Novel Treatments for Chronic Ocular Surface Pain

Precis

Several etiologies can contribute to ocular surface pain including nociceptive, peripheral neuropathic and central neuropathic mechanisms. Clinical clues can help identify contributors to ocular surface pain in a patient. In individuals whose pain persists despite targeting nociceptive contributors, neuropathic mechanisms should be considered and addressed using oral, topical and/or adjuvant agents.

Introduction

Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”¹ Ocular surface pain (OSP) is a nonspecific symptom that can have a tremendous impact on quality of life.² Individuals use various descriptors to characterize pain that include dryness, burning, grittiness, itching, shooting, discomfort, tenderness, and/or aching, to name a few. Oftentimes, OSP is chronic in nature, lasting >3 months, although the intensity of pain can wax and wane over time. Furthermore, OSP can occur spontaneously or be triggered by stimuli such as light, wind or temperature change.³ In the past, ocular pain has often been lumped under the umbrella term “dry eye”, as tear film abnormalities are one cause of OSP.⁴ However, it is now understood that factors beyond aqueous tear deficiency (ATD) may drive OSP and it is necessary to identify and address all potential contributors to pain. In general, contributors can be split across two broad categories: nociceptive contributors, defined as pain that arises directly from tissue damage at the level of the ocular surface and neuropathic contributors, defined as pain caused by a lesion or disease within peripheral or central nerves that connect the ocular surface to the brain.¹ Or, as is the case in many individuals, pain contributors can arise from a combination of these two entities. Given the multiple potential contributors to OSP, a standardized examination and multimodal approach is necessary. In this paper, we aim to review recent advances in the diagnosis and management of OSP, with a focus on treatments for neuropathic ocular surface pain (NOP). Of note, the pathophysiology and treatment of ocular pain due to entities such as scleritis, uveitis, or anatomic abnormalities, to name a few, are not within the scope of this paper.

Methods

The contents of this review were compiled from original articles, reviews, meta-analyses, and randomized clinical trials accessed from the PubMed database. For the nociceptive section, we searched under the term “treatment of dry eye disease” and further filtered for randomized clinical trials published within the past year. We specifically focused on treatments for nociceptive sources of pain outside the purview of anti-inflammatory therapy. This search returned 60 articles with 4 included in the review. For the neuropathic section, we used the search words “neuropathic ocular pain treatment” or “neuropathic ocular pain”. This search returned 280 articles with 26 summarized and included in the review. Studies from ClinicalTrials.gov were selected if they were ongoing and/or recruiting participants. For all searches, articles written in languages other than English were excluded.

Body

Common Sources of Nociceptive Pain

As described above, many different contributors can lead to chronic OSP. Common nociceptive causes of pain include ATD, evaporative tear deficiency, Meibomian gland dysfunction (MGD), and anatomic abnormalities (e.g., pterygium).⁵ Treatment of nociceptive pain is based on identifying and targeting the underlying cause of pain. As such, a standardized approach to the evaluation of OSP is needed to identify such causes.

Clinical Assessment of Nociceptive Pain

Detection of nociceptive sources of pain begins with a thorough medical history (Figure 1), looking for relevant co-morbidities such as auto-immune disease and sleep apnea, to name a few. Validated dry eye questionnaires, [such as Dry Eye Questionnaire-5 (DEQ-5)⁶ and Ocular Surface Disease Index (OSDI)⁷] can be used to assess for the presence and quantify the overall severity of symptoms. Pain specific questionnaires, including Numerical Rating Scales,³ the Ocular Pain Assessment Survey (OPAS),⁸ and Neuropathic Pain Symptom Inventory-Eye (NSPI-Eye), can be used to assess the intensity of pain and examine for neuropathic pain features (e.g., evoked vs. spontaneous pain).⁹ Next, the ocular examination begins from across the room with an evaluation of blink rate and efficacy, periocular skin health, and eyelid anatomy. At the slit lamp, eyelid and ocular surface health should be evaluated with the use of dyes (e.g., fluorescein and/or Lissamine green). Specific attention should be focused on conjunctival and/or corneal staining, tear stability, tear lake height, and anatomic abnormalities of the eyelid, conjunctiva, and cornea. Adjuvant tests may include InflammaDry (a qualitative assessment of ocular surface matrix metalloproteinase 9 levels, Quidel, San Diego), Schirmer test (with or without anesthesia, a measure of tear production), and infrared imaging of the Meibomian glands (looking for Meibomian gland dropout).

Figure 1.

Diagnosis and management of nociceptive causes of pain

Footnotes

DM: Diabetes Mellitus; HTN: Hypertension; PTSD: Post-traumatic stress disorder; TBUT: Tear Break Up Time.

Novel Treatments for Nociceptive Pain

Several novel treatments are being investigated that target nociceptive contributors to OSP. In ATD, anti-inflammatories are being studied with the hope that they will be more effective or better tolerated than currently available agents (e.g., cyclosporine 0.05%, cyclosporine 0.09%, lifitegrast). Various compounds being investigated in ongoing human trials include, but are not limited to, reproxalap, a reactive aldehyde species (RASP) inhibitor¹⁰ [ClinicalTrials.gov Identifier: NCT05424549, NCT05062330, NCT04735393], tanfanercept ophthalmic solution, a novel TNF-α inhibitor¹¹ [ClinicalTrials.gov Identifier: NCT05109702], and compound A197, an immunomodulatory agent [ClinicalTrials.gov Identifier: NCT05238597].

Furthermore, several agents are being investigated that target aspects of disease outside of inflammation. For example, varenicline, a selective nicotinic acetylcholine receptor (nAChR) agonist, has recently been approved as a nasal spray for the treatment of dry eye disease (DED).¹² In the nasal cavity, activation of nAChR along the branches of the trigeminal nerve stimulates tear production. In a phase 3 multicenter, randomized controlled double-masked trial of 758 individuals with DED (defined by OSDI>23, corneal staining>2 in one region or total>4, Schirmer’s with anesthesia ≤10mm that increased by ≥7mm with nasal stimulation), varenicline nasal spray (0.06mg and 0.03mg) more frequently led to a ≥10mm increase in Schirmer test scores at four weeks compared to placebo (0.06mg: 49.2%; 0.03mg: 47.3%; placebo: 27.8%, p<0.05 for all).¹³ While it is not yet known which sub-type of DED will most benefit from which therapy (anti-inflammatory vs. nasal stimulation), the expanding armamentarium of treatment options to target nociceptive components of OSP is encouraging.

MGD and eyelid abnormalities are other potential contributors to OSP. A novel treatment currently under investigation for evaporative tear deficiency associated with MGD is 100% perfluorohexyloctane (NOV03, Novaliq, Heidelberg, Germany). Perfluorohexyloctane interacts with the lipophilic component of the tear film, forming a layer at the tear film-air interface that prevents evaporation of the aqueous constituent of tears.¹⁴ A phase 2 randomized, multicenter, double-masked, saline controlled study of 336 participants with evaporative DE (OSDI≥26, tear break up time (TBUT) ≤5 seconds, Schirmer≥5mm, meibum quality score≥3, corneal staining between 4–11) evaluated the efficacy of NOV03 with two dosing regimens [(one drop in both eyes four times a day (QID) or twice a day (BID)] for eight weeks.¹⁴ Total corneal staining improved (compared to baseline) to a greater extent in the NOV03 groups compared to control at 8 weeks (Δ= −2.11, −1.78 and −0.93 for NOV03 QID, BID and saline group, respectively). Results from an ongoing phase 3 clinical trial [ClinicalTrials.gov Identifier: NCT04139798] are yet to be released, but this line of investigation again highlights the utility of targeting aspects other than inflammation when addressing ocular surface diseases, including MGD.

Common Sources of Neuropathic Pain

Neuropathic contributors have more recently been established as causes of chronic OSP.⁴ NOP can be subclassified based on the location of dysfunction (e.g., peripheral, central, mixed), the inciting injury (e.g., post-surgical, viral, traumatic, chronic ATD), and pertinent co-morbidities (e.g., migraine, fibromyalgia). In all sub-types of NOP, common features include 1) pain described as burning, with a component of photosensitivity and/or wind hyperalgesia,³ 2) subjective symptoms that are out of proportion to observable ocular surface signs,¹⁵ and 3) a failure to respond to treatments aimed at optimizing ocular surface health.¹⁶

Clinical Assessment of Neuropathic Ocular Pain

In addition to evaluating for nociceptive sources of pain, several clues can point to a neuropathic source of pain (Figure 2). First, corneal sensitivity should be evaluated with a cotton tip or dental floss [(qualitatively graded on a scale of 0 (no sensation) to 3 (increased sensation)]. Abnormalities in corneal sensitivity are one clue that neuropathic mechanisms may be contributing to pain. In the research setting, quantitative measures of sensitivity can be obtained using a Cochet-Bonnet or Belmonte esthesiometer.^{17, 18} The “anesthetic challenge” is performed to evaluate the location of abnormality. For this test, individuals are asked to rate ocular pain intensity in each eye prior to a drop of anesthetic, and then re-rate pain 30 seconds to 2 minutes after anesthetic placement. Pain that completely resolves with anesthesia suggests a nociceptive or peripheral neuropathic source. On the other hand, persistent pain with anesthesia suggests a central or non-ocular contribution to pain. The test is inconclusive if no pain is reported prior to anesthetic placement.¹⁹ In addition, the slit lamp examination can be complemented with in vivo confocal microscopy (IVCM) imaging, which allows visualization of corneal nerves and dendritic cells. As there are no built-in software to evaluate images, qualitative reductions in nerve density and the presence of hyperreflective bulbs at the terminal nerve endings (termed microneuromas) have been reported as signs that peripheral neuropathic mechanisms contribute to pain.^{20, 21}

Figure 2:

Diagnosis and management of peripheral and central neuropathic pain

Footnotes

BID: Twice a day; OU: both eyes; ASTs: Autologous serum tears; PRGF: Plasma rich in growth factors; TRPV1: Transient Receptor Potential Vanilloid-1; TRPM8: Transient Receptor Potential Melastatin 8; TNS: Trigeminal nerve stimulation; SGB: Stellate ganglion block, SPG: Sphenopalatine ganglion.

Treatment Options for Neuropathic Ocular Pain

The treatment approach for NOP first involves treating all nociceptive source of pain (Figure 3). However, if pain persists or no nociceptive sources of pain are identified, neuromodulatory approaches with eyedrops, oral medications, and/or adjuvant strategies should be considered. Topical neuromodulatory approaches are considered first-line therapies in individuals with a suspected peripheral neuropathic component to pain. There is biologic plausibility that targeting peripheral nerve abnormalities in a timely manner may help delay or prevent progression to central neuropathic pain.²² Several topical therapies have been studied in this regard.

*Figure 3:

Treatment options for nociceptive and neuropathic ocular pain

Footnotes

*This figure was created with biorender.com

Topical anti-inflammatory therapies

Shared with nociceptive pain, topical anti-inflammatory medications have also been used to target peripheral neuropathic pain as they have been shown to decrease pathological firing of peripheral nociceptors and promote healing of damaged nerves.²³ Moreover, an inflammatory response may be elicited by the interaction between immune cells (mast cells, macrophages, eosinophils lymphocytes) and sensory nerve endings responding to external stimuli.²⁴ Furthermore, nerves themselves may be a source of inflammation (e.g., neurogenic inflammation) by the excessive or prolonged release of neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY).²⁴

Currently, topical therapies such as cyclosporine A (CsA), lifitegrast and corticosteroids have been used to target inflammation. CsA is a calcineurin inhibitor that regulates T cell activation, migration, and release of inflammatory cytokines.²⁵ Its topical use has been shown to decrease corneal proinflammatory cytokines such as IL-1B, TNF-α and IL-6.²⁶ While studies are needed to evaluate its use in individuals with NOP, CsA has been found to have a beneficial effect on peripheral nerve anatomy. In a prospective study of 42 individuals with Sjögrens-related dry eye, IVCM images showed improved nerve fiber tortuosity (2.2±0.2 vs. 3.8±0.1, p<0.05) and reflectivity (2.1±0.2 vs. 3.8±0.1, p<0.05) compared to pre-treatment values.²⁷ Lifitegrast is another available anti-inflammatory that inhibits the interaction between lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), interrupting migration of dendritic cells thus mediating inflammation on the ocular surface.²⁸ However, the effect of lifitegrast on peripheral nerve anatomy/function has not been specifically studied.

Finally, topical corticosteroids are a mainstay anti-inflammatory therapy as they inhibit phospholipase A2, blocking production of cytokines, leukotrienes, prostaglandins and thromboxanes.²⁹ Corticosteroid eye drops used in conjunction with other topical therapy have been found to improve pain in individuals with a suspected peripheral neuropathic component (unremarkable ocular surface examination and IVCM with reduced corneal nerve density and microneuromas), as seen in a case of an individual with persistent pain nine months after LASIK.³⁰ The patient was initially treated with topical loteprednol, then topical fluorometholone, preservative-free artificial tears, autologous serum tears and punctal plugs, reporting improvement in OSP five months after therapy initiation.

Neurotrophic Factors

Eyedrops with neurotrophic factors promote survival and growth of neurons which help restore morphologic features by induction of neuronal sprouting.^{20, 31} It is hypothesized that long-term use of therapy (at least three months) helps reduce abnormal firing of injured peripheral nerves, thus achieving a modulatory response slowly reducing symptoms of NOP.²⁹ Several topical therapies (e.g., autologous serum tears, plasma rich in growth factors) with varying concentrations of neurotrophic factors have been proposed as treatment options for individuals with peripheral NOP. Suggested candidates for these therapies include those with persistent symptoms of pain/discomfort (secondary to ocular surgery, trauma and/or systemic autoimmune disease), refractory response to topical anti-inflammatory drops and with nerve abnormalities visualized on IVCM.

1. Autologous Serum Tears

Autologous serum tears (AST) contain several neurotrophic and epithelial growth factors, such as nerve growth factor (NGF), insulin-like growth factors, vitamin A, TGF-β which promote proliferation, differentiation, and maturation of the normal ocular surface epithelium.³² AST have been found to improve pain and nerve anatomy in individuals with peripheral NOP. In a retrospective study of 16 individuals with severe photosensitivity that was out of proportion to examination findings, 20% AST eight times a day for 3.6±2.1 months improved light sensitivity (post treatment: 1.6±1.7 vs. baseline: 8.8±1.1, p=0.02). Furthermore, improvements in nerve anatomy on IVCM were noted with increased total nerve length (post-treatment: 15451±1595μm/mm² vs. pre-treatment: 9208±1264, p<0.005) and a decreased frequency of microneuromas (post-treatment: 7.6% vs. pre-treatment: 62.5%).²⁰ ASTs have also been found to improve OSP beyond photosensitivity. One retrospective cohort study of 16 subjects with severe OSP out of proportion to examination findings that was refractory to topical therapy noted improved pain with AST 20% eight times daily for 3.8±0.5 months, (range 1–8 months) [(post-treatment: 3.1±0.3 vs. pre-treatment: 9.1±0.2, p<0.0001].³³ Post treatment IVCM nerve parameters also improved with increased density (17,351.3±1,395.6μm/mm² vs. 10,935.5±1,264.3μm/mm², p<0.0005) and decreased presence of microneuromas (6.25% vs. 100% p<0.05) compared to baseline measurements.³³ These studies suggest AST effect on pain and photosensitivity is at least in part mediated by their neuro-regenerative capacity.

2. Plasma Rich in Growth Factors

Other blood-derived products such as platelet rich plasma (PRP) and plasma rich in growth factors (PRGF) have potential in treating NOP. These eye drops are similar to ASTs but contain higher concentrations of platelet-derived factors, such as epidermal growth factor (EGF), transforming growth factor beta (TGF-β), insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF).³⁴ In vitro studies using pure-PRP have indicated that some of its constituents such as IGF-1 and PDGF are the main peptides involved in Schwann cell proliferation and migration promoting peripheral nerve regeneration.³⁵ Further research is required evaluating the effect of PRP and PRGF in individuals with NOP.

3. Recombinant Nerve Growth Factor

Recombinant human nerve growth factor (rhNGF) ophthalmic solution (20μg/mL Cenegermin) is the first drug approved by the FDA for the treatment of neurotrophic keratitis (NK).³⁶ NGF is part of the neurotrophin family, which stimulate axonal growth by activation of transcription factors that regulate gene expression.³⁶ The mechanisms of action of NGF is dependent on two receptors, tropomyosin receptor kinase A receptor (TrkA) and the p75 neurotrophic receptor (p75NTR). In physiological states, expression of NGF, TrkA and p75NTR play a critical role in corneal epithelial cell migration and differentiation.³⁶ Currently, there are no published studies evaluating the effect of rhNGF in NOP; yet studies have demonstrated its neurogenerative qualities.³⁷ A prospective, observational case series of 18 individuals with grade 2 or 3 NK were treated with Cenegermin six times daily.³⁸ After 8 weeks, epithelial defects healed in 78% of individuals and IVCM revealed increased corneal nerve fiber length particularly in the superior [post-treatment: 3.66mm/mm² (IQR: 6.63) vs. pre-treatment: 0mm/mm² (IQR 2.82), p<0.01] and temporal [post-treatment: 4.63mm/mm² (IQR: 7.26) vs. pre-treatment: 1.99mm/mm² (IQR 3.74), p=0.01] corneal quadrants. Fortunately, nerve length continued to improve at four and eight months follow up after terminating 8 weeks of therapy. Given these findings, there is interest in studying Cenegermin specifically in individuals with NOP outside the purview of NK.

Cryopreserved Amniotic Membrane

Cryopreserved amniotic membranes (CAM) possess regenerative effects as it permits the synthesis of neurotrophins, anti-inflammatory, antifibrotic and mitogenic factors which contribute to neuronal growth and maintenance.³⁹ A retrospective case series of ten eyes with peripheral NOP (diagnosed by the presence of ocular pain out of proportion to examination findings, complete resolution of pain with an anesthetic, diminished baseline corneal nerve density and presence of microneuromas on IVCM) demonstrated improved pain severity after one CAM placement (in place for 6.4±1.1 days, range 2–14 days, post-treatment: 1.9±0.6 vs. baseline: 6.3±0.8, p=0.0003). Five eyes reported discomfort to the polymethyl methacrylate (PMMA) ring, leading to CAM removal earlier than anticipated [4.0±0.7 days (range 2–6 days)]. In these subjects, despite early removal, pain severity still improved by 63.1±12.5% (post treatment: 2.4±0.9 vs. pre-treatment: 6.8±1.0, p=0.009). However, pain improvement was greater in participants who retained the CAM for the planned time (7.5±1.34 days, 76.7±8.7% improvement in pain, post-treatment: 1.4±0.5 vs. pre-treatment: 5.6±1.0). On follow up (9.3±0.8 months, range 7.6–13.8 months), only two patients reported recurrence of pain, both after six months.³⁹

IVCM was performed in four of the 10 eyes, with increased nerve density 48.8±16.5 days after CAM placement compared to baseline (21,891.3±2040.5μm/mm² vs.17,700.9±1315.7μm/mm², p=0.047). These results again support the neuroregenerative role of various topical therapies in improving pain in individuals with a suspected peripheral neuropathic component.

Novel Treatments for Peripheral Neuropathic Ocular Pain

Several novel treatments, most of which target receptors on the terminal endings of peripheral nerves, are being studied for future management of peripheral NOP. Such therapies include Transient Receptor Potential Vanilloid-1 (TRVP1) modulators, Transient Receptor Potential Melastatin 8 (TRPM8) agonists, and endogenous opioid peptide modulators.

1. Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonists

TRPV1, found on afferent peripheral nerve fibers, is a ligand-gated ion channel sensitive to heat, low pH <6.5, osmolarity changes, and inflammatory mediators (e.g., arachidonic acid metabolites). The above stimuli elicit a conformational change in the channel, increasing the probability of its opening.⁴⁰ In vivo studies using cloned TRPV1 receptors indicate that capsaicin activates TRPV1, leading to an influx of sodium and calcium ions, cell depolarization, and neuronal firing.⁴¹ Several ongoing clinical trials are evaluating capsaicin (as an 8% dermal patch or 0.075% gel) for the treatment of peripheral neuropathic pain (e.g., post-herpetic neuralgia, post-traumatic or post-surgical nerve injury) [ClinicalTrials.gov Identifier: NCT01252160] and diabetic neuropathy [ClinicalTrials.gov Identifier: NCT03113448]. The theory is that prolonged and repeated nerve activation causes “defunctionalization” of TRPV1 reducing receptor responsiveness by downregulating gene expression and depleting pro-inflammatory and pro-algesic factors (e.g., substance P).^{40, 42} However, this approach is likely not practical as an eye drop since exposure to capsaicin (commonly found in pepper spray) leads to pain, burning, tearing, blepharospasm, and/or conjunctivitis depending on the dose and duration of contact.⁴³

However, TRPV1 receptor antagonists may have benefit for individuals with OSP, and this approach has also been studied in individuals with pain states outside the eye, including postherpetic neuralgia [ClinicalTrials.gov Identifier: NCT01557010] and dental pain [ClinicalTrials.gov Identifier: NCT00986882]. In fact, TRPV1 receptor antagonists were examined as a treatment for acute post-surgical OSP, in the setting of photorefractive keratectomy (PRK). A phase 2 crossover study [ClinicalTrials.gov Identifier: NCT02961062] randomized 40 participants into two treatment sequences (group 1: vehicle followed by SAF312 and group 2: SAF312 followed by vehicle). Preliminary results show improved mean pain scores (range 0–100) on visual analog scale (VAS) six hours after PRK with SAF312 compared to vehicle compound (34.63±4.05 vs. 45.76±4.10). Currently, this compound is being studied as a potential treatment for chronic post-operative OSP with peripheral neuropathic features [ClinicalTrials.gov Identifier: NCT04630158].

TRPV1 receptor antagonists have also been used to treat OSP in the setting of tear abnormalities. Tivanisiran (formerly SYL1001) is a small interfering (siRNA) targeting and reducing TRPV1 expression.⁴⁴ Two clinical trials (SYL1011_II, n=60 and SYL1001_III, n=66) randomized individuals with ATD (OSDI 13–70, ocular pain ratings between 2–7 on VAS, corneal staining≥1, TBUT <10seconds and Schirmer’s with anesthesia <10mm) into placebo and treatment groups of different concentrations.⁴⁵ After using Tivanisiran drops (concentration 1.125% or 2.25%) for ten days, pain scores improved significantly when compared to placebo (change from baseline, ~1.75 and ~1.5 vs. ~0.8, p<0.05, respectively). Given the promising results, a larger study is ongoing [ClinicalTrials.gov Identifier: NCT05310422]. Overall, TRPV1 antagonists show potential as novel treatment options for peripheral NOP, but more data is needed from ongoing studies.

2. Transient Receptor Potential Melastatin 8 (TRPM8) Agonist

Within the transient receptor potential (TRP) cation channel family, TRPM8 is a cold-sensing receptor located on the ophthalmic branch of the trigeminal nerve.⁴⁶ This receptor is highly sensitive to temperature change and is stimulated by cooling agents such as menthol.⁴⁶ It is distributed both on the cornea and the skin of the eyelid; the latter location provides an alternative administration site to topical instillation. It is hypothesized that activation of TRPM8 can produce a soothing sensation (particularly in the setting of inflammation) by central synaptic release of glutamate, which suppresses signaling from afferent noxious nociceptive fibers.⁴⁷ A prospective open label study of 20 subjects with presumed NOP (pain refractory to conventional topical agents >3 months, discordance between symptoms and signs) were given a TRPM8 agonist [Cryosim-3 (C3) 2mg/mL] applied by wiping a gauze on the closed eyelid four times a day. Five subjects discontinued use due to ineffectiveness or drug intolerance. Fifteen subjects reported improved eye pain [26.47±11.45 vs. 30.60±12.8, p=0.009, (score range 0–60)], burning sensation (0.40±0.33 vs. 0.57±0.37, p=0.002, range (0–1, 0=never; 1=all the time) and photosensitivity (0.57±0.26 vs. 0.76±0.24, p=0.03, range (0–1, 0=never; 1=all the time) at one week post-treatment compared to baseline.⁴⁷ Interestingly, outside the eye, both TRPM8 receptor agonists and antagonists have been used to attenuate pain perception in animal models.⁴⁸ Further studies in humans with suspected peripheral NOP are needed to test their efficacy.

3. Endogenous Opioid Peptides

Another area of therapeutic interest is modulation of endogenous opioid peptides such as enkephalins, endorphins and dynorphins) as a treatment of OSP.⁴⁹ Corneal nerves release enkephalins in response to the presence of a inflammatory insult, which then bind to ocular mu and delta receptors.⁵⁰ These peptides provide a very short-lived analgesic response since they are rapidly broken down by enzymes, neprilysin neutral endopeptidase (NEP) and aminopeptidase N (APN).⁵⁰ As such, inhibiting the breakdown of these substances is one potential drug target. In a mouse model of corneal pain using an enkephalin enzyme degradation inhibitor (PL265), reduced corneal pain, measured by decreased mechanical, chemical hypersensitivity and low expression of the nerve injury marker activating transcription factor 3 was noted as compared to a control group treated with phosphate-buffered saline.^{49, 50} Further research is necessary to determine whether this compound would have relevance in humans.

Central Neuropathic Pain

The options discussed above for the treatment of peripheral NOP have a shared goal of reducing abnormal firing from peripheral nociceptive nerves. In some individuals, however, peripheral neuromodulation is not enough, and modulation of central nerves is needed to manage pain (Figures 2 and 3). Importantly, whether being applied peripheral or centrally, neuromodulation is a slow process which requires prolonged and repetitive use of therapy for at least three months, with continued improvement often seen out to 1–2 years.

Oral medications

Oral neuromodulators such as gabapentin and tricyclic antidepressants are commonly used in chronic pain conditions in which central neuropathic mechanisms play a role. These conditions, such as chronic migraine and fibromyalgia, to name a few, share mechanisms in common with NOP.⁴ Thus, it makes biological sense that oral neuromodulators have also been applied in the treatment of individuals with NOP with a suspected central component. Clues to the contribution of central mechanisms in OSP include the presence of cutaneous allodynia (pain to light touch in the periocular area) and persistent pain after topical anesthesia.

1. Alpha-2-delta (α2δ) ligands

Gabapentin (Neurontin) and pregabalin (Lyrica) are commonly used as first line therapies for treating diabetic neuropathy, post herpetic neuralgia and neuropathic pain.⁵¹ Gabapentin and pregabalin act as ligands to the α2δ subunit of voltage gated calcium channels and decrease calcium influx inhibiting release of excitatory neurotransmitters such as glutamate and norepinephrine.⁵¹ Gabapentin is typically started at 300mg daily slowly titrated to 600–900mg three times a day. Pregabalin is typically started at 75mg once nightly and titrated to 150mg twice daily. α2δ ligands have been studied in individuals with NOP. A retrospective study of 35 patients with OSP >3 months with poor response to topical therapy and a disconnect between symptoms and signs examined the effect of oral gabapentin (600 to 1200mg/day) along with topical therapy (e.g., lubricants and anti-inflammatory drops).⁵² Thirteen individuals reported improved ocular pain scores after treatment with gabapentin compared to baseline, 26.0 (21.0–35.0) vs. 38.0 (22.0–38.0), range 0–60, p=0.011, respectively.⁵² These results were supported by a retrospective study of eight individuals with ocular pain with NOP features.⁵³ All were started on a α2δ ligand therapy (300mg daily for gabapentin and 25–75mg daily for pregabalin) slowly titrated to 600–1200mg three times a day for gabapentin and 150mg twice a day for pregabalin.⁵³ Two individuals reported complete pain relief, one with 800mg of gabapentin administered three times a day and the other used 150mg of pregabalin twice daily, combined with topical and other oral medications. A total of four subjects reported significant improvement using gabapentin, one used 1200mg three times a day, another used 900mg three times a day, and the remainder two patients used gabapentin 600mg twice a day. Two individuals reported no improvement.⁵³ Randomized clinical trials are needed to further study the utility of this modality in individuals with NOP.

2. Tricyclic Antidepressants

Another category of oral neuromodulators are tricyclic antidepressants (TCA), which are divided into secondary (e.g., nortriptyline) and tertiary amines (e.g., amitriptyline). Secondary amines act by inhibiting noradrenaline reuptake while tertiary amines inhibit noradrenaline and serotonin reuptake.⁵⁴ TCA are used for management of major depressive disorder and have been used effectively as first-line agents in treatment of neuropathic pain.^{29, 54} In a retrospective study, 30 patients with NOP (defined by discordance between signs and symptoms, persistent pain after topical anesthesia) were prescribed nortriptyline starting at a dose of 10mg and escalated to 100mg based on treatment response and tolerability.⁵⁵ All patients were using other topical (e.g. steroids, ASTs, anti-inflammatory therapies) and/or oral medications (e.g. α2δ ligands, low dose naltrexone, to name a few) along with nortriptyline. Twelve individuals (40%) reported a 50% improvement in pain, six (20.0%) a 30–49% improvement, six (20.0%) a 1–29% improvement, four (13.3%) no improvement, and two (6.7%) increased pain after an average of 10.5±9.1 months (range 1–35 months).⁵⁵ Results from these studies suggest that medications used for the treatment of neuropathic pain outside the eye can be repurposed to treat NOP, yet further research is required to understand the independent contribution of these agents to the treatment of OSP.

3. Naltrexone

Low-dose naltrexone (LDN) is an opioid receptor antagonist (μ and δ) which is thought to cause upregulation of opioid signaling increasing the production of endogenous endorphins producing an analgesic effect.⁵⁶ LDN also has anti-inflammatory qualities as it inhibits toll-like receptor 4 therefore reducing neurotoxicity and inflammation.⁵⁷ LDN (1.5–4.5mg) has been used an off-label treatment in fibromyalgia,⁵⁸ complex regional pain syndrome (CRPS)⁵⁹ and refractory painful diabetic neuropathy.⁶⁰ A retrospective study of 59 patients with central NOP (photosensitivity, minimal clinical signs, persistent pain after anesthesia) were treated with oral LDN (starting dose 1.5mg, escalated to 4.5mg) every night for a least four weeks. Participants continued with topical therapy and in some cases oral therapy with α2δ ligands and antidepressants (tricyclic and/or selective serotonin reuptake inhibitors).⁵⁶ Pain improvement was noted when comparing the last and first visit (49% improvement) while using treatment for 14.87±11.25 months.⁵⁶ However, prospective studies are needed to validate these findings and test the isolated effect of LDN.

Adjuvant therapy

Adjuvant agents are often used both in conjunction with and in individuals with intolerance to oral therapy. Transcutaneous electrical nerve stimulation (TENS) and botulinum toxin A (Botox) are two such adjuvant therapies often used in migraine that have been applied to NOP.⁶¹ In addition, periocular nerve blocks, often used to treat individuals with neuralgia, are another adjuvant treatment option applied to individuals with NOP.

1. Transcutaneous Electrical Nerve Stimulation (TENS).

TENS has been used to treat several painful conditions including migraine,⁶² diabetic neuropathy,⁶³ and fibromyalgia.⁶⁴ It is hypothesized that the effect of TENS occurs due to the Gate Control Theory⁶⁵ which implies inhibition of peripheral nociceptors and ascending central pathways. Others have attributed its effect to modulation of descending pain pathways. Studies have documented the effect of TENS in individuals with NOP. In one study, ten individuals with chronic ocular pain with suspected NOP (incomplete response to topical therapy, persistent pain after anesthesia) were given a TENS unit for home use (RS Medical RS-4i Plus Sequential Stimulator unit, Vancouver, Washington).⁶⁶ Participants placed two pairs of electrodes bilaterally on the forehead and at each temple. Subjects used the device for 30-minute session up to three times daily at an amplitude of their choice (manually determined by increasing the electrical signal until the point of pain and then decreasing it to one level below). After a mean follow up of 6.6±3.6 months, ocular pain (0–10 scale) decreased by 27.4% (p=0.02) when compared to baseline scores.⁶⁶ Cefaly^® (Cefaly Technology, Seraing, Liege, Belgium), another device specifically developed as a trigeminal nerve stimulator (TNS) is a FDA-cleared device used for the abortive and prophylactic treatment of migraines.⁶² In a retrospective study of 18 subjects with suspected NOP (incomplete response to topical therapy, persistent pain after anesthesia, discordance between symptoms and signs, photosensitivity), subjects were given Cefaly^® for home use and instructed to place the electrode on their forehead and complete a nightly 20-minute TNS session at least three times a week for six months.⁶⁷ Over time, a gradual reduction of pain was noted, with the difference becoming significant ~3 months (pain intensity at six months and baseline: 4.3±3.0 vs. 6.2±2.1, p < 0.01), burning sensation (2.87±3.42 vs. 6.2±2.3, p < 0.01), light sensitivity (4.6±3.1 vs. 7.2±2.5, p < 0.01) and wind sensitivity (4.3±3.1 vs. 6.3±2.7, p<0.01).⁶⁷ There are other TENS modalities (e.g., Scrambler therapy) that have been reported to have beneficial effects in cancer pain, post-surgical pain, postherpetic neuralgia (PHN), and spinal canal stenosis.⁶⁸ As such, randomized trials using different TENS modalities, in isolation and as an adjunctive therapy for NOP are needed to further evaluate the efficacy of electrical neuromodulation in NOP.

2. Botulinum Toxin A

Botulinum toxin type A (BoNT-A) is approved for use in individuals with chronic migraine⁶⁹ and is speculated to modulate pain by inhibiting the release of calcitonin gene-related peptide (CGRP) which sensitizes nociceptors activating pain fibers.⁶⁹ Chronic migraines are usually treated with injections in 30–40 sites around the head and neck for a total of 155–195 units given at ~3-month intervals.⁷⁰ The impact of BoNT-A on photosensitivity and dryness intensity has also been examined. One cross-sectional retrospective study evaluated the effect of BoNT-A on ocular symptoms in individuals with chronic migraines (n=117).⁷⁰ Photosensitivity scores after receiving BoNT-A decreased by a mean of 2.64±2.56 (95% CI −3.18 to −2.11, range 0–10, p<0.001) and dryness scores by a mean of 0.72±2.11 (95% CI −1.18 to −0.25, range 0–10, p=0.003) over an average of 64.2±54.2 days since the last injection received.⁷⁰ A modified BoNT-A protocol (35 units applied at 7 sites: procerus, corrugator, and frontalis muscles) was also applied to individuals with suspected NOP without a history of migraine.⁷¹ In a case series of four subjects with severe photosensitivity and other features of NOP (symptoms out of proportion to signs, poor response to topical therapy), the frequency and severity of photosensitivity (3.25±0.4 from 4.8±0.4, range 0–5) and eye discomfort (2.25±1.0 from 4.5±0.6, range 0–5) improved one month after BoNT-A. Interestingly, the improved symptoms occurred without notable changes in ocular surface parameters, indicating that pain was not being driven by tear and anatomic abnormalities in this population.⁷¹ Other agents that block CGRP such as erenumab, eptinezumab, galcanezumab, fremanezumab⁷² may also have a beneficial effect on NOP, but this approach remains to be tested.

3. Periocular nerve blocks

Periocular nerve blocks have also been evaluated in NOP, especially in individuals with refractory response to oral medications and/or with pain confined to a specific anatomical area.⁵ As applied to NOP, the approach aims to block terminal branches of supraorbital, supratrochlear, infratrochlear and infraorbital nerves.⁵³ Typically, a combination of anesthetic and corticosteroid is used such as 4mL of 0.5% bupivacaine mixed with 1mL of 80mg/mL methylprednisolone acetate. In a retrospective review of 11 patients with suspected NOP (defined previously), nerve blocks improved pain in 7 out of 11 patients, with effects lasting from hours to months.⁵³ These findings were substantiated by a case report of a 66-year-old male with NOP (evidenced by extreme photosensitivity, mechanical hyperalgesia, periocular pain with allodynia to light touch, unremarkable slit-lamp examination, refractory response to topical and oral medications) who reported substantial relief in symptoms for seven months after treatment.⁷³ Similarly beneficial effects were reported after a single bilateral nerve block in a 21-year-old man who developed severe bilateral ocular pain three months after PRK with improvement in pain intensity to a score of 2 out of 10 from baseline scores of 8 out of 10, (range 0–10), with beneficial effects lasting for three weeks. Repeat injections performed over 3.5 years showed improved symptom intensity lasting 4–6 months.⁷⁴ These results suggest that nerve blocks can improve ocular pain in individuals with NOP, particularly in the those with cutaneous allodynia and periorbital pain.

4. Autonomic Nerve/Ganglion Blocks

Patients with refractory pain may require more invasive procedures such as blockade of sphenopalatine (parasympathetic efferent control) and stellate ganglions (sympathetic efferent control).⁴ Sympathetic fibers arising from the first thoracic segments for the head, neck, heart and superior extremities ascend through the sympathetic chain and synapse at the superior, middle and inferior cervical ganglions.⁷⁵ The stellate ganglion is present in 80% of the population and is comprised of the fusion between the inferior cervical ganglion and first thoracic ganglion.⁷⁵

Stellate ganglion blocks (SGB) may be used as therapeutic purposes for sympathetically mediated pain such complex regional pain syndrome (CRPS), post-surgical pain, and PHN.⁷⁶ A ten year retrospective study of 105 patients with a diagnosis of CRPS, PHN or acute herpes zoster (AHZ) and refractory pain received a total of 809 ultrasound guided SGB after management of their respective diagnosis with treatment consisting of opioid analgesics, nonsteroidal anti-inflammatory (NSAIDs) agents, anti-epileptics, anti-depressants complemented with physiotherapy and occupational therapy.⁷⁷ Over the 10 years of retrospective data collection, SGB were performed with different local anesthetic variations, including 5mL of bupivacaine 0.5%; 5mL of ropivacaine 1%; 3mL of ropivacaine 1%; or 2mL of ropivacaine 1% plus 30μg of clonidine in 1mL saline. On average, 50% of the patients (who received between four and ten SGB) reported a reduction in pain across all three-diagnosis groups compared to pre-ganglion block pain scores (1.9±4.5 vs. 4.9±2.4, range 0–10, p<0.001).⁷⁷ Yet, 22% of subjects with CRPS (n=61) and 33% with either PHN or AHZ (n=44) did not report improvement.

The sphenopalatine ganglion (SPG) is located below the maxillary branch of the trigeminal nerve in the pterygopalatine fossa). Pain conditions which are parasympathetically driven, such as cluster headaches and migraines, SPG blocks may reduce pain refractory to conventional therapies.⁷⁸ A double blinded, placebo-controlled study (n=38) of individuals with chronic migraines were randomized to receive a series of 12 SPG blocks with either 0.3cc of 0.5% bupivacaine or saline delivered intranasally twice weekly over a 6-week period.⁷⁹ The bupivacaine group reported a significant reduction in pain after treatment at 15 minutes (post-treatment: 2.53±2.61 vs. saline group: 3.51±2.39, p<0.001), 30 minutes (post-treatment: 2.41±2.61 vs. saline: 3.45±2.36, p<0.001) and 24 hours (post-treatment: 2.85±2.74 vs. saline: 4.20±2.62, p<0.001) compared to saline group.⁷⁹ Furthermore, the effects of repeated SPG blocks were also studied and demonstrated a non-significant, but decreasing trend in migraine pain during the 6-week study period. Given the beneficial effects of autonomic blocks in treating comorbid pain conditions (e.g. migraines) commonly seen in individuals with NOP, fluoroscopy guided intranasal SPG blockage was attempted in an individual with ocular pain and NOP features; yet an improvement in pain was not achieved.⁵³ Overall, current data is not conclusive on whether and when autonomic mechanisms (sympathetic, parasympathetic or both) contribute to OSP, and as such more studies are required to evaluate this subject.

5. Transcranial Magnetic Stimulation (TMS)

TMS is a noninvasive procedure which consists of placing a magnetic coil near or on the body creating an electromagnetic field that provides enough energy to flow into the desired tissue depolarizing or hyperpolarizing neurons provoking an action potential.⁸⁰ TMS is most often used in the treatment of depression but has also been testing in individuals with chronic pain.⁸¹ A prospective study evaluated the effect of repetitive TMS (rTMS) in 48 patients with unilateral chronic neuropathic pain (e.g., atypical facial pain, central post-stroke pain, neuropathic lower limb pain or phantom pain of extremities) refractory to other treatments.⁸¹ Subjects received rTMS on the contralateral motor cortex to the pain-affected side at a frequency of 10Hz daily for a total of nine treatments. After six weeks, 28 patients reported reduction in pain compared to mean baseline pain scores, including 22 individuals with atypical facial pain (6.2 vs. 2.8, range 0–10, p<0.001).⁸¹ Studies are needed to specifically evaluate TMS, and other therapies used to treat neuropathic pain outside the eye, as a treatment in NOP.

Conclusion

In conclusion, recent advances have identified that peripheral and central neuropathic mechanisms are important drivers of chronic OSP in some individuals. Given this knowledge, several topical, oral, and adjuvant therapies that target nerve dysfunction have been examined as treatments for NOP. Some of these strategies can be easily integrated into the eye care setting (e.g., use of oral neuromodulators, BoNT-A, TNS) while others require specialized equipment (e.g., autonomic ganglion blocks). Given the expanded treatment possibilities, research is needed to develop better diagnostics that can determine when neuropathic mechanisms underlie pain and the location of nerve dysfunction. Additionally, prospective, randomized studies are needed to more robustly study treatment modalities (in isolation and combination) as most available studies have been retrospective studies in limited populations. Furthermore, adjuvant therapy options such as TMS and Scrambler, which have been applied to individuals with neuropathic pain outside the eye, need to be tested specifically for NOP. Finally, there is a need to determine which therapies are best for an individual patient based on individual contributors of pain, in order to deliver precision medicine. These research avenues are important as chronic OSP is a debilitating condition that can negatively impact quality of life. Better diagnostics and improved therapeutics, precisely applied to a patient, will hopefully reduce morbidity, and improve quality of life of individuals suffering from NOP.