# Central Nervous System Mechanisms and Treatment Response in Chronic Ocular Surface Pain: Protocol for a Cross-Sectional Observational Phenotyping Study

## TL;DR

This study explores whether chronic eye pain is caused by issues in the brain rather than the eye itself, which could lead to better treatments.

## Contribution

The study introduces a comprehensive cross-sectional observational protocol to investigate central nervous system mechanisms in chronic ocular surface pain.

## Key findings

- The study will use clinical, neurobiological, and treatment response features to define nociplastic pain in chronic ocular surface pain.
- Multimodal sensory testing and brain imaging will assess CNS involvement in participants with chronic ocular surface pain.
- Findings may lead to new CNS-targeted treatments for a subset of patients with chronic ocular surface pain.

## Abstract

Chronic ocular surface pain (COSP), occurring either in isolation or as part of numerous ocular conditions, such as dry eye syndrome, is a leading cause of eye care visits in the United States. Conventional treatments directed at the ocular surface—the perceived pain source—are often inadequate for pain relief. We hypothesize that some individuals with COSP are experiencing symptoms driven by central nervous system (CNS) dysfunction, similar to chronic overlapping pain conditions, rather than solely pathological problems in the eye. Some individuals with chronic overlapping pain conditions (eg, fibromyalgia) show evidence of nociplastic pain mechanisms, where the pain results from amplified or dysregulated CNS signaling and sensory processing. Although data exist suggesting the presence of nociplastic pain features in COSP, there is a need for comprehensive studies.

Our aim is to rigorously define the role of nociplastic pain in COSP with a large, representative cohort of 200 participants with COSP using established clinical, neurobiological, and treatment response features. We propose that as sign and symptom discordance increases, features indicative of nociplastic pain will also increase.

In aim 1, we will clinically phenotype participants with COSP, using validated patient-reported outcome measures and standard ocular exams. In aim 2, we will compare the neurobiological features of nociplastic pain across the discordance spectrum among a subset of aim 1 participants using multimodal evoked sensory testing (pressure, thermal, and visual testing) at sites both local to and remote from the eye. Participants will also complete structural and functional brain magnetic resonance imaging to assess regions important for pain perception and modulation. In aim 3, we will examine and validate predictors of COSP pain responses before and after application of a topical anesthetic to the ocular surface, which should block peripherally induced discomfort to allow for clarification of pain origination.

We received funding for this project in August 2024. Recruitment and enrollment began in January 2025 after protocol development and piloting were completed. This study is ongoing with 59 participants enrolled and 51 participants completing the study visits as of January 2026.

Findings from the study have the potential to fundamentally change the way ocular pain syndromes are conceptualized, diagnosed, and treated. This work will not only help identify new CNS-directed pain treatments for a subset of patients with COSP but also help us better understand why many peripherally directed therapies are destined to be ineffective in a subset of individuals experiencing COSP.

DERR1-10.2196/84240