Introduction
Neuropathic ocular pain (NOP) in dry eye disease (DED) has hitherto remained an underdiagnosed and challenging condition to treat. The pathogenesis of NOP includes injury to the corneal nerves, leading to chronic afferent pain signaling driving neural plasticity and peripheral and central neuronal sensitization. The development of neuropathic pain occurs through changes in both peripheral and central neurons leading to allodynia and hyperalgesia. Peripheral sensitization stems mainly from the release of inflammatory cytokines during and after tissue injury and altered responsiveness of peripheral sensory neurons, whereas central sensitization results from the generation of complex genomic, signaling, neuroinflammatory and electrophysiological alterations in the central nervous system that amplify afferent pain signaling. Not infrequently, central pathogenetic processes drive painful symptoms (pain, allodynia, photophobia, neuro-behavioral manifestations), and these may be refractory to treatments targeting the peripheral tissues or nerves.
Given that NOP is complex, that it may coexist with nociceptive mechanisms, yet it includes predominantly neuropathic mechanisms, there is rarely a single treatment that entirely eliminates symptoms. While conventional therapies for DED, such as artificial or autologous serum tears (AST), antiinflammatories, or topical cyclosporine, could affect nociceptive pain by decreasing the release of cytokines and proinflammatory neuropeptides from injured nerves, they have little to no effect on centrally mediated NOP syndromes. Conventional topical treatments also appear to afford limited improvement in the morphologic status or function of corneal nerves. The advent of novel imaging modalities, including in vivo confocal microscopy (IVCM), has made it possible to obtain high resolution, noninvasive, layer by layer imaging of the corneal ultrastructure. The direct visualization of corneal nerves contributes to the evaluation of NOP and possibly to the monitoring of therapeutic response. Furthermore, recent therapeutic strategies have been targeted at reversing neuronal damage through nerve regeneration. However, peripherally targeted approaches do not address those patients with a primary central component to their symptoms. Diagnostic and therapeutic strategies that hinge upon diagnostic criteria, such as the use of specific questionnaires, the lack of response to tears, or the proparacaine challenge test that differentiates between peripheral and centralized NOP in DED have great value in guiding treatments. , NOP patients who present with persistent pain symptoms despite prior use of tears or the instillation of topical anesthetic drops, such as proparacaine hydrochloride, are more likely to have centrally mediated pain that mandates adjunctive systemic treatments.
In this respect, a multidisciplinary approach consisting of ophthalmologists’ and pain specialists’ collaboration may be helpful, as well as a multimodal approach to address both peripheral and centralized pain using topical and systemic therapies. NOP also has a significant negative impact on quality-of-life measures with regard to mood, sleep, activity, relationships, and enjoyment, highlighting the importance of adjunctive behavioral therapy, as well.
Topical Therapies for Peripheral Sensitization
If a primarily peripheral etiology for NOP in DED is suspected, i.e., pain responds to application of topical anesthetic, the treatment goal is to promote healing and regeneration of damaged nerves, to reduce any further pathological signaling via injured or sensitized nociceptors, and to prevent the development of central sensitization. This can potentially be accomplished through different nerve regenerative therapies. Further, patients with symptoms of hypersensitivity to evaporation may respond to physical shields that can act as barriers to evaporation.
Nerve Regenerative Therapies
AST eye drops are prepared from patient serum. AST contains neurotrophic growth factors including nerve growth factor (NGF) as well as transforming growth factor β (TGF- β), insulin-like growth factor-1, fibronectin, and epidermal growth factors. Several studies have described the successful use of AST in DED that may be attributed to these neuroregenerative properties. Concentrations ranging between 20% and 100% increase nerve density and tortuosity as well as epithelial healing. One recent report evaluating AST in neuropathic corneal pain from various etiologies including DED even correlated the decrease in patient pain scores with an improvement in corneal nerve density based on IVCM assessment.
It must be noted that the inflammatory microenvironment appears to significantly influence peripheral nerve degeneration. Studies using IVCM have demonstrated substantial correlation between increased numbers of dendritic cells and decreased corneal innervation. This signifies a possible corneal neuroimmune crosstalk. Some groups therefore suggest the concomitant use of low dose steroids with AST for successful nerve regeneration, the premise being that steroids would decrease the inflammatory load on the ocular surface, perhaps allowing for uninterrupted neuronal regeneration. Furthermore, steroids may further contribute to analgesia by suppressing any aberrant, ectopic peripheral electrical signaling originating in injured neuronal pathways.
Autologous platelet-rich plasma contains even higher concentrations of therapeutically relevant biological factors including NGF and epidermal growth factors than autologous serum, with reported efficacy in refractory DED. Alio et al. investigated the efficacy of a 6-week course of autologous platelet-rich plasma in 368 patients with refractory DED. 87% of individuals had subjective improvement and 76% had objective increase in corneal fluorescein staining. NOP symptoms were not specifically addressed in this study. However, these blood products are presently not FDA approved, and their use in DED remains investigational.
NGF plays an important role in the regeneration of nerves through the induction of neuronal sprouts and restoration of injured neuron function. NGF also facilitates the growth and differentiation of sensory neurons with improvement of hyperalgesia and allodynia in the animal models of NOP. Oxervate (cenegermin-bkbj) is an ophthalmic solution of human recombinant NGF that has received FDA approval for neurotrophic keratitis and is under investigation for DED treatment in the United States and Europe.
Self-Retained Cryopreserved Amniotic Membrane (CAM) has neurotrophic, antiinflammatory, and antifibrotic effects that facilitates ocular surface rehabilitation. CAM is well tolerated and affords symptom relief as well as improved staining of the ocular surface in DED. Some groups have reported encouraging preliminary results with self-retained CAM specifically in patients with NOP and rapid symptom relief. A small prospective trial of 17 subjects demonstrated the efficacy of CAM in improving corneal sensitivity and increasing corneal nerve density assessed via IVCM in DED.
Contact Lenses (Both Scleral and Silicone-Hydrogel)
When conventional topical therapies fail to afford adequate relief, patients with DED and NOP may derive benefit from trials of extended wear of silicone-hydrogel contact lenses or scleral contact lenses to accelerate corneal restoration. While the mechanisms underlying relief have not been elucidated, protection of corneal nociceptors from environmental stimuli likely plays a role. Several studies have described pain relief with therapeutic soft contact lenses in NOP secondary to ocular surface disease. Wearing soft contact lenses in patients with DED from Sjögren’s syndrome improved their OSDI scores to a greater degree than AS.
The lenses that have proven most effective at maintaining the nociceptive barrier are the fluid-filled scleral lenses such as PROSE (Prosthetic replacement of the ocular surface ecosystem, Boston Foundation for Sight). However, the potential infectious risk with prolonged use makes this less feasible as a long-term option. Further, these patients may suffer from concomitant hyperalgesia and contact lens placement on the ocular surface may exacerbate noxious stimuli in this subset. Finally, a recent study indicated that wearing PROSE long term did not promote corneal nerve regeneration when assessed by IVCM.
Investigational Therapies—Topical TRPM8 Agonism
The transient receptor potential melastatin 8 (TRPM8) cation channel is a cold-sensing receptor localized to nerve endings in the cornea and eyelid. Since TRPM8 activation can inhibit other nociceptive inputs, TRPM8 agonism may potentially relieve NOP in DED. In view of its distribution not only in the cornea but also in the eyelid, TRPM8 can be activated by the application of topical agents to the eyelid without the direct instillation of eye drops into the cornea. In a recently published pilot study of 15 patients with NOP secondary to DED who underwent topical application of a selective TRPM8 agonist, cryosim-3, to their eyelids for 1-month, significant reduction in the intensity of eye pain and an increase in quality-of-life measures were noted after 1 week of treatment and sustained at 1 month. The Schirmer and OSDI test scores were similarly improved following 1 month of therapy.
Systemic Therapies for Central and Peripheral Sensitization
NOP patients who present with persistent pain symptoms despite the instillation of topical anesthetic drops, such as proparacaine hydrochloride, may have a central pain component to their symptoms. , This in office test is thus crucial for treatment selection. Further, NOP with a prominent central contribution to symptomatology may suffer from concomitant neuropsychiatric conditions such as anxiety and depression as well as neurocognitive abnormalities that further confound therapeutic approaches. While pharmacotherapy may afford significant relief among patients with a prominent central component of NOP, evidence for this is scarce especially in the setting of DED. Further, multiple simultaneous medications may be necessary for symptom control as has been found in other studies for nonocular neuropathic pain. Yet, there is a variety of systemic therapies that may have some benefit for the treatment of NOP which will be discussed below.
Gabapentinoids
Gabapentin and pregabalin bind to the α2 delta subunit of voltage-dependent peripheral and central calcium channels and decrease neuronal calcium influx thus reducing the release of excitatory neurotransmitters and stabilizing central nervous system neurons. Gabapentin is well established as the first-line therapy for diabetic neuropathy and has been investigated for other systemic neuropathic pain conditions. Gabapentin is typically initiated at a daily dose of 300 mg for neuropathic pain disorders with instructions to subsequently titrate to a recommended dose of 1200 mg daily with a maximum daily dose of 3600 mg (1200 mg three times daily or 900 mg four times a day). This gradual dose titration can often offset the most common side effects including dizziness, sedation, and somnolence. Gabapentin as well as pregabalin decrease postoperative pain after eyelid surgery and photorefractive keratectomy. Both of these agents are labeled for the treatment of postherpetic neuralgia. On the other hand, more recent literature describes potentially limited benefit for pregabalin in NOP and other dry eye symptoms after Laser-Assisted in Situ Keratomileusis (LASIK).
One might conclude that together, there is support for the use of these systemic agents more broadly in neuropathic pain syndromes involving the eye. However, there are limited studies examining its utility in NOP secondary to DED. In a case series of eight patients, six showed complete or partial resolution of NOP on oral gabapentinoids, while the remainder showed no improvement. Ongun et al. evaluated a cohort of 72 patients with ocular pain from DED in whom adjunctive gabapentin was associated with a decrease in pain scores as well as improvements in OSDI score and Schirmer’s test results. Notably, the study design incorporated a dosing schedule below the recommended dose of gabapentin 1200 mg daily. Relatively high doses of gabapentinoids have also been used anecdotally with success to treat DED and ocular pain unresponsive to conventional therapies at (gabapentin 900–1200 mg 3 times daily; pregabalin 150 mg twice day). In case higher doses of gabapentinoids have to be used for treating intractable NOP, caution is advised in patients with renal dysfunction, in the elderly, or in those prone to imbalance and falls.
Tricyclic Antidepressants
The International Association for the Study of Pain (IASP) advises secondary amine tricyclic antidepressants (TCAs) such as nortriptyline, desipramine, or amitriptyline for the first-line treatment of neuropathic pain. TCAs bind to serotonin and noradrenaline transporters and inhibit the reuptake of these endogenously analgesic neurotransmitters resulting in their increased levels in the synaptic cleft. Analgesia is thus conferred by enhancement of central endogenous neuroinhibitory circuits. In addition to inhibition of endogenous analgesic neurotransmitter reuptake, TCAs have several other effects that may contribute to their efficacy in neuropathic pain, such as N-methyl- d -aspartate (NMDA) antagonism and sodium channel blockade. TCAs are initially prescribed at a nightly dose of 10–25 mg and titrated by 10–25 mg every week depending on response and tolerance, this can be every 3–7 days up to a maximum of 150 mg nightly. No data are presently available on the off-label use of these agents in DED, but they may be considered for ocular pain concomitant with a more generalized pain syndrome, e.g., fibromyalgia. In a retrospective study of 30 patients with refractory centralized NOP treated with nortriptyline (10–100 mg), 17 (56.7%) of whom had underlying DED, 24 (80%) individuals reported an improvement in pain scores at 4 weeks as compared with baseline. Specifically, >50% improvement was reported in 12 (40%) patients, 30%–49% improvement in 6 (20%) patients, and 1%–29% improvement in 6 (20%) patients. Yet, since these agents possess anticholinergic properties, caution is advised in cases of actual ocular dryness because this may be intensified, as well as in patients with coexisting disease such as glaucoma, urinary retention, cardiac disease, or seizures.
Opioids
Opioids such as tramadol may provide some relief in the management of intractable neuropathic pain, whenever other treatments have failed, but they are often limited by the development of tolerance and their side effects including addiction, dependence, constipation, and potentially respiratory depression and death. Further, these systemic therapies should be utilized in conjunction with a pain specialist who is familiar with their therapeutic effects and drug monitoring. If necessary, tramadol, a weak opioid, might be considered, but should be noted, that it has not been investigated for ocular pain, and therefore its role in management of DED with NOP is unknown. Tramadol acts as a μ-opioid receptor agonist and monoamine reuptake inhibitor. The starting dose of tramadol is 50–100 mg daily in neuropathic pain with gradual titration to a maximal dose 400 mg daily. Once again, caution should be used with this medication class due to its adverse effects profile. Yet, overall, opioids should be rather avoided in this setting due to their propensity for several unwanted effects, including but not limited to the generation of opioid induced hyperalgesia, a state of aberrant enhanced responsiveness to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain.
Low-Dose Naltrexone (LDN) is a μ- and δ-opioid receptor antagonist, and thereby upregulates opioid signaling and the release of endogenous endorphins. LDN also acts as an antagonist for toll-like receptor 4 (TLR4) that has been linked with neuropathic pain. At low doses (1.5–4.5 mg daily), naltrexone exerts an antineuroinflammatory effect, reducing the effect of proinflammatory cytokines. LDN has been investigated for efficacy in fibromyalgia pain syndrome and refractory neuropathic pain syndromes such as diabetic neuropathy. , One recently published report demonstrated for the first time that LDN is effective and safe in refractory NOP, based on a nearly 50% improvement in the mean pain score in a cohort of 39 patients of whom 20 (66.7%) had underlying DED. Notably, all patients had a central pain component with incomplete symptom relief after topical anesthetic drops and the improvement in pain was found even in the presence of other concomitant systemic medications.
Anticonvulsants Other than Gabapentinoids
In addition to the above systemic pharmacotherapies, other agents have been used to address chronic neuropathic pain that have not been previously investigated in chronic NOP but may be beneficial in this regard. These include a variety of antiepileptics (e.g., carbamazepine, oxcarbazepine, topiramate) that act via inhibition of sodium channels or other neuroexcitatory suppressant actions. Carbamazepine, for example, is an anticonvulsant that has been used successfully for relief in trigeminal neuralgia, and by extrapolation may have a potential role in managing NOP. The starting daily dose is 200 mg and gradually titrated on a weekly basis. The typical effective dose range is 800–1600 mg divided in two to four daily doses.
Serotonin-Norepinephrine Reuptake Inhibitors
Serotonin-norepinephrine reuptake inhibitors such as duloxetine and venlafaxine have dual mechanisms of action with both central analgesic as well as antidepressant properties. These agents have been extensively studied for systemic neuropathic pain and duloxetine has FDA approval for the management of diabetic neuropathy. A metaanalysis on systemic pharmacotherapy for neuropathic pain in adults included nine studies investigating duloxetine. Seven of these studies showed encouraging results at daily doses of 20–120 mg with the final recommendation showing strong evidence for its use for neuropathic pain.
Combination Therapies
The initial drug selection is guided by several factors, such as prior therapeutic trials, coexisting conditions (fibromyalgia, other painful conditions, depression), and specific side effect profile of each individual agent in the context of coexisting disease (such as renal insufficiency that may impair the clearance of gabapentinoids, or glaucoma, urinary retention, cardiac disease, or seizures, that may prevent the use of TCAs). Each therapeutic trial with a specific agent should be based on careful dose titration up to recommended maximal dose for each drug, and in case of a favorable response, maintenance for a few months and reassessment. In case of lack of response, the drug should be weaned off, and another agent from a different category may be tried. Furthermore, combination therapy is often required in refractory cases of eye pain, involving the combined use of a gabapentinoid with an analgesic antidepressant or LDN, etc.
Procedural Therapies
More aggressive invasive and noninvasive nonpharmacologic and pharmacologic procedural interventions can also be employed for the treatment of NOP. Adjuvant invasive procedures should be reserved for NOP that is refractory to other topical and systemic therapies.
Transcutaneous Electrical Nerve Stimulation
Transcutaneous electrical nerve stimulation (TENS) is a noninvasive form of neuromodulation that has been used to successfully address various chronic pain conditions by delivering electrical current to peripheral nerves through cutaneous electrodes. In a recent report, 9 out of 10 patients with ocular pain reported decreased pain intensity by ∼27.4% with the use of the device for a 3-month period. In another study of 14 patients with chronic NOP secondary to various etiologies, there was a significant reduction in ocular pain scores within 5 min of treatment with a TENS device called RS‐4i Plus Sequential Stimulator (RS-4i, RS Medical, Vancouver, WA). Specifically, the intensity of ocular pain measured using the Defense and Veterans Pain Rating Scale (DVPRS, 0–10 scale) decreased by > 2 points in each eye without significant side effects. Another TENS device that may be potentially useful for NOP is called Cefaly (Cefaly US, Inc, Wilton CT). Cefaly is placed centrally in the supraorbital region and externally stimulates branches of the ophthalmic division of the trigeminal nerve (V1). This device has demonstrated efficacy in preventing migraines and it is certainly plausible that its use would benefit any associated NOP. However, investigations are yet to quantify its effect in this setting. TENS is contraindicated in pregnancy, patients with epilepsy, and those with implanted devices such as pacemakers and defibrillators.
Intranasal Electrical Nerve Stimulation
A noninvasive intranasal neurostimulation device called TrueTear (Allergan, San Diego, CA, USA) was recently approved in individuals with DED for augmenting tear production. TrueTear is a handheld device with two prongs applied in the nostrils for 30–60 s of stimulation and activation of the nasolacrimal reflex. A study of 75 patients with DED treated with one session described significantly decreased ocular pain and increased tear volume from baseline. Interestingly, the improvements in ocular pain and tear volume were not directly correlated and those patients with low to moderate pain scores had the greatest degree of symptom reduction.
Periorbital Nerve Blocks
The analgesic effect of nerve blocks in NOP derives from the targeting of afferent pain signals from sensory nerves innervating the cornea or adjacent tissues such as the fornix or conjunctiva, or from modulating sympathetic and/or parasympathetic autonomic neural pathways that contribute to neuronal sensitization. Not only nerves directly subjected to injury but uninjured nerves, adjacent to the injured ones have been shown to promote neuropathic pain and this may apply to NOP, as well. Ocular and periorbital neural pathways (supraorbital, infraorbital, supratrochlear, and infratrochlear nerves) anatomically converge at the spinal trigeminal nucleus and integrated neural input leads to the perception of ocular pain. Thus, the blockade of periorbital nerves adjacent to the injured corneal nerves may suppress ectopic firing and decrease nociceptive signals to the spinal trigeminal level. This would translate into overall decreased perception of NOP. In a case series of 11 patients treated with periorbital nerve blocks for ocular pain from various etiologies, pain relief lasting up to 7 months was reported in 7 cases. Furthermore, sympathetic efferent blockade (by superior cervical ganglion blocks) or parasympathetic blocks (such as sphenopalatine ganglion blocks) depending on unique dichotomous clinical subcategorization of patients may be beneficial in NOP as in other oculo-facial pains.
Botulinum Toxin Type a (BoNT-A/Botox)
Botulinum toxin type A (BoNT-A/Botox) is approved for the treatment of chronic migraines refractory to prophylactic medications. Botox modulates pain through the inhibition of inflammatory mediator release such as calcitonin gene-related peptide (CGRP). In a retrospective study of 91 patients with chronic migraines who received Botox injections, there was significant improvement in not only migraine pain but also dry eye symptoms and photophobia. Symptomatic improvement was independent of an associated improvement in the baseline tear volume, implicating other factors in this effect. This has prompted the use of Botox for suspected NOP alone without chronic migraines. In this preliminary investigation of six patients with severe DED and NOP, periocular Botox injection significantly reduced mean scores for ocular discomfort (0–5 scale) from 4.67 to 2.83 at 1 month. Anti-CGRP agents, such as erenumab, galcanezumab, and fremanezumab, may have a similar application in NOP via similar mechanisms but there are no available data in this regard.
Intrathecal Targeted Drug Delivery
The placement of a high cervical intrathecal pump for the delivery of bupivacaine and low dose fentanyl has been described for recalcitrant NOP in post-LASIK cases. The invasive nature of the intervention and potential for complications precludes routine application and should be reserved only after exhaustion of all other options.
Complementary Therapies
For patients who continue to describe inadequate pain relief despite multimodal treatments with one or more of the above, the use of complementary therapies may afford some relief and/or have a pharmacotherapy sparing effect in many patients.
Omega-3 Fatty Acid Supplementation
Nutritional strategies such as an increased omega-3:omega-6 fatty acid ratio regulates systemic inflammation and is being investigated in chronic pain. While omega-3 fatty acids were effective at decreasing symptoms in a case series of neuropathic pain , there was no effect on ocular pain in a randomized controlled study. Omega-3 fatty acid supplementation has further been reported to increase tear film break-up time and improve results of Schirmer’s test in clinical trials at doses of 1 g 2 to 3 times a day. This may help to decrease associated NOP in DED.
Vitamin B12 Supplementation
Vitamin B12 supplementation has been used to manage neuropathic and postsurgical pain. In vivo studies indicate that vitamin B mediates its analgesic effects either by increasing serotonin levels in the brain or the activation of opioid receptors. It was recently reported that vitamin B12/hyaluronic acid eye drops alleviated DED by attenuating inflammation and oxidative stress. There is also evidence that vitamin B12 improves corneal reinnervation and reepithelization following injury.
Acupuncture
Acupuncture stimulates the production of endogenous opioids as well as the gene expression of various neuropeptides and has been used for the adjunctive treatment of various neuropathic pain conditions. One prospective randomized study recently investigated acupuncture for the treatment of DED. The active treatment group ( n = 24) demonstrated significant improvements in the OSDI score from baseline of 34 ± 17 to 19 ± 17 at 1 week ( P < .01) and 16 ± 12 at 6 months ( P < .01). The sham group ( n = 25) also showed improvement although to a lesser degree, with a decrease from baseline OSDI of 36 ± 20 to 24 ± 22 at 1 week, and 25 ± 18 at 6 months.
Cognitive Behavioral Therapy
Cognitive behavioral therapy (CBT) has also been shown to be efficacious in chronic pain syndromes but has not been studied specifically for DED or ocular pain. Patients with chronic ocular pain appear to have underlying dysfunctional coping mechanisms and CBT may therefore be beneficial at enabling them to cope with these psychological sequelae of their chronic pain. While randomized controlled trials are necessary in the context of chronic NOP, this approach may be implemented safely with the goal of mood regulation and improved overall quality of life.
Investigational Therapies—Endocannabinoid System Modulation
The endocannabinoid system is ubiquitous throughout the body including ocular tissues; it is a current target in the treatment of various pathophysiologic processes characterized by ocular pain, inflammation, and nerve damage. The activation of the cannabinoid type 1 receptor contributes to central and peripheral analgesia, whereas modulating the cannabinoid type 2 receptor has immunomodulatory potential. Novel strategies of drug development and even drug delivery such as the topical administration of cannabinoids in the eye are being investigated.
Conclusion
Despite progress in elucidating the underlying mechanism of NOP in DED, the management of these patients remains a significant challenge in clinical practice. No single treatment will likely be effective and personalized multimodal therapy will be necessary to address the complex mechanisms underlying this disease.
References
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