Cornea
December 2021
by Liz Hillman
Editorial Co-Director
Itching, burning, aching, dry, gritty: Patients describe ocular surface pain in a myriad of ways. For some reason, said Anat Galor, MD, the corneal nerves are firing. It’s the physician’s job to figure out why, and in some cases, the reason is not so clear.
“Nerves can fire for two reasons; either they’re firing because there is something in the environment causing them to fire, which would mean they’re firing appropriately. … We call that nociceptive pain. Or they are firing because they’re abnormal—or both,” she said.
She said that it’s unknown just how many patients have a neuropathic component to their eye pain, especially because it doesn’t necessarily exist in isolation, but alongside other conditions. Dr. Galor estimated that in her comprehensive dry eye clinic, 1–5% have pure neuropathic ocular pain without an obvious nociceptive source. In her ocular pain clinic, that percentage is higher.
When a patient comes in using the variety of adjectives to describe pain, it’s time to put on your detective hat. While there is no gold standard diagnostic test to confirm that pain symptoms are coming from a neuropathic origin, Dr. Galor said there are findings on history and physical examination that can help physicians reach that conclusion. These include specific risk factors like pain that started immediately after surgery or painful comorbidities elsewhere, such as migraine and fibromyalgia. The characteristics of the eye pain can also help, such as describing burning pain or intensification of pain with exposure to wind or light. “While not definitive, these risk factors and characteristics make you think about the potential for a neuropathic source of pain,” Dr. Galor said.
Signs of neuropathic pain include abnormal nerve sensitivity, which can be assessed in the clinic with the tip of a cotton swab. Patients with neuropathic pain oftentimes have abnormal sensitivity, either decreased or increased. Another sign of neuropathic pain is an abnormal response to a drop of anesthetic. Dr. Galor asks patients to rate their pain prior to the drop and reassess pain about 30 seconds after a drop of anesthetic is placed in the eye. If the pain doesn’t go away, it suggests a central or non-ocular surface source of pain.
“We have a lot less data on oral and adjuvant therapies for the treatment of eye pain compared to the treatment of pain elsewhere, so we’re extrapolating what we know about treating neuropathic pain elsewhere in the body and applying this knowledge to eye pain, assuming shared mechanisms.”
Anat Galor, MD
“We’re also looking for a disconnect. If the patient tells us they’re feeling painful sensations but we’re not seeing a lot of abnormalities on the ocular surface, this suggests a potential neuropathic component to pain,” Dr. Galor said.
Deborah Jacobs, MD, MSc, said it’s rare to have a patient come in complaining of or referred for eye pain specifically. She said they’re often diagnosed with dry eye but found to not have responded to treatment, or they have symptoms but not much in the way of signs; then the physician considers neuropathic pain. Dr. Jacobs said her diagnosis of such patients is based on history, surveys such as OSDI and the Ocular Pain Assessment Survey, as well as examination techniques such as corneal sensation testing, vital dye staining, the proparacaine test, Schirmer testing, and sometimes confocal microscopy.
“Corneal confocal microscopy can be helpful in supporting the diagnosis, distinguishing peripheral vs. central disease, and seeing evidence of inflammation, but this remains primarily a research tool as there are no standardize metrics for clinical practice,” Dr. Jacobs said.
In terms of treatment, Dr. Galor said what many physicians are already doing for typical dry eye therapy is a good start.
“You want to treat all nociceptive sources of pain,” she said. “Anti-inflammatories are a good choice if inflammation is present on the ocular surface as inflammation will cause nerves to function improperly. If first line therapies do not work in alleviating the pain, it is important to move on.”
For peripheral neuropathic pain, Dr. Galor often uses autologous serum tears or biological products. For centralized pain, Dr. Galor uses oral medications that modulate nerves. She noted that these therapies, including gabapentin, pregabalin, and nortriptyline, are used to treat pain elsewhere and have a reasonable side effect profile. In specific cases, she uses adjuvant therapies. She considers botulinum toxin injections and trigeminal neurostimulation in individuals with “migraine-like” eye pain (pain that starts spontaneously and associates with headache and photosensitivity). She has found the periocular injections with bupivacaine and methylprednisolone are often helpful in individuals with post-surgical pain.1,2,3
“We have a lot less data on oral and adjuvant therapies for the treatment of eye pain compared to the treatment of pain elsewhere, so we’re extrapolating what we know about treating neuropathic pain elsewhere in the body and applying this knowledge to eye pain, assuming shared mechanisms,” she explained.
Dr. Jacobs said there are many options for modulating peripheral signaling if that’s a component: topical medications, lubrication, plugs, therapeutic contact lenses, botulinum, or nerve blocks. She also mentioned use of systemic agents if there is a central component and noted that multimodal treatment is often required.
Are the treatments curative or just palliative for neuropathic pain? Both, Dr. Galor said.
“The symptoms are coming from the fact that the nerves are malfunctioning, and these therapies are trying to normalize nerves. However, these treatments are not instantaneous. Normalizing nerve function can take years and a lot of patience on the part of the patient. However, most of my patients slowly get better over months to years if they stick with a treatment plan.”
Dr. Galor said she makes sure to tell patients that there is no magic bullet; therapies for neuropathic pain take time.
“People who have reasonable expectations buy in and give us the time we need to try different strategies to find something that works,” she said.
In terms of what’s new, Dr. Jacobs said there has been some research on the prevalence of neuropathic pain after cataract surgery, as well as reports on diagnosing neuropathic pain, differentiating central from peripheral processes, and treatment of neuropathic pain.
Companies are looking into the treatment of ocular pain, Dr. Galor said, but there is nothing specifically approved for the treatment of neuropathic ocular pain yet. Her ideal treatment would be a topical therapy that maintains corneal sensation and the biologic function of nerves but eliminates pain.
Oxervate (cenegermin-bkbj, Dompe) is approved for neurotrophic keratitis, a condition distinct from neuropathic pain, in which a patient presents with decreased sensation and epitheliopathy but typically no pain. Dr. Galor said that nerve growth factor may help a subset of patients with neuropathic pain. However, it is not known if the same dose used for neurotrophic keratitis would improve pain in patients with a neuropathic contributor. While ophthalmologists often use products off label with success, the price tag of Oxervate means physicians can’t “play around with the medication” compared to less expensive therapies, Dr. Galor said.
In addition to targeted therapies, Dr. Galor sees a need for better diagnostics.
“We don’t have a way to test peripheral nerve function or image central nerves. It would be helpful to have such diagnostic tests and pair different therapies to specific diagnostic findings,” Dr. Galor said.
About the physicians
Anat Galor, MD
Staff Physician
Miami Veterans Affairs
Medical Center
Associate Professor of Ophthalmology
Bascom Palmer Eye Institute
Miami, Florida
Deborah Jacobs, MD, MSc
Associate Professor of Ophthalmology
Harvard Medical School
Boston, Massachusetts
References
- Venkateswaran N, et al. Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients. Am J Ophthalmol Case Rep. 2020;19:100809.
- Diel RJ, et al. Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections. Br J Ophthalmol. 2019;103:1024–1029.
- Small LR, et al. Oral gabapentinoids and nerve blocks for the treatment of chronic ocular pain. Eye Contact Lens. 2020;46:174–181.
Relevant disclosures
Galor: Allergan, Dompe, Novaliq, Novartis, Oculis, Oyster Point Pharma, Shire
Jacobs: None
Contact
Galor: AGalor@med.miami.edu
Jacobs: Deborah_Jacobs@MEEI.HARVARD.EDU
