Issue: July 10, 2019
July 05, 2019
4 min read

Corneal neuropathic pain: a complex, often misdiagnosed and difficult-to-manage clinical entity

Sensitization of the nerves in the cornea and brain triggers pain reactions even in absence of any stimuli.

Issue: July 10, 2019
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Corneal pain is a defense system that signals injury or loss of ocular surface homeostasis. However, not rarely patients may report significant symptoms while presenting few or no signs of inflammation. This clinical entity, defined as neuropathic pain, has gained increasing interest in recent years, and efforts have been made to clarify the pathophysiology.

“Neuropathic pain occurs when corneal nociceptors become dysfunctional. They develop increasing hypersensitivity to physiological or noxious stimuli, including air drafts, temperature change and endogenous chemical changes or may start firing independent of any stimulus. Patients are typically sensitive to light. At a following stage, central sensitization may occur: The central nerves in the brain become sensitized and detect pain independent of anything that is happening in the eye. At this stage, pain becomes chronic and very difficult to manage,” Stephen Pflugfelder, MD, said in an interview with Ocular Surgery News.

Symptoms are chronic irritation or pain, which can mimic the symptoms of dry eye.

Stephen Pflugfelder, MD
Stephen Pflugfelder

“A lot of patients are misdiagnosed as having dry eye, but when they are examined, they have very minimal or no sign of dry eye,” Pflugfelder said.

A decade ago, patients were thought to have some psychological overlay, hysterical pain and hypochondria, and suffered the additional frustration of not being believed and understood. Now this problem is common enough that most physicians, especially cornea specialists, have seen it and know how to approach it.

Causes of corneal neuropathic pain may stem from corneal nerve damage, surgical trauma (most commonly LASIK) and abnormal healing, he said. Nerves become more responsive to the environment and generate defense reflexes.

Peripheral vs. central

“When a patient reports persistent symptoms out of proportion to any objective findings, we can be quite sure that we are dealing with neuropathic pain. First, we try to decide whether the pain is resulting from sensitized nociceptors or whether it is central pain, and the way this can be done is by putting anesthetic on the eye and asking the patient if the pain diminishes or even goes away. If it does, it is a sign that we are dealing with peripheral sensitization,” Pflugfelder said.

Treatment in these cases will aim at decreasing the sensitivity of corneal nerves or shielding them from the environment. One option is soft or scleral contact lenses, which protect the cornea from air drafts and temperature changes. Alternatively, autologous serum or plasma drops might help repair the nerves and make them respond more normally. These treatments are often used as first-line therapy. Dry eye should also be treated if there is evidence of it as a trigger.


If patients do not respond to the anesthetic and continue to have irritation or pain, they likely suffer from central neuropathic pain. This condition is difficult to manage effectively and requires a systemic approach with medications such as gabapentin or pregabalin, which are used also for fibromyalgia and other chronic pain problems, naltrexone, an opioid receptor antagonist, or Cymbalta (duloxetine hydrochloride, Eli Lilly), an antidepressant that is also used for pain.

Typically, the patient initially feels irritation, which is for some time manageable but becomes chronic over time for reasons that are not completely understood.

“Peripheral pain can eventually become central, which might happen quickly or more slowly and progressively. The time of this conversion is variable, and there is no way to predict it,” Pflugfelder said.

Unrelenting, disabling pain

Neuropathic pain at whatever stage often requires multiple therapies and a trial-and-error approach.

“If we are lucky, the patient will get relief from at least one of the treatments, but the problem rarely ever goes away, unfortunately. If I can make it manageable, so that the patients can do their jobs and lead a fairly normal life, then I would call this a treatment success,” Pflugfelder said.

Corneal neuropathic pain is bothersome and in some cases disabling. Daily tasks such as reading, driving and working at the computer are heavily affected. Patients may see several doctors and are often treated for dry eye. Their symptoms may be dismissed because there are no objective findings, and their frustration builds.

There is no evidence that neuropathic pain can be prevented, but diagnosing and treating it early, when it is still at the peripheral stage, may help to keep it from becoming centralized.

“If you find out that the pain is coming from corneal nerves, if it goes away with anesthetics, be proactive in using contact lenses or blood products to alleviate it and keep it peripheral,” Pflugfelder said.

Neurological disorders

Corneal neuropathic pain has several features in common with neurological disorders such as fibromyalgia and migraine headache. They share the hypersensitivity to normal stimuli and the tendency to become chronic, have a similar mechanism of onset and often go hand in hand.

“Quite a few patients who have chronic eye pain might have fibromyalgia or more often migraine headaches. There is no evidence so far, but in my experience patients with migraine are more susceptible to developing chronic neuropathic pain as a consequence of corneal surgery. I do warn them if they ask for my advice,” Pflugfelder said.


Corneal neuropathic pain should never be neglected, misdiagnosed or underestimated, he said.

“We are seeing more and more of those patients, and they are more symptomatic,” Pflugfelder said. “We must be prepared to see increasing numbers and diagnose them correctly, differentiating them from dry eye cases, which are also on the increase. Doctors should have a high index of suspicion for the problem if patients have dry eye and they do not respond to treatment.” – by Michela Cimberle

Disclosure: Pflugfelder reports no relevant financial disclosures.