Last updated:
7/18/2025
Years published: 2021, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Divy Mehra, BS, Anat Galor MD, MSPH, Surgical Services, Miami Veterans Affairs Medical Center and Bascom Palmer Eye Institute, University of Miami and Noah Hanna, Corneal Neuralgia Patients Group, for the preparation of this report.
Summary
Neuropathic or nociplastic ocular pain (NOP) is a condition characterized by a group of long-lasting eye pain symptoms that are caused by nerve problems. People with NOP may feel burning, stinging, or shooting pain in one or both eyes. They may also be extremely sensitive to light or wind. Pain from NOP may start suddenly or after an injury or surgery. It can affect one or both eyes. The pain may be constant and intense, making it hard to work or go about daily life. If untreated, it can cause serious emotional distress.
These symptoms happen because the nerves in or around the eyes are not working normally (nerve dysfunction). If the nerve problem is caused by a specific injury or disease, the pain is called “neuropathic.” If the nerves are not working, but there is no clear injury or disease, it’s called “nociplastic” pain.¹
NOP can happen along with other problems of the eye it can also happen by itself as an isolated condition.2
In the past, many people with NOP were mistakenly diagnosed with dry eye (DE). Dry eye is a general term that refers to symptoms like eye dryness, discomfort and vision that gets blurry or changes.³
The exact number of people affected by NOP is not known yet. NOP can be one cause of dry eyes. Dry eyes are very common in the general population and many people with dry eyes also have many of the symptoms that are reported in NOP.4,5,6
While dry eye symptoms are often linked to problems with the eye surface, studies show that the severity of these symptoms does not always match what doctors see during an eye exam.8,9 This means many people are likely experiencing symptoms because of nerve dysfunction.
Problems with corneal nerves, nerves in the front surface of the eye, can lead to pain. Sometimes the nerves become less sensitive (called hyposensitivity) and sometimes they become more sensitive (called hypersensitivity).¹⁰ When nerves are hyposensitive, the surface of the eye may be damaged, but the person does not feel much pain.¹¹ When nerves are hypersensitive, people can feel intense pain even when the eye looks mostly normal. These problems with the corneal nerves may explain why people with nerve-related pain often do not get relief from standard dry eye treatments.¹²
Diagnosis is suspected in people who have symptoms like burning pain or sensitivity to light or wind, have risk factors like having had eye surgery, migraines, fibromyalgia, or a traumatic brain injury, and whose symptoms do not improve with standard eye treatments.12-16
In many people with NOP, there is not much visible damage on the eyes. Because of this, their symptoms may be dismissed or misunderstood. Some are even thought to be overly anxious or seeking medication. This can leave people feeling frustrated and hopeless. It’s important that patients, eye doctors, and pain specialists learn more about this condition, take it seriously, and treat people with empathy and urgency.
Introduction
The cornea has the highest density of sensory nerves in the body¹⁷ which means it can produce very strong sensations of pain. Eye pain is a major reason why people visit eye doctors or pain clinics. It can have a huge impact on a person’s quality of life and mental health.¹⁸
There are many causes of eye surface pain, including problems with tear film, physical damage to the eyelids or cornea, environmental exposures like dry air or pollution, or nerve problems. These nerves include not only the peripheral nerves in the eye (nerves on the side of the eye), but also the central nerves that connect the eye to the brain.¹⁹ Pain from these causes is usually divided into two types. Nociceptive pain comes from physical issues like poor tear production or anatomical changes in the eye. Neuropathic and nociplastic pain, on the other hand, comes from nerve dysfunction.
NOP fits into a broader group of terms like “eye pain,” “ocular surface pain,” and “oculofacial pain.” The difference is that the pain mainly comes from the nerves, not the surface of the eye. Although there’s no official guide for diagnosing NOP yet, new discoveries about how the eye and nervous system work have helped doctors better understand NOP.
People affected with NOP present with ocular pain in one or both eyes that may be escribed as:
Pain may occur spontaneously or be evoked by light (e.g., fluorescent room lights, sunlight), wind (e.g., indoor fans, in-clinic “air puff test” for eye pressure) and/or temperature changes (e.g., air conditioning, hair dryers, seasonal variation).
The onset may be sudden, as is usually the case when there is an identifiable trigger (such as trauma or surgery on the eye), or it can be slow and unnoticeable.
While the pain is typically chronic, its severity can range from mild to extremely painful.20
While in NOP the symptoms are related to the eyes, many people experience pain or aching in areas around the eye (e.g., heavy eyelids, pressure around the eyes, aching in the cheek bones, forehead, or temple) or describe pain radiating from the eye to the back of the head.
Most people with NOP do not have any visible ocular defects or only have mild ocular surface findings despite the pain they feel.
Because there are many symptoms that are common in NOP and dry eyes, a thorough ocular surface examination is needed when either condition is suspected. In general, absent or minimal signs of ocular surface disease (e.g., corneal epithelial disruption, low tear production, rapid tear break up, anatomical abnormalities, meibomian gland dysfunction) points to NOP as the main cause of pain.
The exact cause of NOP is not fully understood, and onset may occur in the presence or absence of a particular trigger. It is suggested that any initial injury to the eye may cause chronic nerve abnormalities in susceptible people, manifesting as chronic ocular pain. The initial trigger may be any of the following:
Symptoms of NOP often begin soon after an initial trigger but can have a delayed onset. Refractive surgeries (e.g., laser assisted in situ keratomileusis (LASIK) and photorefractive keratectomy [PRK]) seem to be the most common triggers for NOP, although chronic ocular pain can occur after any ocular surgery.16 NOP occurs together with ocular surface abnormalities and these abnormalities may further impact peripheral nerve function. However, NOP often occurs in the absence of any identifiable cause and does not require any initial damage to the eye for diagnosis.
At a deeper level, NOP is thought to be caused by nerve abnormalities (i.e. sensitization) at the peripheral level (i.e., corneal surface or periocular skin) and/or in central pathways (i.e., in brain structures such as the trigeminal sensory pathway, thalamus, cerebral cortex).21 These changes result in over-activation of the neural cells that feel pain (sensory neurons). This is experienced as increased sensitivity to feeling pain and an extreme response to pain (hyperalgesia) or a type of nerve pain where stimuli that doesn’t normally cause pain are perceived as painful (allodynia).22 In the eye, hyperalgesia is often experienced as sensitivity to wind and allodynia as sensitivity to light. Importantly, nerve changes are dynamic, and there is no timetable for development of abnormalities or improvement in function. Thus, treatments may improve nerve function and pain even years after the onset of symptoms.
Some researchers think that global abnormalities in sensory processing, meaning the way the brain and nervous system interpret signals like touch, temperature, or pain, can be a potential cause of NOP. This can involve glial activation (glial cells are helper cells in the brain and spinal cord and when too active, they can increase pain signals) and pre- and post-synaptic upregulation. Synaptic upregulation refers to changes at the connections between nerve cells (called synapses) where signals are passed and inflammation in the brain and nervous system can make nerves more sensitive and contribute to ongoing pain.
In addition to these nervous system changes, researchers are also studying the role of systemic inflammation (widespread inflammation throughout the body) and genetic predisposition, meaning some people may be more likely to develop chronic pain because of their genes.
NOP may affect people of any age, sex, ethnicity, or background. NOP often occurs with pain in other areas of the body (e.g., fibromyalgia, chronic joint pain, peripheral neuropathy) and with headaches (e.g., migraine).23 Many people with NOP also have mood disorders (e.g., depression, anxiety). However, it is not understood if this is a cause or consequence of disease or if these conditions are related.24
A thorough history and clinical exam are needed for a diagnosis of NOP. As there are no universal criteria for diagnosis, NOP is a clinical diagnosis. A combination of history, symptoms, physical examination and imaging findings are used to diagnose NOP, after ruling out other causes of ocular pain. The examination of an individual with suspected NOP begins with a comprehensive history. This will include collecting information on initial triggers for pain, how long someone has had the pain, what relieves helps the pain and what makes it worse, and treatment history.
It is helpful to assess current symptoms using standardized questionnaires to determine the severity and type of symptoms, related factors and changes in someone’s ability to do everyday tasks (functional disability). The modified Neuropathic Pain Symptom Inventory (NPSI-Eye)25 and the Ocular Pain Assessment Survey (OPAS)26 are two validated questionnaires that assess, quantify, and characterize pain symptoms. In addition, the OPAS evaluates the impact of pain on quality of life. These questionnaires can be used to determine baseline symptoms, guide treatment and monitor for changes over time.
One clinical indicator of NOP is disproportionately intense symptoms when there are few or minimal signs of ocular surface disease. Therefore, an unremarkable ocular surface exam or unchanged symptoms after treatment of the ocular surface should raise the possibility that neuropathic or nociplastic mechanisms are the cause of pain. In particular, topical lubricating drops (eye drops) often provide no or minimal relief of ocular symptoms and can even worsen symptoms in people with NOP and hyperalgesia.
Corneal sensitivity can be examined in clinic by using a cotton tip or dental floss to touch the eye. The reaction to the touch, corneal sensation, is measured in all ‘quadrants’ (central, superior, inferior, nasal, temporal) or simply in the center of the cornea.27 In clinical settings, sensitivity is often assessed qualitatively using a 0-3 numerical scale (0= no sensation, 1=reduced, 2=normal, and 3=increased). In research settings, sensitivity can be evaluated by using more sophisticated tools like the Brill, Cochet-Bonnet, or Belmonte aesthesiometers.28 Cochet-Bonnet uses a 6cm nylon microfilament that is slowly brought in contact with the cornea and retracted until sensation is felt. Corneal sensation is quantified on a 0-6 cm scale, with 0 cm representing no sensation and 6 cm full sensation. A limitation of Cochet-Bonnet is that most healthy individuals can detect the sensation at 6 cm, which limits the ability to test for hypersensitivity. The Brill aesthesiometer is a new commercially available device that applies air to the cornea to create pressure or tension (mechanical stimuli). It has a 6-point testing range (1 representing the lowest air flow and 6 indicating that the air flow was not felt at the highest level). The device potentially detects both decreased (level 5 or 6) and increased (level 1) sensitivity, although this concept needs to be further examined. Individuals with NOP can have decreased, normal, or increased corneal sensation, but individuals often report corneal hypersensitivity.
In people with suspected NOP, examining the effect of a topical anesthetic (a medication applied to the skin to numb that area) on pain can help determine the source of pain. Application of a topical anesthetic (such as proparacaine 0.5%) quiets corneal nerve inputs and largely eliminates nociceptive and peripheral neuropathic sources of pain.
Imaging of the cornea using in vivo confocal microscopy (IVCM) provides an anatomic picture of corneal nerves and inflammatory cells, most often in the central cornea.29 The subbasal nerve plexus, a dense area of nerves found just under the corneal basal epithelium, is commonly imaged, although nerves can also be detected in the stroma. Nerve abnormalities have been described in various dry eye disease sub-types. These most often include decreased nerve density, an increased number of inflammatory cells in individuals with aqueous tear deficiency (ATD) (i.e., decreased tear production), and systemic immune disorders.30 Microneuromas, or abrupt endings of nerve fibers on imaging, have been identified as potential markers of peripheral neuropathic pain31, although this finding requires further study.
Treatment
The primary goal in treating NOP is to improve the function of the eye’s nerves and to reduce or avoid harmful stimuli that can worsen pain by triggering a chain reaction known as the neuropathic cascade.
After a detailed evaluation, the first step in managing NOP is to address all possible sources of nociceptive pain, the pain that comes from actual or potential tissue damage. If these sources are not treated, they can continue to send pain signals that may lead to long-term changes in how nerves located outside the brain and spinal cord function (called peripheral nerve abnormalities).
Common treatments at this stage include:
If pain continues despite these treatments or if there are clinical signs suggesting nerve-related pain such as pain that seems too severe for the eye’s appearance, sensitivity to light touch on the cornea (the clear front part of the eye), or pain that persists even after the eye is numbed, then therapies targeting the underlying nerve dysfunction should be considered.
With this approach, most individuals with NOP experience improvement, both in pain levels and in their ability to function at work and in daily life.
In cases where the pain is thought to originate from central mechanisms (meaning changes in how the brain and spinal cord process pain sensations), oral medications known as neuromodulators are often prescribed.
First-line options include medications like α2δ (alpha-2/delta)-calcium channel blockers, such as gabapentin and pregabalin.³² These help reduce the transmission of pain signals in the nervous system. Other oral medications may be added or used alone, including:
If the pain seems to be due to issues in the peripheral nerves (nerves closer to the surface of the eye), then local treatments can be considered. These include blood-derived eye drops such as autologous serum tears (AST).³³ AST are made from the patient’s own blood and contain growth factors like nerve growth factor (NGF), epithelial growth factor (EGF), transforming growth factor-beta (TGF-β), plus other helpful vitamins and proteins. These ingredients support both nerve repair and the health of the eye’s surface.
Platelet-rich plasma (PRP) is a blood-derived treatment with even higher concentrations of growth factors and proteins that support healing. PRP has been used successfully in people experiencing eye pain after LASIK surgery, among other conditions.
Access to AST and PRP may be limited to academic centers or specialized eye banks, as they require specific equipment and processing capabilities.
Additionally, other experimental topical agents such as insulin eye drops and topical NGF are being studied, especially in people with reduced corneal sensitivity. However, these treatments have not yet been extensively tested in large, controlled clinical studies.
For people experiencing light or wind sensitivity, special glasses may help:
These glasses are often used alongside other medical therapies to improve comfort and quality of life. There is a strong association between NOP and other neurologic and psychiatric mood disorders, and, therefore, interdisciplinary treatment is essential to deliver effective holistic care.
Additionally, NOP can coexist with neuropathic pain elsewhere in the body, like joint/back pain, fibromyalgia, headaches and other chronic pain disorders. These conditions are common and can be very incapacitating. Individualized and regular support from doctors and other healthcare providers, addressing both medical and mental health issues, can be very important in helping people cope with these distressing and chronic conditions.
Because of the complexity of NOP and the many diagnostic tools and treatments now available, people with NOP may need to be seen by several specialists who should work together as a team in a coordinated way. Care from specialists familiar with NOP can significantly improve treatment outcomes and quality of life.
A multidisciplinary team may include an ophthalmologist, neurologist, pain or headache specialist, acupuncturist, psychologist, psychiatrist and primary care physician, as appropriate. As in other pain conditions, psychotherapy techniques (e.g., cognitive behavioral, desensitization, relaxation and acceptance-based therapies) can be helpful. Restoring comfort and function are fundamental goals of treatment. To get there, both individualized and multidisciplinary care are needed to treat the psychiatric and neurological symptoms.
Several investigational therapies are being evaluated for use in NOP. New topical medications are under investigation in clinical trials. These include:
Standard oral treatments such as calcium channel blockers, tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are good options. Other oral neuromodulators may be considered, such as antiepileptic drugs (e.g., topiramate, lamotrigine, carbamazepine), analgesics like mexiletine and low-dose naltrexone, which may help regulate immune and nervous system activity.
Opioids are generally avoided in the treatment of NOP because of their potential to worsen nerve sensitivity over time, a condition known as hyperalgesia. While they may offer short-term relief, their long-term impact on nerve function is often negative.
NOP often overlaps with migraine headaches. Because of this, certain migraine treatments have been tested for NOP with promising results, including:
In people with chronic pain following eye surgery, local nerve sensitization around the eye can be one of the factors for the pain. These patients often show signs of cutaneous allodynia, meaning the skin around the eyes is painful to touch. In such cases, periocular nerve blocks may offer relief. These injections combine an anesthetic (a numbing medicine like bupivacaine or lidocaine) with a corticosteroid (such as methylprednisolone, triamcinolone, or dexamethasone). The areas where the injections can be made in this procedure can be identified by feeling around the bony landmarks around the eye, without needing special imaging tools.³⁷
For people with severe treatment-resistant NOP, more advanced options may be considered at pain specialty centers. These can include sphenopalatine ganglion blocks, which affect parasympathetic nerve activity, and superior cervical ganglion blocks, targeting sympathetic nerve control. These procedures typically require fluoroscopic guidance and are not performed in standard ophthalmology clinics. In extremely rare and severe cases, cervical intrathecal pain pumps have been used to manage persistent eye pain.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Corneal Neuralgia Patients Group. Facebook. https://www.facebook.com/groups/1713169018917451/.Accessed July 14, 2025.
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