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Peer Review | Jul/Aug '16

Pain Without Stain Is Just That: a Pain

Every eye doctor has encountered that patient: the one with debilitating symptoms, minimal signs of disease, and no response to the less-than-adequate dry eye treatments used routinely. Dry eye disease (DED) is one of the most frequently diagnosed ophthalmic disorders, and its incidence is on the rise.

Recently, there has been a paradigm shift in the way in which this routine diagnosis is understood. In the past, the characteristic “dry eye” sensation of this disorder was considered to be solely related to tear film dysfunction and ocular surface compromise. Now, the data implicate neuropathologic changes as a major contributor.1 The neuropathic pain model builds off the historic categorization of aqueous-deficient DED versus evaporative DED but takes it one step further2; it postulates that the initial insult due to tear system dysfunction can, over a period of time, cause remodeling of the neural sensory circuits, innervating the eye so that sensation of dry eye persists despite otherwise standard management of the disorder.3 This shift in describing certain DED patients as having more of a chronic neuropathic pain disorder has, in turn, provided us with new avenues to diagnose and treat these patients adequately. Some even propose calling the condition burning eye syndrome (BES).4

Pain sensation in the eye is mediated by sensory innervation from the ophthalmic division of the trigeminal nerve. Mechanical, thermal, or chemical insults, as well as an inadequate tear film, can activate nociceptive nerve cells, causing eye pain.1 Although activation of this pathway is partly a natural response to try to protect the eye from damage, the inflammatory component can ultimately lead to pathology. Chronic insults from DED can cause peripheral sensitization by lowering the threshold for activation of corneal pain fibers along with increased responsiveness of nociceptors to non-noxious stimuli.2 In the case of neuropathic DED, the chronic inflammatory remodeling of tissues and neural circuits is now thought to cause maladaptive sensitization of corneal nerve endings, resulting in hyperalgesia.2 Over time, peripheral sensitization can lead to increased central sensitization, which, in turn, leads to heightened awareness of pain.


The diagnosis of DED has historically focused on inspecting either the integrity of the patient’s ocular surface or tears. I (TKA) now start the examination in the waiting room by having the patient fill out an Ocular Surface Disease Index (OSDI) questionnaire. Alternative options include the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire5 or the Dry Eyes Questionnaire-5 (DEQ-5), to name a couple. Having patients complete the questionnaire not only standardizes their complaints, making the disease easier to categorize, but also attempts to quantify their quality of life.

Certain point-of-care tools, such as InflammaDry (Rapid Pathogen Screening), require that no eye drops be instilled before the test is performed. Thus, it is important to educate your entire staff to schedule DED patients with special annotation so that your technicians perform all of the necessary tests in the proper stepwise approach. Before any manipulation is done to the ocular surface, I typically order an InflammaDry, followed by Schirmer and tear osmolarity testing.


After quickly reviewing the patient’s history to rule out an organic cause of his or her symptoms, I review the questionnaire and pay particular attention to complaints of hyperalgesia, dysesthesia, and allodynia, which all suggest a neuropathic origin. Typically, the point-of-care tests will be normal, or only the InflammaDry may be positive. Review of tests is followed by a thorough physical exam, paying close attention to the eyelids—with the snapback test looking at laxity and floppiness—meibomian gland expressibility, quantity and quality, eyelashes, corneal and conjunctival staining, tear break-up time, and tear meniscus. Often, patients with a large neuropathic component present with this “pain without stain,” and most of the above listed details will be within normal range. Another quick tool for the diagnosis of neuropathic DED is instillation of a drop of topical anesthetic onto the ocular surface; patients with a peripheral sensitization will note significant resolution of symptoms with just one drop.


Treatment of this disorder has classically been focused around alleviating the “dry” component of the “dry eye” sensation by lubricating the surface. In addition to artificial tears, therapy consists of lifestyle changes, improved lid hygiene, omega-3 supplementation, oral MMP-9 inhibition with doxycycline, and punctal occlusion.6 Although I always start with a few of these therapies, often these treatments do not work on patients with neuropathic pain because of their aberrant circuitry. After the initial conservative measures, I will start serum tears four to six times a day. The thought is the nutrients and growth factors in the serum soothe the nerves providing relief and some desensitization. Thus far, data suggest that serum tears only work as long as one is using the drops; however, our ability to visualize and monitor changes in corneal nerves is improving day by day, and this will deepen our knowledge of which changes are temporary and which ones are more permanent.

In addition to serum tears, adding on an anti-inflammatory with either a temporary mild steroid such as fluormethalone or prednisolone or a more permanent cyclosporine or tacrolimus drop can also be effective. If there is a strong inflammatory component suggested by the InflammaDry, I will start 0.5% to 1% cyclosporine, bridged by a month of fluormethalone, as the cyclosporine eye drop emulsion can be irritating to the surface. It will be interesting to see how Xiidra (Shire), the latest FDA-approved medication for DED, affects patients with BES. If the patient has been compliant with all the variations in eye drops and is still symptomatic, contact lenses, either soft or scleral/PROSE can be tried.

Finally, systemic pharmacotherapy with tricyclic antidepressants, carbamazepine, GABAergic drugs, serotonin-norepinephrine reuptake inhibitors, opioids, and class 1B sodium channel blockers can be initiated to help control pain.3 Other treatments include parenteral vitamin B12 used in conjunction with 0.05% cyclosporine eye drops and artificial tears in a patient with coincidentally low vitamin B12 levels, as described in one case report.7 Another study reports the use of bupivacaine and low-dose fentanyl for intrathecal delivery at the C1 spine level.8 Although many ophthalmologists may shy away from more aggressive methods of pain management, it is helpful to take the multidisciplinary route in the patient with refractory disease.


Ultimately, it is key to recognize and acknowledge the patient’s experience, empathize with the potential disability associated with BES or neuropathic ocular pain, and provide the myriad options now available to us. The goal is not to promise eyes that feel and see like they did when patients were in their 20s but to get to a functional state with some improvement in quality of life.

1. Belmonte C, Garcia-Hirschfeld J, Gallar J. Neurobiology of ocular pain. Prog Retinal Eye Res. 1997;16(1):117-156.

2. Kaštelan S, Tomić M, Salopek-Rabatić J, Novak B. Diagnostic procedures and management of dry eye. Biomed Res Intern. 2013;2013:309723.

3. Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100(1):128-134.

4. Kalangara JP, Galor A, Levitt RC, Felix ER, Alegret R, Sarantopoulos CD. Burning eye syndrome: do neuropathic pain mechanisms underlie chronic dry eye? Pain Med. 2016;17(4):746-755.

5. Grubbs Jr JR, Tolleson-Rinehart S, Huynh K, Davis RM. A review of quality of life measures in dry eye questionnaires. Cornea. 2014;33(2):215.

6. Mcmonnies CW. The potential role of neuropathic mechanisms in dry eye syndromes [published online ahead of print July 15, 2016]. J Optom. doi:10.1016/j.optom.2016.06.002.

7. Shetty R, Deshpande K, Ghosh A, Sethu S. Management of ocular neuropathic pain with vitamin B12 supplements: a case report. Cornea. 2015;34(10):1324-1325.

8. Hayek SM, Sweet JA, Miller JP, Sayegh RR. Successful management of corneal neuropathic pain with intrathecal targeted drug delivery. Pain Med. 2016;17(7):1302-1307.

Kinza T. Ahmad, BS
Kinza T. Ahmad, BS
  • Meharry Medical College, Nashville, Tennessee
  • Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, in Little Rock, Arkansas
Tayyeba K. Ali, MD
Tayyeba K. Ali, MD
  • Assistant Professor of Ophthalmology, Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, in Little Rock, Arkansas
  • tkali@uams.edu

Jul/Aug '16