Nerve-Related Corneal Pain

Neuropathic corneal pain (NCP)—a subtype of neuropathic pain—is relatively recently recognized, poorly defined, and underinvestigated, yet it can substantially affect patients’ quality of life (QOL). This article summarizes current knowledge of the underlying mechanisms, clinical presentation, diagnostic approaches, treatment options, and perioperative management strategies for NCP.

UNDERSTANDING NCP

Neuropathic pain, as defined by the International Association for the Study of Pain, is “pain caused by a lesion or disease of the somatosensory nervous system.”^1,2 NCP refers to chronic corneal pain experienced by patients in response to nonnoxious stimuli.

The cornea, the most densely innervated tissue in the body, is supplied primarily by sensory nerves from the ophthalmic branch of the trigeminal nerve via the long ciliary nerves.^3-5 These sensory nerves transmit mechanical, chemical, and thermal stimuli to the brain, triggering pain perception and defense mechanisms, such as the blink reflex.^5,6 In patients with NCP, these nerves become sensitized owing to nerve damage and chronic inflammation, a phenomenon known as peripheral sensitization.⁷ Peripheral sensitization decreases the pain threshold, heightens responses to stimuli, and leads to chronic spontaneous pain perception.⁸ Chronic peripheral sensitization can progress to central sensitization, which is characterized by hypersensitivity of the central nervous system, resulting in pain perception disconnected from peripheral stimuli.^7-9

NCP can arise from local insults to the eye that mediate nerve damage^4,10-12 or as a manifestation of systemic pathologies affecting sensory pathways.^13,14 The most common ocular conditions associated with NCP include dry eye disease (DED)^12,15 and postoperative states, such as after refractive or cataract surgery.^16-18 Other ocular pathologies linked to NCP include herpetic keratitis,^19,20 infectious keratitis,⁴ trauma,¹² and radiation keratopathy, among others.⁴

A number of chronic systemic conditions, such as small fiber neuropathy (eg, due to inflammatory, autoimmune, dysimmune, and metabolic causes),¹² headaches,²³ trigeminal neuralgia,¹⁰ and fibromyalgia,²⁴ have been associated with NCP.^21,22 Mental health issues, including depression,²⁵ posttraumatic stress disorder,²⁵ and anxiety,¹⁵ as well as inflammatory and autoimmune conditions, such as Sjögren syndrome²⁶ celiac disease,⁷ systemic lupus erythematosus,²⁷ sarcoidosis,²⁸ and inflammatory bowel disease,²⁹ have also been linked to NCP.

CLINICAL PRESENTATION AND DIAGNOSIS

Patients with NCP may present with a wide range of symptoms, including pain,¹⁶ discomfort,³⁰ photoallodynia,³¹ burning,³⁰ irritation,¹¹ and severe dryness.¹¹ Diagnosis can be challenging due to a lack of clear slit-lamp examination findings that correspond to the intensity of symptoms. Moreover, overlap with other ocular surface diseases (OSDs), including DED, can lead to underdiagnosis and misdiagnosis.³²

Symptom Assessment and Questionnaires

Traditional dry eye questionnaires cannot differentiate DED from NCP,^33-35 but specialized questionnaires have been developed to assess ocular pain.

Ocular Pain Assessment Survey. This validated 27-question survey evaluates eye pain intensity over 24 hours and 2 weeks, nonocular facial pain, QOL, aggravating factors, associated symptoms, and symptom relief.³⁶

Neuropathic Pain Symptom Inventory-Eye questionnaire. Adapted from the Neuropathic Pain Symptom Inventory, this 12-question survey assesses neuropathic-like eye pain severity and characteristics.^37,38

Clinical History and Examination

A thorough systemic and ocular history is essential to identify predisposing factors. Coupled with detailed ocular examinations, the history helps rule out nociceptive and inflammatory causes of pain.³ Routine testing includes a Schirmer test, corneal fluorescein staining, conjunctival lissamine green staining, and tear breakup time.

Although ocular findings in NCP may be disproportionate to the patients’ symptoms, DED signs can further complicate diagnosis because nociceptive and neuropathic pain may be present concurrently.⁴

Functional Sensory Testing

Functional sensory testing can distinguish between peripheral and centralized ocular pain. A commonly employed method involves the instillation of a topical anesthetic drop (eg, 0.5% proparacaine hydrochloride).⁷ Patients rate their discomfort on the visual analogue scale (0–10) before and 90 seconds after instillation:

• Centralized pain (minimal or no improvement);
• Peripheral pain (total pain alleviation); or
• Mixed pain (partial relief).

This step is essential for identifying the pain origin and guiding treatment selection.^7,39

Corneal sensation testing can provide additional information, though the strategy is more valuable for diagnosing neurotrophic keratopathy than NCP. The DEWS II report recognized neurosensory abnormalities as a DED etiology.³² Galor et al found that increased corneal sensitivity correlated with ocular symptoms in DED patients.⁴⁰ Additionally, fibromyalgia patients without ocular disease exhibited increased corneal sensitivity and DED-like symptoms.⁴¹ Emerging technologies, such as noncontact esthesiometry (Brill Engines), may help measure hypersensitivity in NCP. Although increased sensitivity may coexist with ocular discomfort and pain, further validation studies are required to evaluate the applicability and diagnostic value of these tests in patients with NCP.

Imaging of Corneal Nerves

An evaluation of corneal nerve structure is essential, particularly for patients with pure peripheral pain. In vivo confocal microscopy (IVCM), a high-resolution imaging modality, allows real-time visualization of corneal nerves with 800x magnification.⁵ Common findings in NCP include decreased nerve density,⁴² increased tortuosity,⁴³ and beading.⁴⁴ Although these features are also seen in DED,^45-47 a recent study by Moein et al identified corneal microneuromas (MNs) in patients with NCP, but not DED, suggesting MNs could serve as objective markers for NCP.⁴⁴ Further studies have shown that MNs can coexist with DED signs, potentially contributing to discomfort.^48,49

A clinical trial funded by the National Institutes of Health is underway to validate MNs, identified via IVCM, as a diagnostic biomarker for NCP.⁵⁰ The US FDA recently accepted MNs as a diagnostic criterion for distinguishing NCP from DED in a randomized, placebo-controlled clinical trial (ClinicalTrials.gov ID: NCT06637527). Emerging research on tear proteomics and genomics also aims to identify associations with pain pathways, paving the way for future therapeutic development.^42,51

MULTIMODAL TREATMENT APPROACHES

Currently, no US FDA-approved treatment exists for NCP. Management focuses primarily on ocular surface homeostasis, antiinflammatory and neuroregenerative therapies, and local or systemic neuromodulation.⁵²

Topical Therapies

Topical therapies serve as first-line treatment for patients with peripheral and mixed NCP. Ocular surface restoration by improving the quality and quantity of the tear film can provide short-term relief of symptoms, prevent further damage, and address coexisting DED.⁷

Antiinflammatory Therapies

Antiinflammatory therapies are critical for alleviating ocular surface inflammation, which contributes to neuronal sensitization. Treatment options include the following:

• Topical steroids with low-preservative formulations such as 0.5% loteprednol etabonate gel or 0.38% loteprednol etabonate (Lotemax, Bausch + Lomb), or compounded nonpreserved formulations, can be used during the therapeutic phase of management^53,54 and
• Very low-frequency topical steroids and/or topical immunomodulators, such as cyclosporine or lifitegrast (Xiidra, Bausch + Lomb),⁵⁵ can be used for maintenance-phase therapy to prevent resensitization.⁵⁶

Topical Neuroregenerative Therapy

Topical neuroregenerative therapies such as autologous serum tears (ASTs) play an important role. ASTs, rich in growth factors such as epidermal growth factor, insulin-like growth factor, and nerve growth factor, can promote nerve regeneration and reduce pain severity.^57-60 Studies have shown significant pain reduction, improved photoallodynia,³¹ and improved in vivo confocal microscopy parameters, including increased corneal nerve density and reduced MNs.⁵⁷ We recommend initiating AST therapy at a 20% concentration and titrating upward (40%–50%) based on patient response. In our experience, starting with higher concentrations may temporarily exacerbate symptoms.

Cryopreserved Amniotic Membrane

Cryopreserved amniotic membranes, such as Prokera (BioTissue), are another treatment option. These membranes contain growth factors and antiinflammatory mediators. Although treatment has been associated with rapid symptom improvement and increased corneal nerve density,⁶¹ reports indicate that up to 40% of patients experience poor compliance due to ring dysesthesia and can have pain recurrence over time. Therefore, amniotic membranes are recommended for managing flare-ups or as an adjunctive treatment during initiation therapy to support faster ocular surface recovery and relieve acute discomfort.

Emerging Topical Therapies

Emerging topical therapies include OK-101 (Okyo Pharma), a lipid-conjugated chemerin peptide antagonist targeting the ChemR23 receptor,⁶² which modulates immune cell trafficking and antiinflammatory cytokine release. OK-101 is currently in a phase 2 clinical trial.^63,64

Systemic Therapies for Centralized Pain

For patients with centralized pain, neuromodulation is the first-line treatment. The International Neuromodulation Society defines neuromodulation as the alteration of nerve activity via targeted electrical or chemical stimuli.⁶⁵ Oral neuromodulators target the somatosensory pathway.

Nortriptyline. This tricyclic antidepressant is effective at lower doses for centralized NCP than those for depression.⁶⁶ Its analgesic effects are mediated via noradrenaline reuptake inhibition and alpha-2 adrenergic receptor activation, alleviating allodynia and hyperalgesia.^66,67

Low-dose naltrexone. This drug is an opioid antagonist that enhances endorphin production by blocking opioid receptors and exhibits antiinflammatory and analgesic effects.⁷⁰ It has been shown to significantly reduce centralized NCP and improve QOL.

Gabapentin. This alpha-2-delta ligand antiepileptic can reduce neuropathic pain and improve patients’ QOL.⁶⁸ The drug inhibits presynaptic nerve trafficking and calcium channel influx, which have been linked to neuropathic pain.⁶⁹ Gabapentin has shown efficacy in DED-associated NCP refractory to topical therapies.⁶⁸

Duloxetine. This serotonin-norepinephrine reuptake inhibitor has central analgesic properties and can be useful as adjunctive therapy for chronic pain.^7,71,72

Carbamazepine. This anticonvulsant locks excitatory sodium channel activity and proinflammatory signaling pathways, making it effective for trigeminal neuralgia and refractory chronic neuropathic pain.^7,73

In general, for systemic therapy, if monotherapy is ineffective or produces side effects at higher doses, combining low-dose dual or triple therapy is recommended.

Neurostimulation

Neurostimulation is a promising adjunct for pain relief.^74,75 By stimulating other myelinated nerves (eg, ethmoidal nerves), nociceptive input to the central somatosensory pathway can be blocked.^75,76 Intranasal neurostimulation, for example, has demonstrated efficacy in addressing the peripheral component of NCP, reducing both pain severity and dryness symptoms.^74-78 Extranasal (transcutaneous) neurostimulation has also shown efficacy in managing peripheral and mixed NCP cases.⁷⁶

Combined Therapy for Mixed NCP

For patients with mixed NCP, a combination of topical and systemic therapies is recommended to achieve optimal symptom control.

PRE- AND POSTOPERATIVE
CONSIDERATIONS

NCP following ocular surgery—particularly cataract procedures,⁷⁹ LASIK,¹⁶ and PRK^4,80—is well documented. Although definitive screening tests for NCP before ocular surgeries are lacking, thorough preoperative assessments with a focus on identifying existing ocular and systemic predisposing conditions remain valuable. For patients with suspected autoimmune disease, serologic testing is recommended. In such cases, the discontinuation of topical steroids at 2 to 4 weeks postoperatively may result in persistent postoperative inflammation and NCP. These patients may benefit from extended antiinflammatory therapy with a slower tapering regimen.

Understanding Postoperative Pain

Although chronic postoperative pain is relatively uncommon, it occurs in approximately 13% to 34% of cases.^82,83 The exact incidence of NCP following cataract surgery, however, remains unknown.

Refractive surgeries such as LASIK^16,17 and PRK^84,85 are effective for correcting refractive errors and are widely performed in the United States.²⁰ Although the occurrence of DED after refractive surgery is well established, an increasing number of patients are also being diagnosed with NCP. These individuals report persistent ocular symptoms lasting 6 months or longer, pain severity comparable to that experienced in postherpetic neuralgia, and a similarly negative impact on their QOL.^17,20,85,86

A recent prospective study identified pre- and perioperative predictors of persistent pain after refractive surgery.⁸⁴ The study highlighted the following significant risk factors:

• Preoperative ocular pain;
• Depressive symptoms;
• The use of antiallergy medications; and
• Postoperative pain within the first 24 hours.

These findings underscore the importance of obtaining comprehensive ocular and systemic histories and counseling patients on potential postoperative pain.

Identifying Risk Factors and Predictors

Consensus on preventing or managing postsurgical NCP has not been reached. Preexisting systemic and ocular symptoms should guide the pre- and postoperative approach. Patients with symptoms out of proportion to signs or preexisting DED should be screened for autoimmune diseases. Individuals who report symptoms such as numbness, tingling, dizziness with palpitations, and heat intolerance should be assessed for somatosensory disorders. Conditions such as small fiber neuropathy and postural orthostatic tachycardia syndrome require consideration in this situation. Additionally, uncontrolled depression and anxiety should be addressed before surgery. Similarly, for patients with diagnosed ocular or systemic pathologies, it is advisable to control the underlying problem before proceeding to surgery.

Postoperative Management Strategies

In the authors’ clinical experience, the following strategies have shown benefit for patients at risk of developing NCP:

• Slow tapering of topical antiinflammatory drops over 3 months instead of the standard 2 to 4 weeks;
• Initiation of ASTs postoperatively to optimize corneal nerve regeneration in cases when pain persists beyond standard postoperative phase and other etiologies are ruled out;
• Close postoperative follow-up to enable early intervention and prevent pain centralization; and
• Referral for IVCM in suspected peripheral cases to confirm NCP diagnosis.

Early recognition and proactive management are key to mitigating the risk of NCP and improving patient outcomes following ocular surgery.

CONCLUSION

The absence of standardized screening, diagnostic, and treatment guidelines complicates NCP management. Continued research and consensus-building among experts are essential to define clear, evidence-based approaches for identifying and treating this debilitating condition.