Understanding the Neurobiology and Pain Pathways of DED

Dry eye disease (DED), as defined by the Tear Film & Ocular Surface Society Dry Eye WorkShop II, is a multifactorial disorder of the ocular surface characterized by a disruption in tear film homeostasis, contributing to ocular symptoms of “tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities.”¹ As the cornea is the most densely innervated tissue in the body, pain is a common symptom associated with DED. With neurobiology and pain pathways playing significant roles in the pathogenesis of DED, understanding how nerve signaling contributes to pain associated with DED can pave the way for better-targeted therapies.

NEURONAL INNERVATION TO THE CORNEA

The cornea is responsible for sensory feedback that contributes to reflexive tearing, blinking, and restorative functions to promote corneal epithelial growth and ocular surface immunomodulation. The corneal nociceptors, trigeminal ganglion, thalamus, and somatosensory cortex in the cerebrum, with conjugation of cranial nerve VII, create the corneal neural pathway and collaborate in a feedback loop to maintain ocular homeostasis.²

The sensory corneal nerves arise from the trigeminal ganglion, specifically the ophthalmic division of cranial nerve V (V1). The long ciliary and nasociliary nerves directly innervate the cornea, forming a radial plexus known as the sub-basal nerve plexus, which is heavily branched. Each terminal nerve has a large receptive field that decreases the cornea’s ability to localize stimuli, but increases sensitization.³ This is consistent for other divisions (V2, V3) of CN V, which innervate the skin and viscera adjacent to the eye. As afferent signaling converges from V1, V2, and V3, referred pain can result, which may contribute to sign versus symptom inconsistency in patients with DED.²

The sensory corneal nerves, including mechano-nociceptors and polymodal nociceptors, are responsible for the transmission of discomfort and pain secondary to mechanical or chemical trauma to the cornea and are located on the same nerve ending, a terminal branch of V1. Thermoreceptors, the third sensory corneal nerve type, are constantly discharged by the influence of background temperature and tear film evaporation.⁴ Polymodal nociceptors are the most prevalent of the corneal nerves and are activated by mechanical, chemical, or acidic irritants. Because polymodal nerves can either be classified as C type (slow conducting) or A delta type axons (myelinated, fast conducting), they perceive immediate fast and/or enduring dull pain. Endogenously, they can be activated by inflammatory mediators secreted by damaged cells.⁵ When polymodal nerves respond to external stimuli, they increase tear production and stimulate the blinking reflex and lacrimation via CN VII. This interconnecting innervation of the ocular surface and the lacrimal gland creates the lacrimal functional unit.⁶ Together with the lacrimal gland, the corneal sensory nerves are essential in maintaining a clear epithelium to prevent ocular irritation, pain, and blurred vision.

Corneal nerves can release neurotransmitters, including substance P (SP), calcitonin gene-related peptide, and neuropeptide Y, which are responsible for the transmission of pain and healing. SP is a neuropeptide integral in the promotion of re-epithelialization after inflammation; when released, it increases epithelial proliferation through keratocyte migration and secretes insulin-like growth factor 1 and epidermal growth factor to promote healing.⁶ SP acts as a pro- and antiinflammatory mediator to fight neurogenic inflammation and infection. Immunoglobulin production and lymphocytic spread are stimulated by SP in innate immunity but can become dysregulated in adaptive immunity, leading to loss of immune balance. This balance disruption promotes ocular surface inflammation, which worsens DED.⁷ SP represents an interesting dichotomic substance associated with the ocular surface, both promoting and combating ocular surface dysfunction. SP analogs are being studied for therapies in neurotrophic keratitis to promote corneal healing and SP antagonists to better control abnormal inflammation.⁸

PATHOPHYSIOLOGY OF PAIN IN DED

Pain can be classified into two different categories: nociceptive or neuropathic. Nociceptive pain occurs as a response to noxious stimuli such as heat, pressure, or chemicals and is typically localized to the site of insult.¹ Nociceptive pain is often acute, resolves with analgesics, and subsides in the absence of noxious stimuli. Neuropathic pain is generally associated with chronic pain and occurs due to damage to the somatosensory nervous system. Neuropathic pain can occur without noxious stimuli, thus lacking biologic value.²

In DED, lack of tear homeostasis leads to inflammation and overstimulation of the corneal nerves. This inflammation heightens the sensitivity of corneal polymodal and mechano-nociceptor nerve endings and causes over-activation of cold thermoreceptors, resulting in symptoms of dryness and pain.¹ Chronic inflammation and subsequent nerve injury changes the gene expression of ion channels and receptors within the trigeminal ganglion and brainstem neurons. These alterations affect neurons’ excitability, connectivity, and firing patterns. The ongoing disruption of molecular, structural, and functional aspects of ocular sensory pathways can lead to neuropathic ocular pain (NOP).¹

NOP can originate from peripheral and/or central sensory neuronal dysfunction. Peripheral sensitization involves increased responsiveness of nociceptors in the cornea due to chronic inflammation or injury and can lead to a lower threshold for pain, causing hyperalgesia or allodynia. Central sensitization is characterized by increased excitability of neurons in the central nervous system. In DED, this process is driven by continuous input from sensitized peripheral nerves, resulting in anatomic and functional alterations in the central nervous system. NOP can also arise from previous herpetic eye infections, corneal surgery, or trauma. Confocal microscopy can demonstrate these morphologic changes in the sub-basal nerve plexus in the cornea of patients with NOP.²

Central neuropathic pain can also result from damage to the central somatosensory nervous system from trauma, stroke, or genetic abnormalities. Genetic differences in catechol-O-methyltransferase (COMT) have been shown to result in variable sensitivity of pain.^9,10 COMT plays a vital role in the body’s response to acute stress with mutations in COMT affecting the body’s ability to regulate epinephrine and norepinephrine.¹¹ Unsurprisingly, studies have also shown that sleep deprivation, stress, depression, and anxiety can also play a role in the development of neuropathic pain.^10,12

Neuropathic pain should be considered in patients complaining of ocular pain and discomfort out of proportion to their clinical signs of ocular surface damage. Additionally, in patients whose dryness or ocular surface pain does not resolve with proparacaine or other local analgesics, neuropathic pain may be the culprit.

THERAPEUTIC IMPLICATIONS

Understanding the role of inflammation in nerve sensitization underscores the importance of antiinflammatory treatment. Neuroinflammation involves the activation of immune cells within the nervous system, releasing proinflammatory cytokines that exacerbate pain.¹³ Persistent inflammation in DED can trigger neuroinflammatory responses, further contributing to neuropathic pain. Corticosteroids, cyclosporine ophthalmic solution 0.09% (Cequa, Sun Ophthalmics), and lifitegrast ophthalmic solution 5% (Xiidra, Bausch + Lomb) are examples of treatment options used to reduce ocular surface inflammation and mitigate nerve sensitization.^2,14 Autologous serum eye drops, rich in growth factors and antiinflammatory components, promote healing and provide trophic support to damaged corneal nerves and are best used for peripheral NOP.² Central sensitization can be targeted through modulating abnormal nerve signaling. Some medications effective in reducing central sensitization include gabapentin, pregabalin, and duloxetine.²

Recently, neurostimulation has emerged as a promising method to boost the production of all basal tear components by targeting the nerves involved in tear production. This can be achieved through various forms of stimulation, such as chemical, electrical, or magnetic. Research indicates that neurostimulation can effectively incite the lacrimal glands, goblet cells, and meibomian glands, leading to improvements in both the symptoms and clinical signs of DED by enhancing basal tear production and tear volume.¹⁵

Several options, including transcranial magnetic stimulation, ocular transcutaneous electrical stimulation, and neuromodulation techniques, such as scrambler therapy and cutaneous nerve blocks, may help improve neural function and relieve corneal neuropathic pain.¹⁶ Additionally, periocular injections of botulinum toxin A have shown promise in subjectively reducing the severity of NOP by targeting both central and peripheral sensitization.^17,18 Other studies have reported that acupuncture can also reduce NOP, although further research is required to elucidate its efficacy and best treatment methods overall.^17,19

Advanced diagnostic tools, such as in vivo confocal microscopy and corneal esthesiometry, can enhance the detection of nerve damage and sensitization in DED.^20-22 Broader use of these tools may allow for more accurate diagnosis and tailored treatment plans.

THE MORE WE KNOW, THE BETTER WE CAN TREAT

The neurobiology and pain pathways in DED play a crucial role in the pathogenesis and symptomatology of the condition. By elucidating the mechanisms of nerve signaling and sensitization, we can develop better-targeted therapies that address the underlying causes of pain in DED.