P-027 - (Poster #27) Neuropathic Pain as a Contributor to Ocular Surface Pain: A Review

Ocular surface pain (OSP) is a common and often debilitating condition traditionally attributed to nociceptive mechanisms such as dry eye disease (DED). However, emerging evidence highlights the contribution of neuropathic ocular pain (NOP) in individuals who report persistent symptoms despite minimal clinical findings. The cornea, innervated by the ophthalmic branch of the trigeminal nerve, is the most densely innervated tissue in the body. Dysfunction of these nerves either peripherally or centrally can result in spontaneous burning, light sensitivity, allodynia, and pain that persists even after topical anesthesia.

Neuropathic pain arises from damage or disease affecting the somatosensory system, while nociplastic pain reflects altered central pain processing in the absence of structural nerve injury. Both mechanisms have been implicated in OSP, particularly among individuals with a history of ocular surgery, trauma, post-herpetic neuralgia, insomnia, or coexisting chronic pain conditions. These categories are not mutually exclusive; many patients experience overlapping mechanisms.

NOP lacks standardized diagnostic criteria and is typically identified through a combination of patient-reported symptoms, sensory testing, and supportive imaging. Recognizing neuropathic and nociplastic contributions is critical, as these forms of ocular pain often require treatments beyond standard ocular surface therapies.

Purpose/Objectives:

This review aims to synthesize current knowledge on the epidemiology, pathophysiology, diagnosis, and treatment of NOP, with the goal of improving recognition and management of this underdiagnosed pain subtype among eye care and pain specialists. We explore how NOP intersects with systemic pain mechanisms and comorbidities, examine diagnostic tools such as in vivo confocal microscopy and quantitative sensory testing, and evaluate both pharmacologic and non-pharmacologic treatment strategies. By characterizing clinical features of NOP and emerging approaches to care, this review seeks to raise awareness of NOP as a significant and often overlooked contributor to chronic pain burden, and to highlight the need for multidisciplinary collaboration in its management.

Methods:

We conducted a narrative literature review using the PubMed database to identify peer-reviewed studies, case series, and reviews relevant to neuropathic ocular pain (NOP). Because much of the literature on NOP is embedded within studies on dry eye disease (DED), we focused on research that reported NOP-specific symptoms, such as burning, allodynia, and photophobia. Keywords included “neuropathic ocular pain,” “dry eye disease,” “confocal microscopy,” “corneal esthesiometry,” “autologous serum tears,” “burning,” and “light sensitivity,” among others. Studies were included if they described epidemiologic patterns, diagnostic strategies, or therapeutic approaches specifically addressing NOP or nociplastic contributors to ocular surface pain.

Emphasis was placed on research that differentiated NOP from nociceptive DED using tools such as the Neuropathic Pain Symptom Inventory for the Eye (NPSI-E), Ocular Pain Assessment Survey (OPAS), and anesthetic challenge testing. We summarized findings across diverse patient populations, including individuals with autoimmune conditions, fibromyalgia, migraine, and those with ocular pain following refractive or cataract surgery. Both established and emerging treatment modalities were reviewed, including topical therapies, systemic neuromodulators, periocular nerve blocks, and behavioral interventions. Key clinical patterns and treatment recommendations were synthesized to support clinicians managing refractory ocular pain with neuropathic features.

Results:

Symptoms consistent with NOP are reported in up to 15% of adults over age 50, particularly among individuals with Sjögren’s syndrome, migraine, fibromyalgia, and those with a history of refractive or cataract surgery. These symptoms often include burning, light sensitivity, and pain triggered by wind or temperature, frequently out of proportion to ocular surface findings.

Diagnostic strategies include validated symptom questionnaires (e.g., NPSI-E), slit lamp examination, in vivo confocal microscopy (IVCM), and corneal sensory testing. Our review identified discrepancies across studies regarding IVCM findings in patients with NOP, with some reporting increased microneuroma frequency and others noting no significant differences. Esthesiometry tools (Cochet-Bonnet, Belmonte) and the proparacaine challenge assist in localizing pain as peripheral or central. Quantitative sensory testing (QST) at non-ocular sites has shown that patients with NOP often exhibit systemic pain dysregulation, consistent with features of nociplastic pain.

In the absence of FDA-approved therapies for NOP, treatment strategies have been adapted from related fields. Topical therapies such as autologous serum tears (AST) have shown efficacy in improving corneal nerve architecture and reducing pain. Local periocular injections of bupivacaine combined with corticosteroids (methylprednisolone, dexamethasone, triamcinolone) may relieve cutaneous allodynia. Botulinum toxin A injections can reduce light sensitivity and modulate central pain processing, as demonstrated by functional MRI studies.

Emerging topical neuromodulators include transient receptor potential vanilloid-1 (TRPV1) antagonists, transient receptor potential melastatin 8 (TRPM8) agonists, nerve growth factor (NGF) analogs, and mesenchymal stromal cell (MSC)-based therapies. Oral neuromodulators such as gabapentin, pregabalin, nortriptyline, and low-dose naltrexone have shown promise, particularly in patients with overlapping systemic pain syndromes. Adjunctive strategies such as cognitive behavioral therapy and exercise offer additional symptom relief.

Given NOP’s overlap with nociplastic pain mechanisms and its frequently invisible structural pathology, individualized, multimodal treatment algorithms that consider systemic health and emotional burden are essential for effective management.

 

Conclusions/Implications for future research and/or clinical care:

NOP is a significant, under-recognized contributor to ocular surface pain that requires clinicians to move beyond a purely anatomical or tear film–centric model of diagnosis. Its overlap with systemic pain syndromes and psychiatric comorbidities, coupled with absent or minimal clinical signs, makes diagnosis and treatment particularly challenging. Effective management requires identifying neuropathic features and employing a multidisciplinary approach.

There is a need for standardized diagnostic criteria and validated biomarkers to distinguish NOP from other ocular pain syndromes. Further investigation into the use of confocal microscopy, QST, and novel esthesiometers will improve diagnostic accuracy. On the therapeutic front, randomized controlled trials are needed to determine efficacy and optimal use of AST, nerve blocks, systemic neuromodulators, and BoNT-A injections.

Ultimately, improving outcomes for patients with NOP hinges on awareness and education across specialties including ophthalmology, neurology, psychiatry, and pain management and on individualized, holistic care strategies that address both physical and emotional aspects of chronic ocular pain.