating an action potential.26
This signal travels along myelinated A-delta fibers (fast, sharp pain) and unmyelinated C fibers (slow, burning/dull pain) through the long ciliary nerves to the trigeminal ganglion, then to the trigeminal brainstem sensory complex, thalamus, and finally the somatosensory cortex and limbic system, where pain is perceived.7
Table 2: Corneal nerve nociceptors.
| Corneal Nociceptor Types | % of Nociceptors | Main Ion Channels | What Activates the Channel | Clinical Relevance |
|---|---|---|---|---|
| Polymodal Nociceptors | ~70% | TRPV1 | Heat | Primary drivers of classic dry eye symptoms |
| TRPA1 | Inflammation | Stimulation leads to inflammation | ||
| ASICs | Acidity | Chronic stimulation may lead to peripheral sensitization | ||
| Hyperosmolarity | ||||
| Chemical irritants | ||||
| Oxidative Stress | ||||
| Mechanonociceptors | ~15 to 20% | PIEZO2 | Direct mechanical force or touch to the cornea | Detects mechanical trauma (e.g., trichiasis, foreign bodies, corneal abrasions, contact lens irritation) |
| Main nociceptor involved in corneal sensation testing | ||||
| Cold Thermoreceptors | ~10 to 15% | TRPM8 | Corneal cooling from tear film evaporation | Regulates basal tear secretions (i.e., stimulation increases basal tear secretions) |
| Hyperosmolarity |
Why this matters for dry eye
Classic DED is fundamentally a nociceptive process. Tear film instability, inflammation, and/or epithelial desiccation activates corneal nociceptors through these ion channels, primarily the TRPV1 ion channel of the polymodal nociceptor.1
Once activated, these receptors generate action potentials that travel along the ophthalmic branch of the trigeminal nerve (V1) to the brain, where they are interpreted as sensations such as dryness, burning, or irritation.26
This mechanism is intuitive: when the ocular surface is stressed or inflamed, corneal nerves detect the dyshomeostasis and signal the brain to initiate protective responses such as blinking and tearing. When the underlying surface pathology improves, nociceptive signaling typically diminishes and symptoms improve or resolve.
The difficult part of DED is when it isn’t that simple…
Short on time? Download the Clinical Guide to Ocular Surface Pain to review key concepts from the article!
The transition from nociceptive to neuropathic ocular pain
While many patients with DED experience symptoms that correlate with observable OSD, clinicians frequently encounter the opposite scenario: patients with severe symptoms but minimal clinical findings.15
“When symptoms greatly exceed signs, clinicians should begin to consider whether neuropathic mechanisms are contributing to the patient's discomfort.”
Neuropathic ocular pain arises from dysfunction or injury within the somatosensory nervous system rather than from ongoing tissue damage on the ocular surface. In these cases, the nerves themselves become abnormal generators or amplifiers of pain signals.
Importantly, neuropathic mechanisms do not preclude traditional DED; many patients exhibit mixed pain mechanisms, with components of both nociceptive OSD and neuropathic pain.
Two important sensory phenomena commonly associated with neuropathic ocular pain are allodynia and hyperalgesia:18
- Allodynia refers to pain triggered by a stimulus that would not normally be painful.
- A classic example is light-induced pain (photoallodynia), which occurs even in the absence of visible inflammation or tissue damage. This differs from photophobia, which is an aversive or uncomfortable response to light that arises from a clear physiological or pathological cause, such as uveitis, corneal abrasion, dry eye, or blepharitis.18
- Hyperalgesia is an exaggerated pain response to a normally painful stimulus.
- One common example is heightened sensitivity to wind, which produces disproportionately intense discomfort relative to the stimulus.18
Two other concepts to understand include wind-up and prolonged pain. Wind-up occurs when repeated nociceptor stimulation causes progressively amplified responses in central neurons—for example, cold air may feel increasingly uncomfortable the longer someone is outside. Prolonged pain is discomfort that persists beyond the initial stimulus, such as lightly touching the eye and experiencing pain for the rest of the day.18
These abnormal sensory responses reflect peripheral and central sensitization within the trigeminal pain pathway, underlying the chronic discomfort seen in neuropathic ocular pain.7
Recognizing when neuropathic mechanisms are present is critical because treatments directed solely at the tear film or ocular surface may fail to address the underlying driver of symptoms. The list below outlines times you should consider neuropathic mechanisms at play.
Clinical features associated with neuropathic ocular pain:
- Symptoms are much greater than ocular surface signs
- Symptoms do not improve as expected with traditional dry eye therapy
- Pain persists after topical anesthetic instillation (e.g., proparacaine)
- Allodynia: Pain triggered by stimuli that are not normally painful (e.g., indoor lights)
- Hyperalgesia: An exaggerated pain response to a mildly irritating stimulus (e.g., wind)
- Spontaneous or persistent burning, sharp, stabbing, electric, or aching pain
- Coexisting chronic pain conditions, such as fibromyalgia, migraine, temporomandibular disorder, irritable bowel syndrome, chronic fatigue syndrome, small fiber neuropathy, or post-TBI symptoms
- Presence of mental health or sleep-related disturbances, such as anxiety, depression, post-traumatic stress disorder, or insomnia
- Pain extends beyond the eye to the eyelids, periocular, or periorbital region
- History of corneal nerve injury or conditions associated with nerve damage, such as LASIK/PRK surgery, herpetic eye disease, chronic ocular surface inflammation, or trauma
- Pain continues even after a trigger is removed (e.g., wind, cold, touch, or light)
Objective evidence of corneal neuropathic pain
For many years, clinicians had no objective way to identify corneal neuralgia, or more broadly, corneal neuropathic pain. Patients could present with severe, sometimes debilitating ocular pain despite minimal or no observable signs of OSD on slit-lamp examination, creating a striking mismatch between symptoms and clinical findings.8
This pattern was especially recognized after corneal procedures such as LASIK or PRK, and has also been described after other ocular surgeries, including cataract surgery, though less commonly.27
In the absence of visible staining, tear film abnormalities, or other conventional findings to explain symptom severity, these patients were historically difficult to fit within the traditional OSD framework. Sadly, as a result, some were unfortunately dismissed as exaggerating, malingering, or having symptoms misattributed to psychogenic causes rather than biologic disease.
The development of in vivo corneal confocal microscopy (IVCM) fundamentally changed this paradigm. IVCM is a high-resolution, non-invasive imaging technique with near-cellular resolution that allows clinicians to examine corneal structures at roughly 600× magnification.28
Importance of imaging the nerve plexus
Most importantly, it can image the subbasal nerve plexus, the dense network of small sensory nerve fibers located between the basal epithelium and Bowman’s layer.25 This plexus is especially important because it contains the terminal sensory fibers responsible for detecting mechanical, thermal, and chemical stimuli and supporting epithelial integrity and ocular surface homeostasis.28,29
By allowing direct visualization of the subbasal nerve plexus, IVCM provided the first objective evidence that some patients with severe ocular pain have demonstrable corneal nerve abnormalities despite minimal OSD on routine examination.28
In this context, abnormal IVCM findings provide evidence of corneal neuralgia or peripheral neuropathic pain, particularly when they show structural damage or remodeling of the subbasal nerve plexus.
Observable abnormalities include:28,29
- Reduced corneal nerve fiber density
- Increased nerve tortuosity
- Microneuromas
- Hyperreflective foci
- Activated dendritic cells suggestive of neuroinflammation
When corneal nerve pathology is invisible
Figure 3 shows an example from one of my own patients, an 86-year-old woman with debilitating eye pain and photophobia who had no observable clinical signs on routine examination and unremarkable traditional OSD testing. IVCM revealed clear abnormalities within the subbasal nerve plexus, including aberrant subbasal corneal nerve morphology with microneuromas and increased dendritiform cell infiltration.
Figure 3: Courtesy of Kaleb Abbott, OD.
This has been a major advancement in how clinicians think about ocular pain and so-called “dry eye.” Rather than assuming that symptoms without signs are psychogenic or exaggerated, we now recognize that some patients have genuine corneal nerve pathology that is simply invisible with conventional clinical testing. In that sense, IVCM has been a game-changer in the field and has certainly changed how ocular pain is understood and diagnosed.
Importantly, a normal IVCM does not exclude neuropathic ocular pain. Some patients may have predominantly central sensitization or functional abnormalities not captured as structural changes on corneal nerve imaging, due to the neuropathic mechanisms being further upstream from the eye.7
Although IVCM is extremely helpful, it is not required for clinical practice or diagnosis. It is best viewed as a useful, often confirmatory tool that can strengthen diagnostic confidence and document damage to the subbasal nerve plexus, but the diagnosis of neuropathic ocular pain still depends heavily on the systemic and ocular history, symptom profile, and clinical context.27
Localizing the source of pain
Once neuropathic mechanisms are suspected; the next clinical question becomes: Where is the pain originating?
Ocular pain may arise from several levels of the sensory pathway:7
- Peripheral nociceptive pain: Pain driven by ongoing tissue injury or inflammation at the ocular surface, detected by intact corneal nociceptors (e.g., tear film instability or epithelial damage in dry eye disease)
- Peripheral neuropathic pain: Pain arising from structural or functional abnormalities of corneal nerves, leading to aberrant signaling (e.g., post-LASIK pain)
- Central sensitization (neuropathic or nociplastic mechanisms): Pain arising from dysfunction within the non-ocular, upstream trigeminal pathway or central pain-processing centers
Distinguishing between these mechanisms helps guide treatment decisions.
Download the Clinical Guide to Ocular Surface Pain for additional IVCM imaging!
Diagnostic topical anesthesia: The proparacaine test
One of the most practical clinical tools for evaluating the origin of ocular pain is the topical anesthetic test, commonly referred to as the proparacaine challenge.
Figure 4: Visual depiction of the proparacaine test.
Figure 4: Courtesy of Kaleb Abbott, OD.
Topical anesthetics temporarily block sodium channels in peripheral corneal nerves, preventing them from transmitting signals. By observing how symptoms change after anesthesia, clinicians can gain insight into whether the pain is originating from the ocular surface or from central neural pathways.
Diagnostic methodology
- Ask the patient to rate their baseline pain using a validated scale or a numeric pain scale (such as a 0 to 10).
- Instill one drop of 0.5% proparacaine or tetracaine.
- Reassess symptoms 1 to 2 minutes after instillation (alternatively, you could ask the patient what percent change they had in symptoms).
Interpretation
- Complete or near-complete resolution of pain: This suggests the primary driver of symptoms is peripheral in nature (i.e., originating on the ocular surface and corneal nerves), since blocking corneal nerve signaling eliminated the symptoms. The symptoms could be driven by nociceptive or peripheral neuropathic mechanisms.
- Partial improvement in pain: This indicates mixed pain mechanisms, where both peripheral (nociceptive or neuropathic) and central sensitization mechanisms are contributing to symptoms.
- Little or no improvement in pain: This suggests central sensitization (neuropathic or nociplastic pain), because the brain continues to perceive pain despite the ocular surface being anesthetized.
It is important to note that the proparacaine test does not differentiate between dry eye and peripheral neuropathic pain (i.e., corneal neuralgia or neuropathic corneal pain). Instead, it helps determine whether pain signals are primarily arising from the peripheral ocular surface or from central neural processing.
No improvement in symptoms could also indicate referred ocular pain, such as as cervicogenic pain, or binocular vision conditions triggering symptoms such as asthenopia.
Mixed pain mechanisms are common
While conceptually it is helpful to know whether proparacaine eliminates eye pain (indicating ocular surface origins) or fails to alleviate any pain (indicating centralized mechanisms), in reality, many patients do not fit neatly into a single category. Instead, they may exhibit a combination of nociceptive and neuropathic mechanisms.
For instance, if a patient reports a 70% improvement in symptoms of burning and photophobia after proparacaine, this indicates that 70% of their symptoms originate from the corneal nerves, while 30% still originate from upstream sources. Even when both nociceptive and neuropathic mechanisms are suspected, it is worthwhile to treat the nociceptive pain (e.g., dry eye) to reduce nociceptive input to the trigeminal nerve sensory pathway.
“The general rule of thumb is to address nociceptive pain before neuropathic pain.”
Proparacaine testing is also helpful for setting patient expectations regarding the maximum degree of improvement likely with ocular-based treatments alone, which generally does not exceed the percentage of improvement observed with proparacaine.
Treatment of nociceptive eye pain
In the context of this article, nociceptive eye pain can be understood as DED. In such cases, clinical signs and patient-reported symptoms are generally well correlated, and pain perception is not significantly influenced by COPCs, psychiatric factors (e.g., anxiety or depression), or lifestyle contributors (e.g., poor sleep).
Patients typically present with classic features of DED, including ocular surface staining, tear film instability, meibomian gland dysfunction, elevated tear film osmolarity, or a positive matrix metalloproteinase-9 (MMP-9) test. Management should therefore focus on identifying and treating the underlying cause of the OSD.
Management of peripheral neuropathic pain
The management of peripheral neuropathic pain (i.e., corneal neuralgia) is centered on restoring corneal nerve health while simultaneously reducing ongoing nociceptive input and suppressing local inflammation. Because peripheral sensitization is driven by both structural nerve injury and persistent inflammatory signaling, the most effective treatment strategies are multimodal and sustained over time.
A useful clinical framework is to approach treatment through three complementary pillars:
- Nerve regeneration
- Inflammation control
- Reduction of nociceptive input
There is some overlap with each of these pillars.
Nerve regeneration and neurotrophic support
The strongest evidence for disease-modifying therapy in neuropathic corneal pain supports the use of blood-derived products in combination with an anti-inflammatory.
Autologous serum tears (AST, oftentimes high concentration, typically 40% or higher), platelet-rich plasma (PRP), and plasma rich in growth factors (PRGF) contain essential neurotrophic and epitheliotrophic factors—including nerve growth factor (NGF), epidermal growth factor (EGF), fibronectin, and transforming growth factor-β—which closely mimic the biochemical composition of natural tears.30 These therapies not only promote epithelial healing but also support corneal nerve regeneration and may improve neuropathic and neuralgia symptoms.30-32
Studies using IVCM demonstrate improvements in the subbasal nerve plexus, including increased nerve fiber density, reduced tortuosity, and decreased microneuroma formation, providing objective evidence that these treatments can restore corneal nerve structure within as little as 4 to 6 months.32,33 However, symptomatic improvement oftentimes trails corneal nerve improvement, taking closer to 9 to 12 months.27
Cryopreserved amniotic membrane
Cryopreserved amniotic membrane therapies (e.g., Prokera or CAM360 Amniograft, Bio-Tissue) provide an additional biologically active approach to ocular surface restoration. These tissues contain anti-inflammatory cytokines, growth factors, and neurotrophic mediators that promote epithelial healing while simultaneously suppressing inflammation.34,35
Importantly, amniotic membranes may facilitate recovery of corneal nerve morphology while simultaneously reducing neuropathic corneal pain symptoms.36
Human nerve growth factor
Cenegermin (OXERVATE), a recombinant form of human nerve growth factor, is a targeted neurotrophic therapy that directly stimulates corneal nerve regeneration.37 While it is FDA-approved only for NK, it may have a potential role in select patients with corneal neuralgia due to its regenerative capabilities.
However, such use is off-label in the absence of NK, and there is currently no published evidence supporting its efficacy specifically for pain. However, it is also important to recognize that some patients with corneal neuralgia may have concurrent NK.38
Topical
Topical treatments with more limited supporting evidence include agents such as lacosamide, low-dose naltrexone (LDN), and enkephalin-based therapies.39 Lacosamide may reduce peripheral nerve hyperexcitability through sodium channel modulation, while LDN has anti-inflammatory and neuromodulatory effects via opioid and Toll-like receptor pathways.39,40
Enkephalin-based therapies aim to enhance endogenous analgesic signaling at the ocular surface. Overall, these approaches remain investigational, and their use is often limited by the need for specialized compounding pharmacies.39
The goal: Suppression of inflammation
Persistent ocular surface inflammation encourages peripheral sensitization by lowering the activation threshold of nociceptors and promoting nerve injury, specifically via the TRPV1 ion channel of the polymodal nociceptor.26 For this reason, long-term anti-inflammatory therapy is helpful.
High-potency topical immunomodulators—including lifitegrast 5% (XIIDRA, Bausch + Lomb), cyclosporine 0.09% (CEQUA, Sun Pharma), and cyclosporine 0.1% (VEVYE, Harrow)—target T-cell–mediated inflammation and help restore ocular surface homeostasis.41 Short courses of topical corticosteroids (e.g., loteprednol, fluorometholone) are often used for induction therapy to rapidly suppress inflammation before transitioning to chronic immunomodulation.
By reducing inflammatory cytokines and immune cell activation, these therapies help create an environment conducive to corneal nerve recovery and work well in tandem with blood-derived therapies.
Reducing nociceptive input
Even in the presence of neuropathic mechanisms, ongoing nociceptive input from the ocular surface can worsen pain and perpetuate sensitization, making reduction of mechanical, evaporative, and inflammatory stimuli a key treatment goal.
This is often achieved through the use of the traditional dry therapies, such as:
- Scleral lenses
- Punctal occlusion
- Perfluorohexyloctane
- Thermal pulsation
- Intense pulsed light (IPL)
- Low-level light therapy (LLLT)
- Oral antibiotics (e.g., doxycycline, azithromycin)
Scleral lenses
Scleral lenses are among the most effective interventions, as they vault the cornea and maintain a constant fluid reservoir over the ocular surface.42 This minimizes mechanical friction and evaporative stress, often reducing nociceptive input to near zero, and has been shown to improve ocular pain and photophobia in severe ocular surface disease.42
Punctal occlusion
Punctal occlusion enhances tear retention, improving lubrication and preserving tear components, including neurotrophic factors that support corneal nerve health.43
Hyaluronic acid (HA)–based canalicular fillers
Hyaluronic acid (HA)-based canalicular fillers (LACRIFILL, Nordic Pharma) provide a reversible alternative to plugs and may further improve tear film stability and epithelial integrity.44
Perfluorohexyloctane
Perfluorohexyloctane (MIEBO, Bausch + Lomb), a semifluorinated alkane, reduces tear evaporation and stabilizes the tear film.45 It is also generally well tolerated and soothing in patients with corneal neuralgia, who are often highly sensitive to topical therapies.
Additional therapies
Thermal pulsation, intense pulsed light (IPL), low-level light therapy (LLLT), and oral antibiotics (e.g., doxycycline, azithromycin) may improve meibum quality, tear film stability, and inflammation.46-49
Although these therapies have not been studied specifically for neuropathic ocular pain, their benefit is likely mediated through reduction of peripheral nociceptive drivers rather than direct neuromodulation.
Adjunctive neuromodulatory therapies
Targeting corneal sensory receptors is an emerging strategy for tear stimulation and pain modulation. Acoltremon ophthalmic solution (TRYPTYR, Alcon), a TRPM8 receptor agonist, stimulates cold-thermoreceptors to increase basal tear production and improve tear film homeostasis.50 TRPM8 activation may also exert analgesic effects through modulation of nociceptive signaling pathways.51
Although acoltremon for neuropathic ocular pain has not been formally studied, early evidence suggests that TRPM8 agonists may provide meaningful pain relief in some patients.52
Treating central sensitization (central neuropathic ocular pain and nociplastic)
Central sensitization is a distinct clinical entity in which pain persists despite minimal or absent peripheral input.7 These patients often show little to no improvement with topical anesthetic (proparacaine), indicating pain is generated or amplified upstream from the ocular surface.7 Traditional dry eye therapies alone are unlikely to provide meaningful relief.
Nonetheless, treating any underlying nociceptive OSD remains essential, as ongoing peripheral input can worsen central sensitization. Multidisciplinary care—including pain specialists, neurologists, and mental health professionals—is often required. Management is complex and best approached with a multimodal framework of pharmacologic, procedural, and lifestyle interventions.
Pharmacologic (systemic neuromodulation)
Gabapentinoids: Gabapentin and pregabalin
Oral gabapentin and pregabalin are among the most used systemic neuromodulators for central neuropathic ocular pain. They bind to α₂δ subunits of presynaptic calcium channels to reduce excitatory neurotransmitter release and neuronal excitability, potentially diminishing central sensitization.53 Early research has shown improvements in ocular pain in some patients refractory to traditional therapies.54,55
Tricyclic antidepressants: (TCAs) and SNRIs
TCAs (e.g., nortriptyline, amitriptyline) and SNRIs (e.g., duloxetine) enhance endogenous inhibitory pain pathways and are sometimes used in combination with gabapentinoids.9
Evidence suggests they may improve symptoms of centralized neuropathic pain in patients with inadequate response to other systemic and topical therapies.9,56 These agents require careful patient selection due to potential systemic side effects.
Low dose naltrexone (LDN)
LDN (typically 4.5mg nightly) has been reported to reduce pain scores and improve quality of life in patients with neuropathic corneal pain, possibly through reduction of microglial activation and neuroinflammation via toll-like receptor-4 antagonism.40
Procedural and interventional therapies
Peripheral nerve blocks
Targeted regional nerve blocks (e.g., supraorbital, infraorbital, supratrochlear, infratrochlear, sphenopalatine ganglion, occipital) using local anesthetics with corticosteroids can transiently disrupt pain signaling and, in some cases, “reset” sensitized pathways. Duration of relief varies, ranging from hours to months.54,57,58
Botulinum toxin (BoNT-A)
Periocular or trigeminal BoNT-A injections may reduce ocular pain and photophobia within weeks by inhibiting neuroexcitatory neurotransmitter release and modulating trigeminal sensitization.59,60
Non-invasive neuromodulation (TENS, etc.)
Transcutaneous electrical nerve stimulation (TENS) applied to trigeminal or periorbital regions may reduce pain. TENS is believed to act via the gate control theory of pain, whereby activation of large-diameter afferent fibers inhibits transmission of nociceptive signals at the spinal or trigeminal level, effectively “closing the gate” to pain perception.61,62 Evidence suggests rapid reductions in ocular pain intensity, though frequent use is typically required for sustained benefit.63
Pharmacologic neuromodulation and trigeminal stimulation
Building on gate control theory, pharmacologic activation of trigeminal afferents may similarly modulate pain signaling. Intranasal varenicline (TYRVAYA, Viatris) and topical acoltremon (TRYPTYR) stimulate trigeminal pathways to increase tear production and may also influence sensory processing.50,64
While direct evidence in neuropathic ocular pain is limited, increased physiologic afferent input may help modulate central sensitization and reduce pain perception.51 In my experience, TYRVAYA works best when dosed 3 to 4 times per day while TRYPTYR works best at 3 times per day when used for this purpose.
Complementary and adjunctive therapies
Acupuncture
There exists some evidence that acupuncture can reduce ocular pain, improve mood, and influence inflammatory cytokines in dry eye/neuropathic pain contexts.65,66 Pain relief is thought to last several days and treatments may need to be twice weekly.67
Physical modalities
Massage, deep muscle stimulation, and myofascial trigger point therapy targeting periocular or craniofacial muscles are used in practice, though rigorous clinical evidence is limited. These may complement neuromodulation by reducing muscular tension and modulating afferent input.68,69
Intrathecal targeted drug delivery
In refractory, severe cases, intrathecal analgesic pumps have been used to control central neuropathic pain and neuropathic corneal pain, though such approaches carry procedural risks and necessitate the involvement of pain management specialists.70-72
FL-41 tinted glasses
FL-41 tinted lenses can reduce photophobia by filtering wavelengths that disproportionately stimulate melanopsin-containing retinal ganglion cells and trigeminal pathways. They are particularly beneficial in migraine-associated photophobia, where trigeminal sensitization is prominent.73,74
Lifestyle and supportive measures for neuropathic ocular pain
Regardless of the underlying mechanism, lifestyle modifications play a critical role in the management of neuropathic ocular pain, as they do in other chronic pain syndromes.
Mental health and sleep
Pain perception is not solely a function of peripheral input but is significantly modulated by central processes, including sleep quality, psychological state, and overall systemic health.20
Accordingly, interventions such as optimizing sleep hygiene, incorporating stress-reduction strategies (e.g., mindfulness-based practices), and addressing co-morbid mood disorders through therapy or counseling are essential components of a comprehensive treatment approach.24,75
Exercise and physical activity
Regular physical activity can improve pain modulation and reduce inflammatory signaling. Exercise may enhance endogenous inhibitory pathways and should be encouraged as part of a comprehensive management strategy.76
Nutrition and systemic health
Nutritional optimization may support neuromodulatory and immune functions relevant to chronic pain states.77 Nutritional deficiencies—particularly vitamin B12 deficiency—are well-established contributors to small fiber neuropathy and may exacerbate or drive neuropathic ocular pain.78
For this reason, over-the-counter lubricating drops like Blink Nourish (Bausch + Lomb) which contains vitamin B12 and other vitamins, are intriguing.
Supplements
Anti-inflammatory supplements containing lutein, zeaxanthin, curcumin, and vitamin D (Blink NutriTears, Bausch + Lomb) may be helpful. High quality omega-3 fatty acids may also provide adjunctive benefit through anti-inflammatory effects and support of neuronal membrane stability.9
These supportive measures, although often adjunctive, can meaningfully reduce symptom burden and improve quality of life in patients with neuropathic ocular pain by targeting the broader biopsychosocial contributors to pain amplification.24,75-77
Future therapies for ocular pain
The landscape of ocular surface pain therapy is evolving, with several emerging treatments targeting peripheral nociceptors, inflammation, and central sensory modulation.
Urcosimod (OKYO Pharma)
Urcosimod is a novel lipid-conjugated chemerin peptide under investigation for neuropathic ocular pain. Early clinical data demonstrates a statistically significant benefit of urcosimod over placebo in pain reduction.79
Urcosimod 0.05% has been granted compassionate use designation for a patient with neuropathic corneal pain.80 The treatment will be studied in a phase 3 pivotal trial.
Ocular cooling (EyeCool Therapeutics)
Targeted cryoneuromodulation is a novel procedural approach to reduce afferent pain signaling from the long ciliary nerves. EyeCool Therapeutics’ investigational ETX-4143 device delivers controlled cooling to the ocular surface and underlying nerves, temporarily disrupting myelin function to attenuate trigeminal pain signaling.
Early human data from Australia demonstrate safety, a short procedure duration (~4 minutes), and pain relief lasting several months.81 Pivotal clinical trials in the United States are expected to begin in 2026.
Topical TRPV1 antagonists
Topical TRPV1 antagonists (SAF312, Libvatrep) are also under investigation, targeting the polymodal nociceptor responsible for driving eye pain, inflammation, and sensitization. Given the central role of TRPV1 in ocular surface pain, these agents may reduce nociceptive signaling at its origin.82,83
Several other therapies are progressing through the research pipeline.9 In human clinical trials, siRNA-based therapies like Tivanisiran (SYL1001) are being investigated to "silence" pain receptors at the genetic level, and the peptide Lacripep has shown promise in reducing eye pain and stinging in phase 2 studies.84
Procedural interventions are also being tested in humans, including Quantum Molecular Resonance (QMR) to promote nerve regeneration and TENS to modulate pain signaling. Meanwhile, animal models (mouse and rat) are being used to explore more targeted mechanisms, such as selective NaV1.7 sodium channel inhibitors, CGRP receptor antagonists to block pain signaling, and purinergic P2X4 receptor antagonists to reduce neurogenic inflammation.9
These emerging therapies mark a new era in ocular pain management. By targeting specific peripheral and central mechanisms, clinicians may soon offer durable, mechanism-based relief, giving real hope for improved comfort and quality of life in patients with chronic ocular pain.
Pearls for approaching ocular pain
- Adopt a two-axis mindset: Evaluate both symptom burden and objective ocular surface health (Figure 1).
- Screen for chronic overlapping pain conditions (COPCs): Ask about systemic comorbidities such as fibromyalgia, migraines, sleep quality, and mental health, which often predict symptom severity more than ocular findings.
- Identify neuropathic red flags: Look for pain disproportionate to clinical signs, allodynia, and hyperalgesia.
- Determine pain origin: Use the proparacaine test to localize nociceptive versus neuropathic or other non-surface originating pain sources.
- Treat appropriately: Follow pain origin; treat nociceptive pain first to reduce ongoing peripheral input before addressing neuropathic mechanisms.
- Set patient expectations: Explain that chronic pain involves the nervous system and that success focuses on functional improvement and long-term management rather than a rapid cure.
Conclusion
The management of ocular surface pain has evolved dramatically from the simplistic "dry eye" or “no dry eye” model. By embracing a neurobiological framework, utilizing targeted diagnostics like the proparacaine test and IVCM, and understanding the profound impact of systemic co-morbidities, clinicians can move beyond palliative lubrication. Differentiating between nociceptive, neuropathic, and nociplastic pain mechanisms helps clinicians tailor treatments accordingly.
Similarly, recognizing when a neurotrophic component is present, thus making signs more prominent than symptoms, informs clinicians on appropriate treatments. This knowledge equips clinicians to deploy highly specific, multi-disciplinary treatment regimens—ranging from serum tears and scleral lenses to systemic neuromodulators and nerve blocks—ultimately restoring comfort and quality of life to a desperate patient population.
