In both dry eye disease and neuropathic ocular pain, inflammatory cells may mediate a component of the discomfort experienced by patients. Antigen-presenting cells, including dendritic cells, can be found within the corneal epithelium and stroma, and are important players in the complex immune functions and responses exhibited by the cornea in both processes (Hamrah et al., 2003). Compared to control patients, in vivo corneal confocal microscopy demonstrates a higher density of dendritic cells in patients with dry eye and corneal neuropathic pain (Kheirkhah et al., 2015; Shetty et al., 2016a; Nicolle et al., 2018). Moreover, in some cases, particularly in aqueous deficient dry eye disease, dendritic cells may be larger and be composed of more individual dendrites than in aqueous sufficient dry eye disease (Kheirkhah et al., 2015). Nicolle et al. (2018) To counterbalance this, endogenous peptides, known as enkephalins, serve to mitigate pain. Moreover, notable effects on in vivo confocal microscopy show a decrease in density of dendritic cells after treatment (Villani et al., 2015). Dendritic cells may express inflammatory cytokines and enzymes that degrade neuropeptides, thereby augmenting corneal nociceptors which are involved in initiating the perception of pain (Shetty et al., 2016a; Shetty et al., 2016b; Khamar et al., 2019). Indeed, it is hypothesized that dendritic cell signaling may be involved in mediating and enhancing nociceptive properties in a variety of dry eye, corneal neuropathic pain, and systemic neuropathy diseases and syndromes (Klitsch et al., 2020). Animal models of dry eye disease have demonstrated that dendritic cells can secrete a variety of proteins that activate downstream chemokines and cytokines that can modulate inflammation on the ocular surface (Gandhi et al., 2013; Zhang et al., 2014). Topical corticosteroids have well known anti-inflammatory effects. Thus, decreasing the density of dendritic cells with topical corticosteroids is one approach that may help in cases of corneal neuropathic pain where confocal microscopy identification of sub-basal dendritic cells is a predominant feature (Villani et al., 2015).

Blood-derived tear preparations contain various growth factors, vitamins, and cytokines and could be considered more similar to natural tears than commercially available over-the-counter artificial tear products. Such tear preparations can be derived from a patient’s own serum as autologous serum tears, from platelet rich plasma, or from allogeneic sources, such as donor cord blood (Tsubota et al., 1999a; Wu et al., 2021). Serum has been shown to promote the differentiation of corneal and conjunctival epithelial cells to express mucins (Gipson et al., 2003). This allows for the migration of corneal epithelial cells in a dose-dependent fashion and may, in part promote corneal epithelial health by stimulating expression of other growth factors and receptors (Phan et al., 1987; Tsubota et al., 1999a; Tsubota et al., 1999b; Geerling et al., 2001). A healthy corneal epithelium helps protect the sub-basal nerve plexus.

There has been some debate about the efficacy of autologous serum tears for dry eye disease. An extensive review by the Cochrane Database Group to identify randomized controlled trials evaluating the efficacy of autologous serum tears compared to artificial tears did not find significant evidence of a long-term durable benefit of autologous serum tears (Pan et al., 2017; Aggarwal et al., 2019). However, some studies have found in pain associated with dry eye, cord blood is superior to placebo (Campos et al., 2020). In non-randomized, observational series, platelet rich plasma drops helped to alleviate pain in corneal surgery-related corneal trauma (Alio et al., 2018).

Neuropathic ocular pain, which is distinctly different from aqueous deficient or sufficient dry eye disease, may benefit from blood-derived tear preparations that studies of general dry eye disease have not been powered to detect. Indeed, in patients with dry eye disease, serum tears have been shown to decrease basal epithelial cell density on confocal microscopy (Mahelkova et al., 2017). While some studies using serum tears in dry eye disease did not identify significant changes in the number of Langerhans cells or activated keratocytes or in the features of the sub-basal nerve plexus, other studies found that corneal nerve morphology improved with fewer neuropathic features using blood-derived tear products (Giannaccare et al., 2017; Mahelkova et al., 2017). The average concentration of serum growth factors vary according to patients who suffer from numerous systemic disease as comparted to healthy subjects with only ocular surface disease. This may be one reason explaining some therapeutic variability of serum tears in different patient populations (Ripa et al., 2020; Siedlecki et al., 2020).

In corneal neuropathic pain, serum tears have been described to be helpful in patients experiencing discomfort to light (photoallodynia) (Aggarwal et al., 2015). Autologous serum has been shown to decrease findings of sub-basal corneal nerve beading and neuromas (Aggarwal et al., 2015). In addition, serum tears have been associated with an improvement in other nerve metrics (as assessed by semi-automated quantification by ImageJ analysis) including total nerve length, nerve number, decrease in nerve reflectivity, and decrease in nerve tortuosity (Aggarwal et al., 2019). Such improvements in nerve metrics have also been correlated with an improvement in ocular pain by patients, suggesting that the resolution of neuropathic features is associated with an improvement in corneal nerve function (Aggarwal et al., 2019). Fresh frozen plasma and platelet-enriched plasma have similar purported benefits as serum tears and are worthy of future inverstigation with regard to ocular neuropathic discomfort/pain (Wang et al., 2021).

Lacosamide (C₁₃H₁₈N₂O₃, molecular weight 250.29 g/mol, pubchem.ncibi.hlm.nih.gov accessed August 1, 2021) is an amino acid molecule that was originally developed as an antiepileptic medication. Its main mechanism of action is to selectively enhance the slow inactivation (as opposed to the fast inactivation) of voltage-gated sodium channels (Errington et al., 2008; Niespodziany et al., 2013; Rogawski et al., 2015). Lacosamide also binds with the collapsin-response mediator protein-2 (CRMP-2), involved in modulating neurite outgrowth, which is important in establishing new neuronal projections in developing neurons as well as in regenerating nerves (Wilson and Khanna, 2015; Wang et al., 2018).

While corneal pain is sensed by mechano-nociceptors and polymodal nociceptors, cold thermoreceptors also play a role in the perception of ocular pain and discomfort (Belmonte and Gallar, 2011). Modulation of cold thermoreceptors, then, has been a potential therapeutic target. Topical lacosamide, in an ex vivo model, has been shown to decrease the hyperexcitability of corneal cold-sensitive nerve terminals (Kovács et al., 2016). In an aqueous deficient animal model (in which the lacrimal glands had been extirpated), the hyperexcitability as measured by the nerve terminal impulses in corneal cold-sensitive nerve terminals was decreased (Kovács et al., 2016).

Lacosamide 1% is produced from preservative-free Vimpat (UCB Inc., Smyrna, Georgia) 10 mg/ml 20 ml vial. It is important to note that Vimpat is a Schedule 5 drug and all state and federal laws and regulations regarding controlled substances must be followed when prescribing and dispensing this drug. The compounding of lacosamide 10 mg/ml is an aseptic transfer from the injection vial to the droptainers or dispensing devices. When assigning a beyond use date, pharmacies must follow corresponding state and United States Pharamcopeia (USP) General Chapter 797 regulations. According to USP General Chapter 797, a beyond use date of 14 days refrigerated may be assigned. The package insert for Vimpat states that it is not to be frozen. The product Vimpat 20 mg/20 ml is available through drug wholesalers only as packs of 10. It is important to find a pharmacy that is willing to make the initial investment in order to stock the medication for compounding use.

Naltrexone (C₂₀H₂₃NO₄, molecular weight 341.4 kg/mol, pubchem.ncibi.hlm.nih.gov accessed August 1, 2021) is an opioid antagonist that was originally developed as a therapeutic for opioid and alcohol addiction, typically at oral doses from 50 to 100 mg daily. Low-dose naltrexone (typically in doses from 1 to 5 mg daily) has been used for treating bodily neuropathic pain (Younger and Mackey, 2009; Metyas et al., 2018). Ultra-low-dose naltrexone (doses below 1 mg daily) may also be used (Toljan and Vrooman, 2018).

Naltrexone is noted to have effects on opioid receptors (commonly described with mu-opioid receptors as well as others) and non-opioid receptors. A non-opioid receptor that seems to be associated with the functionality of naltrexone as it pertains to pain modulation is the Toll-like receptor, which is found on macrophages and microglia. Microglia are involved in pain through the binding of a protein, high mobility group box 1, HMGB1) which binds to Toll-like receptors 2 and 4 (Watkins et al., 2007). Toll-like receptor expression has been noted to be upregulated in neuronal injury (Owens et al., 2005). Microglia may then increase the expression of tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators via Toll-like receptor as well as NF-ΚB signaling, indicating a close relationship between inflammation and pain (Nadeau and Rivest, 2000; Thibeault et al., 2001). Ultimately, glial activation is thought to enhance neuroexcitability, which may be associated with the increased perception of pain (Watkins et al., 2007). Naltrexone has been shown to inhibit the IL-6 and TNF-alpha that is produced after Toll-like receptors have interacted with their cognate ligands, which can thereby mitigate pain in animal models (Grace et al., 2015; Cant et al., 2017).

Models of ocular surface injury (penetrating trauma or alkali injury) have been associated with retinal damage and inflammation within the brain by virtue of microglial and macrophage activation (Ferrari et al., 2014; Paschalis et al., 2018). This has suggested that modulation of ocular surface neuropathy can be beneficial in a wide array of conditions. Indeed, oral low-dose naltrexone has been described to be beneficial to patients with a central component of neuropathic ocular pain. Patients treated with oral low-dose naltrexone as monotherapy or as part of a multimodal therapeutic approach was assocated with a decrease in their mean visual analog pain score as well as decrease in their mean quality of life score as assessed by the OPAS (Dieckmann et al., 2021). Topical low-dose naltrexone has been used in a diabetic murine model demonstrating improvements in corneal nerve sensitivity to a filament (von Frey) similar to that used to test human corneal sensation (Cochet-Bonnet enesthesiometer) (Zagon et al., 2014).

Interest in naltrexone’s potential to ameliorate corneal neuropathic problems, such as ulcerations and delayed re-epithelialization, have led to interest in producing contact lenses that would allow for the ability to deliver a more constant level of low-dose naltrexone to the cornea’s sub-basal nerve plexus (Alvarez-Rivera et al., 2019).

Presently Naltrexone, as an eye drop, requires specialty compounding. Naltrexone eye drops are reconstituted from active pharmaceutical ingredient powder because a commercial product does not currently exist. This preparation is considered high-risk compounding because pharmacies start the process with non-sterile powder and sterilize the solution via membrane filtration as the final step. Naltrexone HCl USP powder is dissolved in sodium chloride 0.9% sterile injection and preserved with benzalkonium chloride solution (though a preservative-free formulation can be prepared as well). The pH may range from 4.5 to 6.2. The solution is drawn up in a luer lock syringe and sterile filtered into droptainers or dispensing devices. For this type of preparation, USP General Chapter 797 allows a Beyond Use Date of 3 days refrigerated or 45 days frozen. Strengths of naltrexone ophthalmic solution range from 0.001 to 0.2%. The compounding of high-risk preparations is performed in an International Organization for Standardization (ISO) 7 ante room and the final filtering and packaging is done in an ISO 5 laminar flow hood.

Because the neuropeptides known as enkephalins can modulate pain, there has been interest in utilizing this pathway as a potential pain therapeutic. Enkephalins are associated with an analgesic effect, but their action is relatively short-lived due to the presence of enzymes that rapidly degrade these neuropeptides. Endogenous inhibitors of enkephalin enzymes do exist and are present in foreign body models of ocular pain (Ozdogan et al., 2020; Lasagni Vitar et al., 2021). Thus, pharmacologic inhibition of such enzymes may be a therapeutic target. In one study, the topical administration of PL265, an inhibitor of enkephalinase, in a murine model of corneal pain reduced corneal mechanical and chemical hypersensitivity (Reaux-Le Goazigo et al., 2019). Targeting corneal mu-opioid receptors with agonists may be another therapeutic target as suggested in murine models (Joubert et al., 2020).