Focused Narrative Review: Non-Pharmacological, Noninvasive Neurostimulation or Neuromodulation Treatment of Ocular Neuropathic Pain.

Corneal or ocular neuropathic pain (ONP), corneal neuralgia or keratoneuralgia, is a poorly defined condition of an abnormal, heightened response to normally non-painful stimuli, characterized by intense irritative symptoms out of proportion to any visible clinical signs, with presence of corneal nerve abnormalities including micro-neuromas on in-vivo confocal microscopy scans, and variable component of central neural dysfunction unrelieved by local anesthetic instillation to the eye. 1–3 Symptomatology of ONP is often mirrored by conditions such as dry eye disease, leading to misdiagnosis or undertreatment. Because this condition is difficult to diagnose and manage, it is useful for clinicians to refer to a recent review of ONP. 4

ONP is often associated with chronic pain syndrome (such as neck and backaches, migraine, fibromyalgia), sleep disorders, anxiety and depression. 5 Since ONP is associated with a history of ocular surgery 6 and conditions such as dry eye disease, it is important to begin with topical anti-inflammatory therapy that can address sources of nociceptive pain, even if the eyes are not overtly inflamed. Ophthalmologists who have access to topical therapies such as plasma or serum eye drops should use these to optimize the ocular surface, reduce neuroinflammation, and promote corneal nerve regeneration. 7–9 ONP could have peripheral, central or mixed components. The mainstay of the central component of chronic ONP with a significant central component is pharmacological, involving combinations of oral anti-depressants, chronic pain medications such as tramadol, and voltage-gated calcium channel inhibitors such as gabapentin and pregabalin. 10 , 11 This condition inevitably requires a multi-disciplinary approach, which includes mental health support and possible behavioral therapy. Although a list of non-pharmacological treatments has been published, this did not provide a description of the relative benefits and pitfalls of the various modalities. 12 We noticed that the reviews published in the domain of neuropathic pain are concerned with pharmacological approaches, invasive modalities involving implants, or psychological rehabilitation. There is an unmet need for reviewing the non-invasive, non-pharmacological interventions that are neurostimulatory as opposed to ablative ones. Because of their preponderance in the literature, we will focus on describing techniques such as extranasal stimulation, transcranial stimulation and transcutaneous stimulation.

It is not our intention to over-generalize the results of non-ocular studies. As there is a lack of direct evidence for the modalities (apart from TENS) discussed in this paper on ocular neuropathic pain, patients should be made aware that efficacy may be uncertain. After the initial local and pharmacological approaches have been attempted, severe cases of ONP may require further non-pharmacological treatment ( Figure 1 ). We suggest that these modalities, should they be available, can be attempted in the following sequence described below. Figure 1 Flow chart showing stepped-care approach in ocular neuropathic pain. Note that the algorithm for using these non-pharmacological therapies (in green) is not based on scientific evidence on their relative efficacy. These treatments may be performed at any stage of the algorithm. If more than one modality is available, the sequence should be based on first principles such as performing the non-invasive modality with least likelihood of side effects first. A flowchart detailing parallel or complementary interventions for ocular neuropathic pain. It begins with ′Diagnosis of Ocular Neuropathic Pain′ involving clinical assessment and questionnaires. It branches into ′Peripheral NCP′ and ′Central/Mixed NCP′. Under ‘Peripheral NCP’ there are ′Local Treatment with Anti-Inflammatory Agents′ includes topical corticosteroids and NSAIDs and ′Analgesia and regenerative local therapies′ involve oral analgesics and serum drops. Under ‘Central/Mixed NCP′ there are Systemic Pharmacotherapy′ includes pregabalin and sodium channel blockers, TCAs and SNRIs. ′Nerve Blocks′ interrupt pain signaling. ′Psychotherapy′ covers cognitive behavioral therapy and mindfulness. ′ENS/TENS′ involves electrical nerve stimulation. ′Electroacupuncture′ modulates opioid release and pain gating mechanisms. ′rTMS/tDCS′ involves repetitive transcranial magnetic stimulation and direct current stimulation for cortical modulation. ′Implantables (Refractory Cases Only)′ refers to deep brain stimulation for resistant pain. Flowchart of interventions for ocular neuropathic pain management. Flow chart showing stepped-care approach in ocular neuropathic pain. Note that the algorithm for using these non-pharmacological therapies (in green) is not based on scientific evidence on their relative efficacy. These treatments may be performed at any stage of the algorithm. If more than one modality is available, the sequence should be based on first principles such as performing the non-invasive modality with least likelihood of side effects first. ENS is suitable for patients with significant peripheral contribution to the ONP. This includes those with dry eye disease that require frequent eye drop administration and those who require local immunomodulation. TENS can be started for motivated patients who wish to have frequent home-based treatment, especially with fibromyalgia, or residual dry eye disease that could not be controlled with standard therapy. If available, start TMS for patients with migraine, underlying mood or psychological disorders, especially in combination with systemic pain management and counseling and relaxation. Failure of TMS or TENS can be followed by TDCS, for patients who are willing to undergo several modifications of treatment protocol, especially if they are also willing to undergo longitudinal brain imaging in a specialized center. Such an algorithm is not based completely on evidence, but also on first principles such as trying non-invasive treatment and more convenient options before more complicated options or those which may involve adverse effects or greater inconvenience. In summary, ophthalmologists should have a high index of suspicion for ONP, especially in cases labeled with dry eye disease that responded poorly to conventional treatment. They should adopt a holistic approach, and involve the appropriate specialists such as psychiatrists, pain specialists and neurologists with a special interest in non-pharmacological therapies. Although some of these therapies still lack robust evidence which can only be obtained after prolonged clinical experience, these newer therapies are non-invasive and have little adverse effects and if available, should be discussed with desperate patients. If possible, such patients should be encouraged to participate in clinical trials, which will result in more evidence for this indication.

The keywords used to search Entrez Pubmed were “Neuropathic pain” and “treatment” with no date range specified. This produced 16,371 articles. Out of these, 4165 articles were reviews, systematic reviews or meta-analyses. Among these, 54 articles contain the terms “ocular” or “corneal”. Manual curation showed that none of these 54 articles describe or compare treatment options related to non-invasive, non-pharmacological modalities based on neurostimulation. Therefore, we will focus on the original articles. When we applied the terms “ocular” or “corneal” and limiting to clinical trials or randomized clinical trials, there were only 6 hits, one of which is a Chinese article that reported a study comparing acupuncture with hyaluronate treatment. The other 5 articles were not related to non-pharmacological treatment. We therefore have to evaluate the non-ocular non-review articles. In this category, 1275 articles were found with “clinical trial” or “randomized clinical trial” and manually curated to exclude pharmacological, cell therapy, implantables, nerve ablation or block, cryoanalgesia, muscle strengthening or traditional herbal or TCM treatments. Removal of pharmacological treatments left 216 articles, and removing invasive spinal cord stimulation with implants, left 168 articles. After removing papers on psychological therapy, scrambler, vibration and electroacupuncture, 124 papers remained. Within this pool, we found 49 papers on magnetic stimulation, 46 papers on direct current or deep brain stimulation, and 29 papers on peripheral or transcutaneous stimulation. In addition, we also searched for “extranasal stimulation” and “ocular”.

In recent years, there have been advances in the treatment of neuropathic pain outside the eye and some of these approaches may be applicable in recalcitrant cases. We aim to summarize the broad modalities of these treatments in Table 1 , but complementary or alternative treatments such as acupuncture in specific type of neuropathic pain (diabetic neuropathic pain) 13 are not in the scope of this review. Table 1 Non-Pharmacological Treatment for Ocular Neuropathic Pain Modality Transcranial Magnetic Stimulation (TMS) Extracranial Direct Current Stimulation (TDCS) Transcutaneous Electrical Nerve Stimulation (TENS) Extranasal Neurostimulation (ENS, iTear100) Mechanism Pulses given 10–20 sec with 30 sec interval Increase the signals that brain sends down the spinal cord to interrupt pain signals, eg, 5 Hz rTMS Uses scalp electrodes, Modulates the resting potential of simulated neurons (depolarise or polarise using anodal or cathodal current) Stimulates impulses from a region of body; large diameter afferents competitively reduces pain signals Increase level of endorphins Stimulates afferent anterior ethmoid nerve which will have output in the form of lacrimal, meibomian gland and conjunctival epithelial secretion Treatment Uses coil placed over head to administer brief magnetic pulses to specific brain cortical region Can be given seated without sedation May need sessions of 20 min daily for two weeks and repeated following month Wearable device used at home that produces low electrical current Uses skin electrodes; Can be titrated; Affects periaqueductal gray, rostral ventromedial medulla and spinal cord pathways Stimulation for thirty seconds twice a day on each side of nose Stimulation can be titrated using a mobile app Advantages Shown to be safe Some types of chronic pain: inhibited by dorsolateral prefrontal cortex Also benefit depression and cognition Safe up to 3A as no brainstem function affected Effective in spinal neuropathic pain Can be home based treatment May not be suitable for overactive bladders, epilepsy, pacemakers Small portable commercial device, rechargeable and convenient Relatively low cost upfront Disadvantages ▪ Exact position of coil depends on position of pain; need to know which cortical area feeds into the thalamus or amygdala which regulates pain ▪ Not yet approved by FDA for pain ▪ No universal methodology for electrode placement ▪ Not yet approved by FDA for neuropathic pain ▪ Current only passes superficial to cortex? ▪ Produces tingling sensation via skin electrodes ▪ Can produce tolerance if same frequency and intensity used daily ▪ Long term effectiveness after cessation uncertain ▪ Not yet approved by FDA for neuropathic pain ▪ Uncertain if it will relieve NCP ▪ May not be comfortable for people with sinus disease Level of evidence Evidence not available for ocular neuropathic pain, but tested in associated conditions like trigeminal neuralgia, migraine and fibromyalgia Evidence not available for ocular neuropathic pain, but has been tested in trigeminal neuralgia and facial pain Level 1 evidence for ocular neuropathic pain but not in the long term Evidence for dry eye disease, pilot study for peripheral type of ocular neuropathic pain Non-Pharmacological Treatment for Ocular Neuropathic Pain Neurostimulation using pulsed radiofrequency therapy is known to be effective for neuropathic pain related to herpes zoster and trigeminal neuralgia. 14 Extranasal therapy (ENS) based on vibrational stimulation of the anterior ethmoid nerve has been used primarily for dry eye disease. This requires extra nasal stimulation twice a day for increasing secretion of tear components including lacrimal glands, meibomian glands and conjunctival Goblet cells. 15 Similar to TENS, stimulation of afferent nerve fibers may in theory reduce the perception of ocular pain based on the gate theory. The main advantage of this is a small commercial device that can be charged through a USB port, is highly portable, and already FDA approved for use in dry eye. In a retrospective pilot study, patients with refractory peripheral or mixed ONP underwent a single session of extranasal stimulation. Visual analog scale was used to evaluate pain intensities in the office before and after 60 seconds of stimulation. Fourteen patients (63.63%) experienced an improvement of at least 50% in their pain scores, 2 patients (9.09%) showed an improvement between 30% and 49.9%, while 6 patients (27.27%) experienced an improvement of less than 30%. 16 Despite these encouraging findings, there is no evidence that ENS has a long-lasting effect and it also may not modulate the central component of neuropathic pain. It may also not be comfortable for patients with a history of sinusitis or chronic rhinitis, since ENN also potentially increases nasal discharge. Transcutaneous nerve stimulation (TENS) stimulates impulses from a region of the body to the brain, thereby reducing pain signals (in competitive fashion) and also increasing the brain level of endorphins. This can use high frequency or low frequency electrical impulses which activate different opioid receptors HF may be more effective in patients taking opioids. The treatment activates large diameters afferent fibers, which send impulses to the central nervous system to activate descending inhibitory systems to reduce hyperalgesia. 17 TENS can restore central pain modulation, a measure of central inhibition, tested previously in fibromyalgia. 18 The pain pathways involved include those in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM) and spinal cord. The strong point with TENS is that it has already been shown to benefit a huge range of conditions including fibromyalgia, arthritic pain, endometriosis and sport injuries. One such study involved patients with neuropathic pain after spinal cord injury. 19 In a randomized controlled trial, it has also been shown to benefit people with painful diabetic peripheral neuropathy. 13 TENS can produce a tingling sensation via skin electrodes. Like ENS, the devices used are generally small, lightweight and portable and can be used on the move throughout the day. TENS is generally considered very safe, except for minor skin irritation due to placement of electrodes. It may not be suitable for people with epilepsy, pacemakers or overactive bladders. A pooled analysis of five studies found TENS to significantly improve neuropathic pain of various etiologies compared to sham TENS. However, the quality of evidence was regarded as very low and the authors were not confident of the actual magnitude of the beneficial effect. 20 As for the application of TENS in ONP, there are still very limited studies reported. In a short-term study where 14 patients with dry eye symptoms and ocular pain underwent TENS with placement of four electrodes and a duration of 30 minutes. Assessment of pain was performed immediately prior to treatment, 20 minutes, 25 minutes into treatment, immediately prior to the end of treatment, and five minutes post-treatment. The TENS procedure significantly reduced the mean pain intensity in both the right and left eyes 5 minutes after treatment compared to prior to treatment (P < 0.05, paired t -test). Interestingly, the use of TENS significantly decreased light sensitivity in both eyes There is however, no evidence for long‑term effectiveness after cessation of TENS treatment. 21 In a retrospective review of patients who had undergone the TENS device at home for at least three months, nine of ten patients reported subjective pain reduction in their ocular pain. Overall, pain intensity decreased by approximately 27.4%, and importantly, no adverse side effects were observed. 22 The amount of stimulation can be titrated. Effective analgesia for chronic pain conditions may be limited by the development of tolerance to TENS if there is repeated application of either low frequency LF or high frequency HF TENS at the same intensity daily (ie, same dose). Strategies to prolong analgesia may include varying these parameters. A different, long‑term study of 18 participants with more than three months of home TENS using a trigeminal neurostimulator reported encouraging findings. At six months, pain intensity, light sensitivity, wind sensitivity and burning sensation were all decreased compared to baseline (p < 0.01 for all); greater decreases in ocular pain were noted in individuals with migraine (n = 10) than those without migraine (n = 8). 23 In a recent randomized controlled trial, participants were randomized (2:1) to a 20-minute high-frequency TENS (hfTENS, 60 Hz) or low-frequency TENS (lfTENS, 3 Hz) intervention, delivered at the forehead three times/week, for six months. The study found that both hfTENS and lfTENS significantly reduced eye pain intensity acutely (within 24-hours of initial treatment), and hfTENS produced long-lasting improvements in the NPSI-Eye subscores of pressing pain (2.50 [5.50] to 1.50 [2.50], p = 0.03) and paroxysmal pain (1.50 [3.50] to 0.00 [1.50], P = 0.02) at three months, though the numerical rating scale of overall ocular pain intensity did not change. 24 There is a commercial variant of TENS called transepithelial electrical stimulation or quantum magnetic resonance (QMR) offered as Rexon-Eye which was developed for the treatment of dry eye. This is however, not a home-based therapy but clinic-based, requiring patients to come for sessions of 20–30 minutes. 25 In a single-arm study of patients with dry eye, 12 sessions of 22 minutes were performed over two months, and a reduction of symptoms (OSDI) and signs of dry eye (staining and TBUT) were observed at the end of treatment, six and twelve months. 26 A similar TENS type of electrical stimulation was performed (five sessions per week over four weeks) on participants with dry eye (symptoms and either low Schirmer’s result or low tear break up times) and found significant improvement in dry eye symptoms and signs compared to participants who used hyaluronate eye drops alone. 27 However, these studies were not performed on patients who suffered from ONP. Recently, our group has published a review on the use of electrical therapies such as QMR in ocular neuropathic pain. 28 Transcranial magnetic stimulation (TMS) or repetitive ( r ) TMS uses a coil placed over the patient’s head to administer brief magnetic pulses to a specific brain location that produces changes in the activity of neurons. The exact position of the coil depends on the position of pain. The treatment also aims to increase the signals that the brain sends down the spinal cord to interrupt abnormal pain signals. This is given seated without sedation, and pulses given over 10 or 20 seconds with a 30 second interval between them. Patients may need 3–4 sessions days apart, then repeated in 2 to 4 weeks. If available, functional MRI can be used to pinpoint brain target, may require a separate mapping session, ideally the pulse that produce a single twitch in the muscle, eg, facial muscle, for fraction of a second. 29 Current evidence suggests that TMS can effectively treat certain types of pain, especially through stimulation of the dorsolateral prefrontal cortex in chronic pain. Long lasting effect achieved in several studies, as shown by a recent review in 2019. 30 A systematic review in 2020 shows that TMS is beneficial for treating neuropathic pain of various origins, such as central pain, pain from peripheral nerve disorders, fibromyalgia, and migraine. 31 High frequency 5Hz rTMS applied to the motor M1 region of the brain has been shown to be effective for these disorders. 32 No adverse effects have been observed with TMS, but it is not suitable for those with cochlear, pacemaker or metallic implants (mainly because of MRI assessment). There have been rare reports of rare epileptic seizures after TMS. However, TMS is currently FDA approved only to treat depression. But this suggests the possibility of using TMS for ONP patients who have concurrent mood disorders which can be improved this form of treatment. 30 Transcranial direct current stimulation (TDCS) uses a wearable device at home that produces low electrical current. This can be used to stimulate specific brain targets in the dorso-lateral prefrontal cortex via scalp electrodes. The direction of current flow differentiates anodal and cathodal stimulation by modulating the resting membrane potential of the neurons stimulated, depolarising or hyperpolarizing neurons. 33 This form of treatment has been shown to benefit depression and cognition and post stroke mobility. There has not been any publications directly related to ONP, but it has been evaluated with mixed results in facial pain and trigeminal neuralgia (Yuen et al 2026). However, there is no universal methodology for placement of electrodes, and TDCS is currently considered as an investigational device and not yet approved by FDA. There is limited brainstem interference on cardiac and respiratory function using up to 3A, which is therefore safe. 33