When it’s not dry eye disease

Neuropathic pain requires a team effort. Be prepared to reach beyond eye care.

What do you do when a patient presents with eye pain that cannot be explained with ocular surface findings? The mystery problem may have a neuropathic etiology — and may benefit from cooperative care with primary care physicians, optometrists, pain specialists and, possibly, psychiatrists or psychologists, say experts.

The ophthalmic community is “starting to realize” that both neuropathic pain and neurotrophic keratitis have erroneously been lumped under the overall dry eye disease category, notes Christopher Starr, MD, of Weill Cornell in New York. “If you treat these patients as just run-of-the-mill dry eye, they are not going to get better,” he says.

Anat Galor, MD, MSPH, Bascom Palmer Eye Institute, Miami, agrees. She points out that, in order to properly treat the “dry eye patient,” clinicians have to subtype the condition. First, clinicians must identify what is causing the nerves to fire — these causes could be environmental or anatomical, such as nerve dysfunction.

“Ophthalmologists are very good at looking at the ocular surface to evaluate tear film status,” Dr. Galor says. “There is a knowledge gap, however, on how to treat persistent symptoms when the tear film has been optimized with currently approved therapies.”

We interviewed physician experts, who shared tips for how to recognize neuropathic pain and treat it.


It’s not as easy as it sounds

Pain specialist Konstantinos D. Sarantopoulos, MD, PhD, University of Miami Miller School of Medicine, says pain could be caused by disease (eg, diabetes), infection, injury or excessive inflammation that affects the nerves.

“If the inflammation is very intense and prolonged, nerves that receive pain signals will become sensitized and will amplify the signal,” Dr. Sarantopoulos says.

Neuropathic pain is a condition in which nerves become more sensitive, may generate spontaneous signals of pain and react abnormally to normal stimuli, Dr. Sarantopoulos explains. Unfortunately, there is no “gold standard” test to diagnose whether an individual’s pain has a neuropathic component or which individuals will develop neuropathic pain that can occur in the setting of persistent ocular surface inflammation or in its absence. Furthermore, inflammatory pain may coexist with neuropathic pain. As such, treatments may need to address each of those components separately.

Listen to the individual

Patients are likely to provide the clues needed to diagnose neuropathic issues, including complaints of burning and evoked pain to wind and light, for example, stating that any amount of sunlight is bothersome. These descriptors often are shared with neuropathic pain outside the eye. In these cases, Dr. Galor says that “it is important to individualize therapy.”

The approach to chronic pain “is often multi-modal, and treatment algorithms need to consider comorbidities, contributors and patient needs and preferences. Isolated eye pain after LASIK, for example, may be approached differently than eye pain in the setting of fibromyalgia or in the setting of migraine. In addition, the effect of eye pain on psychological status needs to be considered and addressed,” Dr. Galor says.

Diagnostic tips

As there is no gold standard confirmatory test for the presence of neuropathic eye pain, “Clinicians should start thinking about neuropathic mechanisms in cases where eye pain is out of proportion to ocular surface findings, in individuals with pain that started after eye surgery (eg, after LASIK) and in individuals with chronic pain outside the eye,” Dr. Galor says.

Even corneal specialists who see substantially more dry eye patients than other specialists may not diagnose neuropathic pain quickly, Dr. Starr notes. But, as the subtype becomes better known as its own entity, he hopes that will change.

“We don’t test corneal sensation enough, and we don’t image the corneal nerves enough, and we don’t do either early enough in these recalcitrant so-called ‘dry eye’ patients,” Dr. Starr says. When ophthalmologists start asking patients about other conditions/medications, or diseases such as fibromyalgia and chronic pain elsewhere, patient-reported symptoms of depression and anxiety often “go hand in hand with neuropathic pain,” he notes.

These patients may need additional treatment for those diagnoses as well, Dr. Sarantopoulos says. “We don’t know if depression or anxiety are a direct consequence of the pain or if there is a genetic determinant to that.”

In evaluating a patient with a presumed neuropathic component to eye pain, Dr. Sarantopoulos may order an MRI of the brain to check the integrity of the nerves deep inside the brain. Some conditions affect these trigeminal nerves, such as multiple sclerosis or tumors.


At our disposal

Many treatments are available for patients with a suspected neuropathic component of pain, most of which are borrowed from the pain field. The trigeminal nerve innervates the eye and the skin, and data support the notion that noninjured adjacent nerves may propagate chronic pain.

“Based on this notion, we consider blocking periorbital nerves with bupivacaine and methylprednisolone in individuals whose pain started after a surgical injury (refractive, cataract or retinal surgery) and/or in patients who have failed oral agents,” Dr. Galor says. “We have used this approach in many patients with variable results. In some cases, we had big successes and were able to achieve complete pain resolution for months with a significant improvement in function.”

Other types of nerve blocks (stellate or sphenopalatine ganglion blocks) may be required in some patients. Additional options include oral agents, such as gabapentin (Neurontin, Pfizer) and pregabalin (Lyrica, Pfizer); adjuvant strategies, such as transcutaneous electrical nerve stimulation; or botulinum injection. The latter is a strategy successfully applied in migraine treatment.

Beyond eye care

Pain may be a common condition, but ocular pain “can be a very, very debilitating condition,” Dr. Sarantopoulos says, and may lead to severe emotional and functional impairment that need to be addressed. Treatment needs to go beyond just treating pain, and there are many strategies to consider, Dr. Galor says.

“Cognitive behavior therapy can help individuals learn healthy techniques to cope with chronic pain. In addition, pharmacologic therapies with agents such as duloxetine can be help reduce depression and anxiety,” she says. “Other therapies, such as acupuncture, have been used to alleviate chronic pain outside the eye and, as such, may have a role in treating chronic eye pain.” Yet, in some diseases, such as narrow-angle glaucoma, some pharmaceuticals in the antidepressant or pain-reliever categories may be contraindicated, Dr. Sarantopoulos adds.

But Dr. Galor points out that ophthalmologists “don’t have to reinvent the wheel to treat patients. We have already formed good relationships with rheumatologists to comanage individuals with Sjogren’s and with dermatologists to comanage individuals with mucous membrane pemphigoid.”

“Ophthalmologists are very good at treating the inflammatory|component, and the pain specialists are very good at treating the neuropathic component of pain,” Dr. Sarantopoulos says, reinforcing the need for comanagement.

Systemic treatment: the next frontier

According to Dr. Starr, the “next big research chapter in the world of ocular surface disease and corneal disease” will be in the area of corneal nerve and the correlation with pain.

“A better understanding of the corneal nerves and corneal sensation abnormalities will change the way we approach all ocular surface patients,” he says. Many treatments for central neuropathic pain are not routinely prescribed by ophthalmologists, and patients often have pain elsewhere or have systemic pain syndromes best treated by a pain specialist or by a referral to a pain clinic (See “Beyond eye care”).

Dr. Sarantopoulos agrees. Many patients he sees have coexistent systemic conditions, he says.

Systemic treatment can include gabapentin or pregabalin, both of which are alpha-2 delta ligands, or tricyclic antidepressants such as amitriptyline and nortriptyline, duloxetine or adjunctive therapies, Dr. Galor says.

When pain has a central component, Dr. Galor uses those oral medications (among others) because pain specialists do. “Other groups have more experience with tricyclic antidepressants like amitriptyline,” she says. “At this time, we don’t know which oral agent is best for the treatment of chronic eye pain with a presumed neuropathic etiology as there have been no head- to-head comparison studies.”

Another adjuvant approach is to use botulinum toxin to treat eye pain. Dr. Galor considers this in individuals with comorbid headache “as this approach is used to treat migraine pain,” she explains. Interestingly, in individuals with chronic migraine pain, she has found injections of botulinum toxin “improved eye pain and the effect was independent of improvement in tear volume. We currently use a modified protocol and inject 35 U of botulinum toxin into seven sites in the forehead for these patients.”

Dr. Galor believes that many of these strategies “can be easily incorporated into the ophthalmologist’s treatment algorithm. A lot of ophthalmologists, for example, already offer botulinum toxin for other indications and thus have the drug available in clinic.

“Most ophthalmologists feel equally comfortable prescribing oral agents for the treatment of ocular diseases (eg, prednisone for the treatment of scleritis),” she says.

In fact, she points out that gabapentin and pregabalin have an excellent safety record and have fewer side effects than prednisone. “It is just a matter of ophthalmologists getting comfortable using these agents,” she says.

The trophic factors in autologous serum “can sometimes help with chronic corneal pain,” Dr. Starr says, as can traditional dry eye treatments and various contact lenses, including the PROSE lens for some peripheral corneal pain syndromes.


As the ophthalmic world learns more about differentiating neuropathic and neurotrophic pain from dry eye, the more likely treatment options will continue to expand as well. Continued comanagement will further help patients, as an ideal regimen may be a combination of topical and systemic treatments.

Another advantage to a cooperative approach — coordinating all this care and keeping the primary care physician in the loop can help reduce redundant treatments and provide some sense of continuity for the patient. OM