My eyes feel dry. Is it all in my head?

The eye is an organ that should not be sensed. However, many individuals report sensing their eyes, using terms such as “dryness,” “irritation,” “aching,” and “tenderness,” to name a few descriptors.[1] In the United States, a population-based study out of Salisbury, Maryland, highlighted that 15% of individuals reported symptoms of dryness, grittiness or sandiness, burning, redness, crustiness of the lashes, or sticky eyelids, often or all the time.[2] As ophthalmologists, the presence of these sensations led to a closer examination of the ocular surface, with a focus on inadequate tear production and epithelial disruption as a cause of symptoms.[3] However, when these metrics proved insensitive to identify the cause of symptoms in many patients,[3] ophthalmologists expanded their search to examine other aspects of tear health, including tear instability (i.e., tear break-up time) and Meibomian gland disease (e.g., dropout and meibum quality) as potential symptom contributors. Over time, point-of-care tests were introduced that examined other potential contributors to eye pain, including high tear osmolarity (TearLab, San Diego, CA) and ocular surface inflammation (i.e., matrix metalloproteinase 9, Quidel, San Diego, CA). However, the addition of these metrics did not improve our ability to explain symptom reports across a large subset of patients.[4,5] In fact, several studies highlighted the disconnect between ocular surface symptom reports and observed signs of disease.[6,7] So, what are ophthalmologists missing?

Interestingly, when the dry eye symptom/sign discordance conundrum is presented to neuroscientists/pain specialists, they cannot understand the dilemma. To them, pain report is ultimately a central phenomenon. It may start with peripheral mechanisms that detect a noxious stimulus in the environment. However, ultimately, peripheral signals are processed and interpreted by the central nervous system (CNS) whose output is the final form of symptom report. Based on this reality, neuroscientists/pain specialists cannot understand why ophthalmologists expect ocular surface signs to fully align with symptom reports when the pain experience relies on so much more than can be detected peripherally.[8]

It seems that ophthalmologists and neuroscientists/pain specialists need to have more interactions and collaboratively investigate mechanisms of ocular surface pain that can be translated into improved diagnostic and therapeutic algorithms. This is greatly needed as ocular surface dysesthesias (unpleasant sensations) have been shown to negatively impact physical and mental health, limiting the ability to work and carry out activities of daily living.[9]

So, what is currently known about ocular surface pain processing?

Starting peripherally, a variety of noxious stimuli can activate one or more corneal nociceptors subtypes. Aδ mechanoreceptors (~20% of corneal fibers, identified by the presence of piezo2 in trigeminal ganglia) can detect mechanical stimuli, such as that which occurs with ocular trauma. Polymodal nociceptors (~70%, identified by the presence of transient receptor potential vanilloid-1, TRPV1, cation channels on their terminal fibers) can sense a variety of stimuli, including mechanical, chemical, and thermal insults. These nociceptors have been shown to react to inflammatory mediators placed on the ocular surface.[10] C-fiber cold thermoreceptors (~10%, identified by the presence of transient receptor potential melastatin member 8, TRPM8, on terminal fibers) can sense temperature change (e.g., as occurs with evaporation of the tear film).[11] Newer data have identified subtypes within these classifications (e.g., low and high threshold cold thermoreceptors[12]) along with novel nociceptors on the conjunctiva and palpebral conjunctivae whose properties are still being defined (personal communication Juana Gallar). Given the number of sensors on the ocular surface, it becomes clear that many triggers, including environmental exposures (e.g., temperature, humidity, and air pollution), anatomic abnormalities, and toxins along with tear and ocular surface abnormalities (e.g., low tear production, ocular surface inflammation, and epithelial disruption), can activate peripheral nociceptors and initiate the pain cascade.

However, a concept that is often not recognized in the field of ophthalmology is that ocular surface nociceptors are not static entities but instead part of a dynamic system that can change due to a variety of conditions, including surgical trauma, chronic exposures (e.g., air pollution and BAK), or tear abnormalities. This plasticity, termed “peripheral sensitization” by the International Association for the Study of Pain (IASP), involves increased responsiveness and reduced thresholds of neurons linked to a variety of modifications, including changes in gene expression, post-translational modifications (e.g., changes in channel sensitivity), and nerve anatomy (e.g., sprouting and conversion of non-nociceptive sensory afferent into fibers exhibiting a nociceptive phenotype).[13]

What about the central processing of ocular surface pain?

Pain signals from corneal nociceptors are transmitted to the trigeminal nucleus caudalis, where they can be modulated by various inhibitory and excitatory mechanisms. Signals then ascend to the brain, reaching areas such as the thalamus, somatosensory cortex, and other brain regions involved in pain perception. Some aspects regarding the central processing of ocular surface pain are likely shared with other body areas, yet others may be unique to the eye. For example, data suggest that the eye is less well represented in brain areas involved in pain discrimination (e.g., somatosensory cortex) but more represented in areas involving emotional pain processing (e.g., insula, amygdala, and prefrontal cortex).[14,15] These neurological findings may lend biological credence to the emotional component that often accompanies chronic ocular surface pain, in which some cases of suicide have even been reported.[9]

Similar to peripheral nerves, central nerves are also dynamic entities whose molecular composition, structure, and function can change with time, which can result in alterations in CNS neuronal responsiveness. This process can lead to an amplified perception of pain, even in the absence of ongoing peripheral input. While CNS contributors to pain are often considered in conditions such as fibromyalgia and interstitial cystitis,[16] CNS influences on chronic ocular surface pain have been less well studied.

What constitutes the pain experience?

Overall, it is important for ophthalmologists to recognize that many components, beyond what can be seen on slit-lamp examination, can impact the ocular surface pain experience. For example, emotional status can impact pain perception. While anxiety, depression, and stress can amplify pain, positive emotions can have a pain-reducing effect.[9] Cognitive factors can also influence pain with expectations, beliefs, and attention influencing how pain is experienced. For example, catastrophizing (e.g., the tendency to describe a pain experience in exaggerated terms, to ruminate on it, or to feel helpless about it) can amplify pain, while distraction techniques or cognitive-behavioral interventions can reduce pain report.[9] Social and cultural factors can also influence pain perception. For example, the presence or absence of a strong social network can positively or negatively impact the pain experience. Environmental factors are also likely important as a stressful environment can exacerbate pain while a familiar environment may mitigate pain. Finally, genetics, age, and gender-related differences likely contribute to the pain experience as these facets have been shown to impact pain sensitivity (e.g., proneness to react to standardized experimental stimuli) and have been noted to be risk factors for chronic pain development.[17,18,19]

How is this relevant to ocular surface pain?

Understanding the multifaceted nature of pain is crucial to developing comprehensive approaches for the treatment of ocular surface pain. Beyond a focus on topical therapies to address tear abnormalities, management strategies can also include oral, psychological, social, and environmental interventions. To achieve this level of personalized medicine, it is essential that ophthalmologists recognize the intricate interactions of various contributors on pain perception and understand that these components may differentially impact pain in an individual patient. In support of these ideas, neuromodulatory strategies have been successfully implemented in some individuals with chronic ocular surface pain driven by presumed neuropathic mechanisms.[20] However, the incorporation of a holistic approach to ocular surface pain management is still in its infancy.

The goal of this editorial is to increase awareness that a variety of factors can influence ocular surface pain perception and to highlight the importance of addressing potential contributors to pain that may not be detected on slit-lamp examination. It is vital that ophthalmologists understand the mechanisms that drive ocular surface pain and identify which contributors are most likely at play in an individual patient. This information can help devise a holistic approach to addressing pain that will hopefully translate into improvements in quality of life and function.

What is the ophthalmologist's role in the holistic treatment of pain?

The ophthalmologist plays a vital role in the management of chronic ocular surface pain by addressing eye-specific components that contribute to pain. In addition, ophthalmologists should consider becoming familiar with central treatments that are used in chronic pain management (e.g., oral neuromodulators and transcutaneous electrical stimulation) and pair up with appropriate services—pain specialists, neurologists, pain psychologists—as needed, to address other aspects of pain. This is especially needed when overlapping or co-occurring chronic pain conditions are noted. A team approach is often needed to provide multifaceted care that addresses physical, emotional, and lifestyle factors, with the ophthalmologist being a central contributor to this process.

About the author

Anat Galor, MD, MSPH is a professor of ophthalmology at the Bascom Palmer Eye Institute (BPEI), University of Miami and a staff physician at the Miami Veterans Administration (VA) Hospital. Dr. Galor runs the ocular surface pain program at BPEI and the Miami VA and has focused her research on understanding mechanisms of pain in dry eye, with an emphasis on studying new diagnostic and treatment modalities. She has lectured and published extensively on how nerve status may underlie the often noted disconnect between dry eye symptoms and signs. This includes individuals with decreased sensation and chronic epithelial abnormalities (neurotrophic phenotype) and individuals with hyper-sensitive nerves and chronic ocular pain with minimal ocular surface abnormalities (neuropathic phenotype). Over the years, she has participated in several dry eye related committees including the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Pain and Sensation Committee and the Dry Eye Awareness Month Congressional Briefing. In addition, she served as President of the Ocular Microbiology and Immunology Group and sits on several educational committees within the Academy of Ophthalmology.