Neuropathic Ocular Pain

Educational Objectives

The goal of this program is to improve the management of neuropathic ocular pain. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate dry eye from other causes of ocular surface pain.
2. Identify signs of damage to the corneal nerves and tissues.
3. Perform diagnostic tests to distinguish between peripheral and central sources of neuropathic ocular pain.
4. Develop multidisciplinary strategies for management of ocular pain.

Summary

Relationship between symptoms and clinical metrics of dry eye: population-based studies found that many patients who reported symptoms of dry eye did not exhibit signs of aqueous tear deficiency, interpalpebral staining, or a low tear lake; many metrics, eg, tear evaporation, eyelid margin disease, tear osmolarity, and ocular surface inflammation, did not correlate with symptoms of dry eye; dry eye can be divided into signs and symptoms; symptoms can be further subdivided into those related to pain or vision

Corneal innervation: the cornea contains nerves that detect touch (mechanoreceptors), evaporation (thermoreceptors), acidity, and inflammation; polymodal receptors sense multiple stimuli and have nerve endings containing transient receptor potential channels, which send signals to the brain when environmental changes are detected; the networks connecting the cornea to the brain are complex, and pain pathways for dryness may differ from those for burning sensations; primary order neurons connect the cornea and conjunctiva to the brainstem; secondary and tertiary neurons connect the brainstem to various areas of the cortex

Differential diagnosis: rationale — distinguish other causes of ocular surface pain from aqueous-deficient dry eye, eg, conjunctivochalasis may interfere with the temporal and medial portions of the tear lake and cause symptoms of dry eye; dynamic testing — performed by pulling up and down on the eyelid to assess laxity; eyelid or conjunctival issues can cause patients to have a sensation of dry eye, eg, spastic entropion can be detected by looking for inward rotation of the lower eyelid while patients closes their eyelids tightly; in thyroid eye disease, scleral show indicates presence of exposure keratopathy; fluorescein staining — inferior corneal staining is often observed with exposure keratopathy (as opposed to interpalpebral staining that is typically seen with aqueous-deficient dry eye); anatomic abnormalities — map-dot-fingerprint dystrophy or Salzmann nodular degeneration can also cause symptoms of dry eye; medications — many drugs used for glaucoma affect the ocular surface; the preservative (eg, benzalkonium chloride) or the drug (eg, prostaglandins) may induce ocular surface disease

Nociceptive vs neuropathic pain: aqueous deficiency, anatomic abnormalities, and toxicity are forms of nociceptive pain, whereas peripheral sensitization may occur after refractive or cataract surgery, and central sensitization may occur after traumatic brain injury (TBI) or in the setting of migraine and fibromyalgia; chronic nociceptive pain can cause peripheral nerves to become dysfunctional, which can cause central nerves to become abnormal, eg, neuropathic pain may be present even though neurotrophic keratitis causes a decrease in corneal sensation; nerve status should be evaluated in patients with dry eye, particularly in symptomatic patients presenting with healthy tear film and no corneal staining

Evaluation of corneal nerves: Belmonte aesthesiometer assesses corneal sensitivity; the mean value at which patients report sensation is 87 mL/min, but the range varies widely among individuals; the clinician should assess how the nerves interpret tear metrics (eg, tear breakup time) rather than the metrics in isolation

Causes of dry eye symptoms: most patients have a combination of ocular surface and nerve abnormalities; environmental offenders (eg, pollution) damage corneal nerves and epithelial cells, and the damaged cells generate inflammatory mediators; Belmonte found that polymodal neurons in the cornea became sensitized when stimulated with inflammatory mediators; studies found that removal of the lacrimal gland and stimulation of the trigeminal subnucleus caudalis resulted in a heightened pain response to hypertonic saline, and touching the periocular area with a feather stimulated ocular pain; this heightened sensitivity is known as secondary hyperalgesia

Assessment of nerve dysfunction: history — inquire about the start of pain symptoms (eg, after refractive surgery) and concomitant diseases (eg, migraine and fibromyalgia); study performed by the speaker showed that patients with pain outside of the eye were more likely to report dryness and eye pain than patients without pain outside of the eye, although clinical signs of dry eye were similar between the groups; results suggest that symptoms of dry eye may be a peripheral manifestation of systemic disease; symptoms — look for hyperalgesia (heightened response to pain) and allodynia (pain from a stimulus that typically is not painful); patients may report hypersensitivity to wind or extreme photosensitivity; findings on examination — pain symptoms out of proportion to clinical signs of disease are indicative of nerve abnormalities; check for corneal sensitivity (dental floss or cotton-tipped applicator may be used); anesthetic test — ask the patient to rate their eye pain, apply a drop of anesthetic, and ask the patient to rate pain again after 30 sec; dissipation of pain suggests nociceptive or peripheral neuropathic pain; persistence of pain suggests a central source of pain; assessment of secondary hyperalgesia — gently touch the skin around the eye; patient-reported pain indicates cutaneous allodynia

Assessment of the ocular surface: fluorescein — allows the clinician to assess anatomic abnormalities, tear lake, tear stability, and corneal staining; lissamine green is used for conjunctival staining; confocal microscopy — can be used to examine density and morphology of nerves; dendritic cells are indicative of inflammation; hyperreflective nerves that appear tortuous and end abruptly (microneuromas) are present with corneal neuropathic pain; however, optimal use for diagnosis of peripheral neuropathic pain requires further study, and test is less helpful for diagnosis of a central component of pain; measurement of efferent responses — describes reaction to a stimulus; includes blink rate and tear production; blood flow through conjunctival venules, thermography, and cutaneous sensitivity can be measured in a laboratory setting

Diagnosis of central neuropathic pain: wind-up phenomenon — refers to increased intensity of pain when exposed to a stimulus repeatedly; higher wind-up scores are associated with higher likelihood of a central abnormality; aftersensation — describes pain that lingers after a stimulus is removed, and presence indicates central neuropathic pain; these tests are typically administered in a research setting but can be adapted for clinical use; patients with higher levels of ocular surface pain have higher levels of wind-up and aftersensation; clinical test — rating the level of photosensitivity from 0 (no sensitivity) to 10 (extreme sensitivity) can be a screening tool for central abnormalities; speaker and colleagues found that rating of ≥2 yielded maximal sensitivity for painful aftersensations (although specificity was ≈50%)

Treatment

General approach: nociceptive sources of pain should be addressed first, and nerve dysfunction should be considered if the pain persists; pain characteristics should be evaluated; postoperative neuropathic pain — typically develops <1 mo of refractive surgery; migraine-like pain — symptoms begin spontaneously and are usually bilateral; patients tend to have personal or family history of migraine and comorbid photophobia; trauma-induced pain — includes patients who developed ocular pain after chemotherapy or TBI; atypical unilateral cases — do not fit the usual presentation of trigeminal neuralgia; patient education — clinician should communicate that long-term therapy is needed, improvement occurs slowly, and multiple modalities are often needed

Peripheral neuropathic pain: autologous serum tears or platelet-rich plasma may be used to deliver growth factors that are beneficial for the epithelium and nerves; recombinant human nerve growth factor drops are commercially available, but it is expensive, only approved for neurotrophic keratitis, and has pain as its main side effect

Central neuropathic pain

Oral neuromodulators: may be used for 1 to 3 yr to manage central neuropathic pain; dose should be increased slowly to avoid side effects and allow for ≥4 wk at a therapeutic dose to determine efficacy; gabapentin or pregabalin may be combined with a serotonin and norepinephrine reuptake inhibitor (eg, duloxetine or low-dose naltrexone); if these are ineffective, tricyclic antidepressants (eg, nortriptyline or amitriptyline) are used; topiramate may be used as third-line therapy; however, patient response to a given neuromodulator varies; response is gradual, and maximal effects of drugs are typically observed up to 1 yr

Peripheral nerve blocks: can be used to target uninvolved peripheral nerves (which are involved in pain propagation) in patients with postsurgical pain or cutaneous allodynia if oral neuromodulators alone are insufficient; injections of methylprednisolone-bupivacaine are administered in the periocular region to target the supraorbital, supratrochlear, and infraorbital nerves; duration of pain relief with a nerve block can last weeks to months; primary risks include bruising and hematoma in the area of injection

Trigeminal nerve stimulation (eg, Cefaly): approved for the treatment of migraine; contraindicated for patients with implantable devices or pacemakers; randomized placebo-controlled study found a significant reduction in ocular pain after >3 mo (but no change with <3 mo of use); anterior ethmoidal nerve stimulator (eg, TrueTear), which induced tearing and reduced pain, has been discontinued, although other companies are researching nasal sprays that induce the same effect

Botulinum toxin: approved for use in patients with chronic migraine and can be used to modulate uninjured peripheral nerves; has been shown to improve light sensitivity and symptoms of dryness, which are common in patients with chronic migraine; however, approval for off-label use is difficult to obtain; preliminary data showed reduced activation in pain pathways after injection

Tinted lenses: photophobia is a significant cause of morbidity; tinted lenses that block the light that patients are most sensitive to may provide relief; FL-41 lenses, which are helpful for migraines, TBI, and ocular pain, block wavelengths from 450 to 550 nm and can be worn indoors without dark adaptation of the retina

Autonomic nerve blocks: some pain conditions are associated with sympathetic or parasympathetic (eg, cluster headache) hyperactivation; modulation of the autonomic nervous system can be achieved by blocking sympathetic (superior cervical) and parasympathetic (sphenopalatine) ganglions; performed under fluoroscopy and may be considered in patients who do not respond to other interventions; in patients with atypical unilateral ocular pain, look for trigeminal neuralgia with vascular compression and other abnormalities (eg, meningiomas)

Emotional response to pain: pain pathways lead to the somatosensory cortex (which senses pain) and amygdala, insula, and prefrontal cortex (which are involved in the emotional response to pain); pain in the eye is wired more closely to these areas of the brain and is more likely to trigger an emotional response than pain in other areas of the body (eg, knee or back); therefore, active coping mechanisms, eg, cognitive behavioral therapy (CBT), meditation, mindfulness, and addressing the emotional component can improve pain symptoms; randomized study showed that, compared with amitriptyline alone, cognitive behavioral therapy and amitriptyline were associated with fewer migraine days in patients with chronic migraine

Readings

Belmonte C, Acosta MC, Merayo-Lloves J, et al. What causes eye pain?. Curr Ophthalmol Rep. 2015;3(2):111-121; Crane AM, Feuer W, Felix ER, et al. Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. Br J Ophthalmol. 2017 Sep;101(9):1238-1243; Crane AM, Levitt RC, Felix ER, et al. Patients with more severe symptoms of neuropathic ocular pain report more frequent and severe chronic overlapping pain conditions and psychiatric disease. Br J Ophthalmol. 2017 Feb;101(2):227-231; Diel RJ, Hwang J, Kroeger ZA, 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 Aug;103(8):1024-1029; Goyal S, Hamrah P. Understanding neuropathic corneal pain--gaps and current therapeutic approaches. Semin Ophthalmol. 2016;31(1-2):59-70; Grixti A, Sadri M, Edgar J, et al. Common ocular surface disorders in patients in intensive care units. Ocul Surf. 2012 Jan;10(1):26-42; Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014 Sep;13(9):924-935; Mecum NE, Demers D, Sullivan CE, et al. Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors. Sci Rep. 2020 Oct;10(1):17225; Meng ID, Kurose M. The role of corneal afferent neurons in regulating tears under normal and dry eye conditions. Exp Eye Res. 2013 Dec;117:79-87; Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. JAMA. 2013 Dec;310(24):2622-2630; Yoon HJ, Kim J, Yoon KC. Treatment response to gabapentin in neuropathic ocular pain associated with dry eye. J Clin Med. 2020 Nov;9(11):3765.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: In her lecture, Dr. Galor presents information related to the off-label or investigational use of a therapy, product, or device. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Galor was recorded exclusively for Audio Digest on October 11, 2021, via teleconference software, in compliance with social distancing guidelines during the COVID-19 pandemic. Audio Digest thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

OP600101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.