NCP can be classified based on its underlying etiologies. Systemic causes of NCP include diabetes, systemic autoimmune diseases, medication-induced neuropathy (e.g., chemotherapy), and trigeminal neuralgia. Ocular causes include herpes simplex keratitis, dry eye disease (DED), refractive surgery, and ocular trauma [4]. In addition, NCP can be categorized based on the level of nervous system involvement, namely peripheral or central NCP [5]. Common causes of peripheral NCP include refractive surgery [6], chronic dry eye [7], and herpetic keratitis [8]. Peripheral sensitization occurs as a result of abnormal regeneration of corneal nociceptors and nerve fibers following corneal nerve injuries. Central sensitization results from elevated excitatory neurotransmitters due to chronic inflammation and, potentially, rewiring of pain perception pathways, which intensifies the perception of pain. Its common causes include small-fiber polyneuropathy, fibromyalgia, and radiation keratopathy [9].

NCP often coexists with conditions that affect pain perception and psychological well-being, such as depression, anxiety, fatigue, and sleep disturbances. These conditions are not causative factors but represent comorbidities that can influence the severity and impact of NCP. Moreover, NCP may be linked to comorbidities including anxiety, depression, and chronic pain syndrome such as migraine [10].

Symptoms experienced by patients with NCP are described as dryness, burning sensation and hyperalgesia which are usually worsened by extreme temperatures, light (photoallodynia) and dry wind. Our group has identified that burning and light sensitivity are the two most common symptoms in NCP [11]. More focus is diverted to understanding the pathophysiology of pain which transitions from a protective physiological reflex to a more persistent and chronic condition [9].

Despite patients frequently reporting pain or pain-like symptoms, standard ophthalmological examinations often do not reveal objective or visible findings. This discrepancy can lead to delayed diagnosis and even many patients being misdiagnosed with dry eye disease (DED), which is a multifactorial condition characterized by an imbalance in tear film homeostasis and ocular symptoms, with tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities playing etiological roles [12]. Importantly, NCP and DED are not mutually exclusive and may coexist, or one may be a precursor or a sequel. These two conditions share partial overlap in symptomatology and underlying pathophysiological mechanisms. DED patients present with a range of symptoms including ocular dryness, burning, aching and tenderness, overlapping considerably with the symptom profile of NCP [7]. Additionally, neuroinflammation response is suggested to contribute to the pathogenesis of both conditions [7]. Due to the mismatch between the severity of symptoms and observable signs, patients’ symptoms are often dismissed as “psychological” or “functional,” leaving them feeling ignored and neglected, worsening their condition [10]. In terms of quality of life, Chin et al reported that patients with NCP had significantly worse quality of life on the majority of the items in the Ocular Pain Assessment Survey and Ocular Surface Disease Index questionnaires compared to those with DED, suggesting NCP is more debilitating than DED [10].

Although patients with NCP and DED share many common symptoms, the differentiating factors are imaging findings, proteomic patterns and clinical features which explain their distinct pathophysiologies. NCP is a neuropathic disorder with nerve dysfunction, corneal microneuromas, neuroinflammation, and pain that is disproportionate to clinical signs whereas DED is an inflammatory and tear film disorder accompanied with epithelial damage, immune activation, and symptoms that are correlating with objective findings. Microneuromas are the key differentiator and NCP patients exhibit higher numbers, larger area and larger perimeter of microneuromas than DED patients. NCP patients have elevated levels of tear proteome associated with neuronal activity and neuroinflammation whereas DED showed proteomic patterns dominated by inflammatory mediators [7]. Treatment wise, some patients with NCP do not respond to conventional treatments used to treat DED and thus differentiating them is essential to offer more effective treatment [13].

In-vivo confocal microscopy (IVCM) has been extensively used to visualize the corneal nerve plexus and corneal cells [14]. Through IVCM evaluation, decreased corneal nerve densities, decreased nerve fiber fractal dimension, increased corneal nerve fiber width, activated keratocytes, smaller corneal epithelial cell size, and an increased number, area and perimeter of micro neuromas in patients with NCP were identified (Figure 1) [11, 15]. Previous study suggested that the presence of microneuromas on IVCM could serve as a biomarker to distinguish NCP from DED, with high sensitivity and specificity [16]. However, recent evidence indicates that microneuromas can be observed not only in patients with NCP, but also in painless DED and even in healthy subjects [17]. From a diagnostic perspective, the mere presence of microneuromas therefore appears insufficient to indicate corneal neuropathic alterations. Quantitative microneuroma metrics, such as perimeter and area, may be required to improve diagnostic specificity [17].

NCP is characterized by increased release of excitatory neurotransmitters at presynaptic terminals, ectopic firing of nerve fibers, nerve sprouting and rewiring, spontaneous generation of action potentials, abnormalities in signal conduction, and transformation of non-nociceptive sensory fibers into nociceptive ones [18]. Nociceptors are important for pain perception and can produce action potentials in response to thermal, mechanical, chemical, or polymodal stimuli [19]. The nociceptors are centrally connected to higher-order somatosensory pain pathways and the thalamus, where pain is perceived. Tissue damage and inflammation of the ocular surface cause peripheral axonal injuries and release of pro-inflammatory mediators, which lower the activation thresholds of ion channels in affected nerve endings. These sensitizing effects may spread to adjacent nociceptors, enhancing peripheral nociceptive signaling and ultimately leading to peripheral sensitization [20].

In addition to the ascending pathways that transmit pain signals, descending modulatory pathways also play a critical role in NCP by contributing to central sensitization and heightened pain perception [21]. Descending inhibitory activity is believed to originate from the reticular system and thalamus, activating central gamma-aminobutyric acid (GABA) receptors, modulating interneurons, and ultimately altering ascending trigeminal pain signals. Normally, interneurons release inhibitory neurotransmitters that suppress nociceptive signaling [22]. However, persistent insult reduces the inhibitory effect of GABA on ascending pathways due to changes in chloride currents [23]. As a result, signals in the ascending pain pathways intensify, contributing to the perception of chronic pain [24]. Furthermore, descending modulation of the trigeminal nuclei can be either inhibitory or facilitatory. Inhibitory control predominates under physiological conditions, while a shift toward facilitatory modulation following tissue or nerve injury may contribute to the development of chronic pain [25].

Genetic polymorphisms can also affect corneal neurophysiology and inflammation by altering the expression of neurokines and neuromediators which influences the clinical presentation and severity of NCP. A recent report discovered a single nucleotide polymorphism (rs140293404), an intronic variant in the gene ENSG00000287251, that has met the genome-wide significance threshold for NCP [26]. Genetic polymorphisms may explain why some are more susceptible to NCP.

Continuous stimulation of corneal nerves causes the release of glutamate from presynaptic afferent neurons, which activates two types of glutamate receptors: N-methyl-D-aspartic acid receptors (NMDAR), responsive to strong stimuli, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), sensitive to weaker signals [27]. The activation of NMDAR results in intense and prolonged neural responses [9]. Peripheral axonal injury induces the release of inflammatory mediators that decrease the threshold potentials of ion channels in nerve endings, intensifying neural responses. Moreover, mechanical stimuli in the cornea are transduced by Piezo2 channels, which are low-threshold mechanically activated channels expressed in trigeminal sensory neurons innervating the cornea [28]. Research indicates that Piezo2 contributes to various forms of mechanoreceptive sensitization, including mechanical allodynia induced by inflammatory responses or injury [29, 30]. In NCP, alterations in Piezo2 channel function may affect innate reflexes and cause mechanical hypersensitivity [31]. Recurrent dysregulation of Piezo2 signaling may facilitate nociceptive sensitization and influence long-term central nervous system responses even after the offending stimulus is removed [32]. A previous study using Piezo2 conditional knockout mice demonstrated that Piezo2 channels in corneal neurons are directly involved in corneal mechano-nociception [33]. However, systemic inhibition of Piezo2 for neuropathic pain relief is not feasible due to its essential role in mechanotransduction processes across multiple organs, including touch, proprioception, and interoception [33]. Despite this limitation, topical inhibition of Piezo2 in the cornea may represent a promising strategy to alleviate discomfort and pain associated with corneal mechanical irritation and warrants further investigation. Additionally, photophobia and photoallodynia are common symptoms in NCP. The presence of melanopsin expression in trigeminal neurons suggests the existence of a functional neural pathway that permits light to influence various sensory processes [34].

Neurotrophins released during neuroinflammation in NCP act as retrograde signaling molecules. Evidence from trigeminal ganglion studies demonstrate that neurotrophins can induce changes in ion channel expression and membrane excitability in sensory neurons. Although the specific role of neutrophils in NCP remains incompletely understood, findings extrapolated from peripheral nerve injury models indicates they may promote nerve depolarization and contribute to altered pain perception through modulation of neuronal properties [35]. Chronic neuropathic nerves may further lead to reorganization, resulting in more excitable and abnormal firing patterns [36]. Furthermore, recent research indicates that immune cells, including dendritic cells, release neuropeptides and neurokines that modulate neuronal excitability, contributing to peripheral sensitization [37]. These collectively exacerbate neuroinflammation, which perpetuates the cycle of NCP [38]. As time passes, sustained peripheral input may facilitate the development of central sensitization, where central neurons become increasingly responsive to similar levels of pain, resulting in heightened pain perception [39].

On a molecular level, neurokines like Interleukin- 1 Beta (IL-1β) and Tumour Necrosis Factor-Alpha (TNF-α) bind to receptors on corneal sensory afferents, modulating neuronal excitability and lowering thresholds for generation of action potential, thus, facilitating the release of neuropeptides such as substance P [37, 38]. Substance P directs immune cells to the terminals of nociceptors, where they release neurokines that contribute to neuropathic pain [40]. Substance P and Calcitonin Gene-Related Peptide (CGRP) have prolonged effects on corneal nociceptors and are strongly implicated in sensory hypersensitivity [35]. Neurokines and neurotrophic factors promote the reorganization and increased sprouting of peptidergic nerve fibers [41]. Additionally, nerve growth factor (NGF), a neurotrophin, increases in the tears of patients with NCP [11], altering the expression of transduction molecules in C- and Aδ-fibers, increasing their excitability [42, 43]. Our group further identified the significantly dysregulated tear proteins in NCP. Specifically, the levels of metallothionein-2, creatine kinase B-type, vesicle-associated membrane protein 2, neurofilament light polypeptide and myelin basic protein were significantly over-expressed [11].

Electrotherapy has been used in the treatment of peripheral neuropathic pain. It involves using electrical impulses to stimulate nerves in the affected area, helping in pain reduction and promoting healing [49]. The analgesic effects of electricity were attributed to the activation of the descending inhibitory pathway, increasing the production of endogenous opioids [50] and other neurochemical compounds such as serotonin [51], GABA [52], and adenosine [53]. The pain reduction could also be attributed to the gate-control theory proposed by Melzack and Wall, which states that pain is modulated by inhibiting small afferent nociceptive fibers through the activation of larger afferent fibers of the spinal cord [54]. This leads to the activation of inhibitory interneurons and reducing nociceptive signaling [55].

Among different electrotherapies, Transcutaneous Electrical Nerve Stimulation (TENS) is a widely used form that involves placing electrodes on the skin near the painful area that deliver low-frequency electrical impulses to stimulate the affected nerves. Previous studies suggest that TENS may reduce nociceptive signaling by decreasing nociceptor activity, modulating the expression of pain-related ion channels, thus inhibiting nociceptor neurotransmission [56]. β-endorphins and methionine-enkephalin levels, which interact with opioid receptors, increase after high-frequency TENS, which may contribute to reduced release of glutamate and substance P in the spinal cord [55].

In diabetic neuropathy, conventional treatments for painful diabetic neuropathy have essentially focused on drug therapies such as gabapentin, pregabalin, duloxetine, and tricyclic antidepressants. However, these drugs are associated with notable side effects involving dizziness, sedation, peripheral edema and anticholinergic effects including cardiac arrhythmias [9]. Despite these treatments, many patients experience persistent pain, incurring substantial indirect and direct economic costs [57]. ES is a potentially safer option due to its minimal contraindications and absence of known drug interactions [58]. Clinical studies reported that ES enhances peripheral cutaneous circulation, potentially through stimulation of sympathetic nerves [59]. Although improved cutaneous circulation has been associated with pain relief in neuropathic conditions [60, 61], the specific underlying mechanisms remain incompletely understood. Additionally, ES has been shown to increase vascular endothelial growth factor (VEGF) levels. VEGF improved the microcirculation associated with neuropathy, which may enhance nerve function [62]. Other studies have demonstrated notable increases in beta-endorphin levels [63], heightened expression of CGRP [64], reduction in inflammatory markers [65], and increased NGF after ES [66]. ES also diminishes pain by inhibiting nociception at the presynaptic level within the dorsal horn, thereby preventing the central transmission of pain signals [67]. Kumar et al reported that TENS resulted in a reduction in pain and discomfort in 83% of patients, although the symptoms recurred approximately after 1 month upon termination of TENS [68]. However, a systematic review presented only a slight reduction in pain intensity favoring TENS. The considerable variation in treatment protocols, such as the intensity, frequency, and duration of TENS application, made it challenging to synthesize the research findings effectively [69].

In this review, we aim to explore the role of electrotherapy in the management of NCP, focusing on its underlying mechanisms, efficacy, and clinical applications. We evaluate current evidence, highlight emerging technologies, and discuss future directions for integrating electrotherapy into clinical practice.

An electronic literature search was conducted on the PubMed database to explore the effects of electrotherapy in the management of NCP. The search utilized a combination of the following terms: “(Electrotherapy OR Electrical Stimulation OR TENS OR Neuromodulation)” AND “(Neuropathic Corneal Pain OR Keratoneuralgia OR Corneal Neuropathy OR Corneal Pain OR Neuropathic Ocular Pain)” AND” (Management OR Treatment OR Intervention)”. Methods of stimulation such as transcranial direct current are not within the scope of this narrative review because it is unclear which pain pathways are involved. The search spanned from the database’s inception to December 18, 2024, with no filters applied. The initial search yielded 179 references published between 1955 and 2024. Articles of various study types, including clinical trials, meta-analyses, randomized controlled trials, reviews, and systematic reviews, relevant to the application of electrotherapy in NCP, were included after duplicate removal. Exclusion criteria included non-English articles and those without full-text availability. Following the application of inclusion and exclusion criteria and a screening of titles and abstracts for relevance, 45 references were deemed suitable for further review (Figure 2). Full-text versions of these articles were assessed for eligibility. Additional relevant studies identified through cross-referencing were incorporated to provide a broader discussion, encompassing the application of electrotherapy in neuropathic pain.

Recent advancements in neurostimulation technologies have led to improved outcomes in reducing chronic corneal pain, particularly in cases where conventional treatments have proven ineffective. Hence, electrotherapy has emerged as a treatment option for managing NCP, offering a potential alternative to traditional pharmacological treatments or as adjunct therapy together with conventional therapy. By delivering targeted ES to affected nerves, this therapy aims to modulate pain signals and potentially promote nerve regeneration [70].

Electrotherapy is contraindicated in patients who are pregnant, epileptic, have cancer, or have cardiovascular disease. It is also contraindicated for those patients who have implanted electrical devices or have recently undergone radiotherapy due to unpredictable tissue response after radiotherapy [92]. Electrotherapy should also be avoided when skin is irritated, infected, bleeding or extremely sensitive [93]. This may narrow the number of patients who can be treated or participants for trials.

Currently, there are no standardized guidelines that exist for electrotherapy in NCP, causing a difference in the parameters used such as intensity, treatment duration and frequency. This makes the comparison of outcomes between studies much harder and hampers reproducibility. Insufficient stimulation may yield suboptimal outcomes, while excessive stimulation could result in adverse effects or diminishing returns. Determining the optimal dose of electrical therapy would be part of future research. Modification of ES according to the unique pathophysiology of corneal nerves may be necessary as it vastly differs from peripheral nerves.

In addition, the above-mentioned studies did not include a comparative arm, making it difficult to conclude whether the observed pain reduction was directly due to ES or attributed to spontaneous improvement or concurrent treatments. Future research should incorporate control groups to establish the cause-and-effect relationships concerning the efficacy of TENS.

Individual differences in the underlying etiology of NCP may also influence the effectiveness of electrical therapy. Factors such as baseline nerve damage, pain sensitivity, and response to treatment may lead to inconsistent outcomes. Moreover, most studies focus on short-term outcomes, with limited data on long-term efficacy and safety. It remains unclear whether the advantages of electrical therapy are sustained over time or require continuous treatment. The need for repeated sessions of electrotherapy over weeks or months may impose a logistical and financial burden on patients.

Furthermore, the use of electrotherapy requires specialized equipment and trained personnel, which may not be readily available in all healthcare settings, limiting its widespread adoption, particularly in low-resource settings and third-world countries. Reliance on subjective assessments, such as pain scores and patient-reported outcomes, may introduce bias. Objective measures, like corneal nerve imaging or electrophysiological data, are less frequently used, making it difficult to assess and adjust therapy dynamically.

Future directions can focus on investigating optimal parameters for various electrotherapy modalities such as TENS or trigeminal nerve stimulation. These can include intensity, duration, and frequency in respective patients to achieve maximal therapeutic outcomes. More effort should also be put in developing individualized electrotherapy regimens based on patient-specific factors so that it is catered to specific patient needs. The combined use of electrotherapy and pharmacological treatments should also be explored to maximize the efficacy of pain management.

Future studies should also aim to explore the molecular and cellular processes by which electrotherapy aids in pain alleviation and nerve regeneration. More detailed research into neurotrophic factors, such as BDNF and NGF, as well as calcium influx, could provide valuable insights. Moreover, follow-up studies can be performed to assess the lasting effects of electrotherapy in chronic NCP management and potential symptom recurrence. The safety of electrotherapy over extended periods while focusing on potential adverse effects can also be assessed on each patient, but objectively quantifying pain level and comfort might be hard. Long-term studies, larger-scale, and comparative or randomized controlled trials are required.