Transcutaneous Electrical Nerve Stimulation for the Long Term Treatment of Ocular Pain

Abstract

Purpose:

Ocular pain is a debilitating condition that is challenging to treat as therapies that target the ocular surface are often ineffective. We previously reported a short-term reduction in ocular pain after one periocular transcutaneous electrical nerve stimulation (TENS) session. The current study aims to elucidate the long-term effect of TENS on ocular pain.

Methods:

Fourteen individuals with eye pain were identified as candidates for a TENS device (RS Medical, Vancouver) for home use after a successful trial in clinic between February 2018 and July 2019 at the Miami Veterans Administration Hospital or University of Miami. Ten of the 14 patients were included in this retrospective review, based on the inclusion of receiving and using the device for a minimum of 3 months. The median age of the 10 patients was 47.5 years, range 32–73 years, and 8 were male. The main outcome measures were (1) frequency of long-term integration of TENS into ocular pain management and (2) patient reported ocular pain intensity (0–10) pre- vs post-treatment.

Results:

Patients reported an initial median use of the device 14.0 times per week and over time reducing the frequency to 3.0 times per week. All reported that the TENS unit was successfully incorporated into their ocular pain management routine for at least 3 months (median duration of use 6.5 months, range 3–14 months). Nine of ten patients reported subjective pain reduction with use of the TENS device at home. Overall, pain intensity decreased by approximately 27.4%, (mean rank=5.6, Z=−2.1, p=0.02) post- vs pre-treatment. No adverse events associated with TENS were reported in any patient.

Conclusion:

Our preliminary data suggest that TENS can be integrated into the long-term management of ocular pain with improvements in overall pain intensity.

INTRODUCTION

The International Association for the Study of Pain (IASP) describes pain as “an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage or described in such terms.”¹ Pain is regarded as chronic when it persists beyond the normal healing time of 3 to 6 months. Chronic pain is a prevalent condition estimated to effect 20% of people worldwide and accounts for 15 to 20% of physician visits.² Interestingly, many parallels can be drawn between the epidemiology of chronic pain and dry eye (DE)³, and there is a recent recognition that many of the sensations reported by individuals formerly classified as having DE would better be described as ocular neuropathic pain. This includes dysesthesias described as “dryness”, “burning”, “aching”, and “tenderness.”^4,5 Similar to chronic pain outside the eye, these symptoms greatly reduce quality of life and cause patients to seek ophthalmic care.⁶ The prevalence of DE symptoms in the United States is approximately 5.28%, with approximately 7.78% among females and 2.96% among males, and it is strongly age dependent, ranging from 0.20% for ages 2–17, to 11.16% for individuals over 50 years old.^7–9

The stepladder approach in the treatment of chronic ocular pain is to first treat nociceptive sources of pain which on the ocular surface would include inflammation^10,11, low tear volume, and meibomian gland disease (MGD).¹² In those in whom pain persists, or in those with a suspected neuropathic component to pain, alternative agents have been used. This includes topical therapies such as autologous serum tears and amniotic membrane, oral therapies, such as pregabalin and gabapentin, adjuvant therapies such as periocular injections of botulinum toxin and periocular nerve blocks with combination of methylprednisolone/bupivacaine³. Similar to chronic pain outside the eye, many patients have persistent pain despite multiple approaches.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive neuromodulating therapy that has been found to be effective in treating various chronic pain syndromes.^13–16 After placing electrodes at the skin surface, electrical signals are transmitted that activate inhibitory interneurons and decrease nociceptor firing, ultimately resulting in inhibited transmission of ascending pain signals.¹⁷ The RS Medical RS-4i Plus Sequential Stimulator is a device that combines the conventional TENS technology with interferential current therapy (ICT). ICT means that the two pairs of electrodes deliver two slightly different frequencies, 5000Hz and 5100Hz, for example, interfering with each other and generating a 100 Hz beat frequency that is more comfortable as it reduces unwanted stimulation of cutaneous nerves.¹⁸ In the current protocol, two pairs of electrodes are placed bilaterally along the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve, on the forehead and at the temple, respectively. In our first study, we demonstrated ocular pain reduction after one 30-minute session of ICT.¹⁹ Specifically, ocular pain was reduced by 58% (4.54±3.18 to 1.92±2.50) in the right eye and 55% (4.46±3.36 to 2.00±2.38) in the left eye. However, it is not known if this approach is feasible as part of the long-term management of ocular pain. That is, can TENS be integrated into the multimodal treatment of eye pain and will it have long term beneficial effects on pain? To bridge this knowledge gap, this study retrospectively reviewed the integration and efficacy of TENS in individuals in whom the device was prescribed for home use.

MATERIALS AND METHODS

Design and Patients

Retrospective study of individuals who received an interferential TENS unit for the treatment of ocular pain between February 2018 to July 2019 at the Miami Veterans Affairs Eye Hospital or the University of Miami Pain Management Clinic. Individuals seen in either clinic are offered an in office TENS trial if (1) they have persistent ocular pain after nociceptive sources are addressed; (2) a neuropathic component to pain is suspected; and (3) they have no contraindications to TENS (epilepsy, pacemaker, skin lesion, or implant at the site of electrode placement). Those that subjectively note an improvement in ocular pain after the session and who are motivated to use the device at home are offered an RS-4i for home use.

Fourteen patients were identified who were offered a TENS unit for home use after successfully completing an in-clinic trial. One patient was excluded for never receiving the device and 3 were excluded for having follow-up times less than 3 months. Of the 10 individuals, median age was 47.5, with a range of 32–73 years. Eight patients were male, 6 self-identified as white, and 5 as Hispanic (Table 2).

Table 2:

Symptom and sign profile of the 10 patients prior to receiving the TENS unit

ID	DEQ5	OSDI	Schirmer’s (right) (mm)	Schirmer’s (left) (mm)	TBUT (right)	TBUT (left)	Inflammadry (right)	Inflammadry (left)	Corneal Staining (right)	Corneal Staining (left)
1	7	77	25	30	10	10	Negative	Positive	0	0
2	12	77	4	4	5	5	Positive	Negative	1	1
3	20	88	7	5	8	9	Positive	Negative	4	1
4	17	27	18	10	7	8	Positive	Positive	3	2
5	20	90	5	8	9	8	Negative	Negative	0	0
6	12	83	12	9	5	7	Positive	Negative	0	0
7	19	30	10	7	3	15	Positive	Positive	5	2
8	13	71	5	4	4	4	Negative	Negative	2	3
9	21	94	3	10	7	5	Negative	Negative	5	7
10	17	67	10	7	10	5	Positive	Positive	1	1

TENS=transcutaneous electrical nerve stimulation; ID=patient identification number; DEQ5=Dry Eye Questionnaire 5; OSDI=Ocular Surface Disease Index; TBUT=tear break-up time

Treatment

Individuals who received the TENS were instructed to use the device up to 3 times a day at an amplitude of their choice. The device is set at pre-programmed interferential 5000/5100 Hz frequencies generating a 100 Hz beat frequency. After placing 4 electrodes in close proximity to the terminal cutaneous trigeminal nerve branches over the forehead and temple (Figure 1), patients manually determine the treatment amplitude by incrementally increasing the signal until the point of pain and then decreasing to one level below. This is done first on the right side and then on the left side.

Figure 1:

TENS applicators in position prior to treatment

TENS=transcutaneous electrical nerve stimulation

Data Collected and Outcome Measures

Information was collected at last follow up, either in-clinic or via a phone interview, to assess frequency of use and ocular pain. The Miami VA Institutional Review Board approved the retrospective review of records which was conducted in compliance with the Health Insurance Portability and Accountability Act (HIPAA) and adherence to the tenets of the Declaration of Helsinki. Patient responses were coupled to a chart review that recorded demographics, co-morbidities, and eye parameters prior to TENS use (Table 1 & 2).

Table 1:

Demographics and co-morbidities of the patient population

ID	Age	Sex	Race/Ethnicity	Ocular co-morbidities	Non-ocular chronic pain conditions	Systemic pain medications	Ocular pain medication
1	46	M	W/NH	PRK, MGD	Psoriatic arthritis, plantar fasciitis	Meloxicam, secukinumab	Cyclosporine, artificial tears, AST
2	55	M	B/NH	PRK, ATD, EDE	TBI, migraines, arthritis, cervical pain	Meloxicam, pregabalin	Cyclosporine, artificial tears, lubricating solution
3	73	M	W/NH	None	Migraines, arthritis, cervical pain	Meloxicam, gabapentin, duloxetine	Cyclosporine, ketotifen
4	32	M	B/NH	None	TBI, migraines, back and knee pain	None	Cyclosporine, steroid
5	55	M	W/H	None	Trigeminal neuralgia, back pain	Carbamazepine, narcotic	Cyclosporine, artificial tears
6	48	F	W/H	LASIK, EDE	Fibromyalgia, depression	Duloxetine	Cyclosporine, ketotifen, AST
7	40	M	B/H	MGD, EDE	Fibromyalgia, back pain, shoulder pain, TBI	Gabapentin, naproxen	Cyclosporine, artificial tears, AST
8	58	M	B/H	ATD, EDE	Migraine, back pain	Doxycycline	Cyclosporine, artificial tears, steroid, lubricating solution
9	47	F	W/H	LASIK, ATD, EDE	TBI, migraines	Carbamazepine, pregabalin, doxycycline, diclofenac	Cyclosporine, AST, artificial tears, lifitigrast
10	32	M	W/NH	LASIK, EDE	Migraines, back pain, shoulder pain, joint pain, arteritis, muscle pain, herniated disc	Gabapentin	Cyclosporine, ketotifen, artificial tears, lifitigrast

ID=patient identification number

F=female; M=male; W=white; B=black, H=Hispanic, NH=not Hispanic

PRK=photoreactive keratectomy, MGD=meibomian gland disease (determined by ≥2 quality of meibum in either eye); ATD=aqueous tear deficiency (determined by Schirmer less than 5mm in either eye); EDE=evaporative dry eye (determined by tear breakup time less than 5 seconds in either eye); LASIK= laser-assisted in situ keratomileusis; TBI=traumatic brain injury; AST=autologous serum tears

All pain scales used a 0–10 scale, with 0 indicating no pain and 10 indicating the most severe pain imaginable. This was assessed for average ocular pain intensity over a 1-week recall, and also for specific descriptors including “sensitivity to wind,” “sensitivity to light,” and “dryness”. Four individuals had bilateral and symmetric eye pain, 5 had asymmetrical eye pain, worse in the right in 3 and left in 2, and one had isolated left eye pain. When rating eye pain, patients rated pain considering both eyes and were asked to rate the overall pain they were experiencing.

Dry Eye Exam

To quantify eye symptoms, patients completed two validated questionnaires: the Dry Eye Questionnaire 5 (DEQ5) which assesses the frequency and severity of dryness and discomfort and the Ocular Surface Disease Index (OSDI), which assesses for spontaneous and evoked eye pain, visual complaints, and impact of symptoms on activities of daily living. Ocular surface assessments included a qualitative measurement of matrix metalloprotease 9 (MMP-9) via Inflammadry (Quidel), tear film break up time (lower values indicate faster break up of tears) and tear production (mm wetting at 5 minutes) via Schirmer strips (a lower score indicates less production).”

Statistical Analysis

Data were analyzed using SPSS 26. Data are reported as frequencies or medians with ranges. Pre- vs post-treatment parameters were examined via Wilcoxon signed-rank test. P values less than 0.05 were considered statistically significant.

RESULTS

Comorbidities

Co-morbid ocular conditions included refractive surgery in 4 patients (40%). All patients were concomitantly treated with a combination of topical therapies including cyclosporine 0.05% (n=10; 100%), artificial tears (n=8; 80%), autologous serum tears (n=4; 40%), ketotifen (n=3, 30%), and corticosteroids (n=2, 20%) based on their individual clinical profiles. At the visit in which the TENS unit was given, DE symptom scores were in the severe range with a median DEQ5 score of 17.0 (range 7–21) and OSDI score of 73.9 (range 27–94). In addition to symptoms of dryness, all 10 patients complained of chronic ocular pain (duration greater than 6 months) and reported evoked pain to wind and light. DE sign profiles varied between patients. 30% of patients had an aqueous tear deficiency (ATD) (defined as Schirmer <5mm in either eye) with a median Schirmer score of 6.0 mm (range 3–25) in the more severely affected eye. 60% had a fast TBUT (defined as <5 seconds in either eye) with a median of 5.0 seconds (range 3–10). 70% had ocular surface inflammation, as evidenced by a positive InflammaDry in either eye. 20% of patients were identified to have MGD, as characterized by a ≥2 quality of their meibum in either eye.

The majority of individuals had comorbid pain conditions including migraines (n=6; 60%), arthritis (n=3; 30%), fibromyalgia (n=2; 20%) and trigeminal neuralgia (n=1; 10%). These conditions were being treated with a variety of oral medications including non-steroidal anti-inflammatory drugs (n=5; 50%), gabapentin (n=3; 30%), pregabalin (n=2, 20%), carbamazepine (n=2, 20%), and duloxetine (n=2, 20%).

Integration of TENS

All 10 individuals were able to incorporate the RS-4i TENS unit into their ocular pain management for a minimum of 3 months (median length of use 6.5 months, range 3–14) and all reported continuing to use their device at last point of contact. The patients reported an initial median use of the device 14.0 times per week (range 3–21), but they started using the device less frequently as they felt the benefits, only using it 3.0 times per week (range 3–21) at last point of contact.

Ocular pain over time

Nine of ten patients reported subjective improvement in ocular pain over time and felt the use of TENS improved their overall pain self-management abilities. One patient reported an increase in pain (7 → 9) pre- vs post-treatment, but she reported that she still used the device consistently. Overall, ocular pain scores decreased by 27.4% (mean rank=5.6, Z=−2.1, p=0.02) post- vs pre-treatment (Figure 2). No significant changes were noted in specific pain symptoms including wind hyperalgesia, photoallodynia, or dryness. No adverse events associated with TENS were reported by any patient.

Figure 2:

Pain scores in individual patients over time in months

DISCUSSION

In this retrospective study, we found that TENS, in conjunction with topical ocular and systemic medications, could be integrated into the overall management of ocular pain and was used by all patients for a minimum of 3 months, with the longest follow-up being 14 months. Compared to pre-treatment levels, individuals reported overall less ocular pain on follow-up. Our data is consistent with our prior study which showed that one 30-minute session of TENS significantly reduced ocular pain during the in-clinic trial.¹⁹ TENS has also been studied in the management of peri-surgical eye pain. One study identified patients who utilized TENS as an adjuvant analgesic either during (n=4) or after ocular surgery (n=6) at a frequency of 2 to 110 Hz (specifics per case not provided). Seven out of 10 patients self-reported analgesic effects, including the 4 patients who utilized TENS during their surgical procedure and 3 of 6 who underwent a 30-minute TENS session post-operatively.²⁰

Neurostimulation has also been used to treat facial pain outside the eye, most robustly in the setting of episodic and chronic migraine.^21–23 Cefaly (Cefaly Technology) is a device that simulates the supratrochlear and supraorbital nerves (branches of V1). It is used both to reduce the frequency of migraine attacks (prophylaxis) and to abort migraine attacks (treatment). For prophylaxis, 67 subjects (mean age 36 years) were randomized to active (60 Hz) versus sham stimulation, applied daily for 20 minutes for a period of 3 months. The mean number of migraine days decreased significantly in the active (6.94 vs 4.88; p=0.023), but not in the sham group (6.54 vs 6.22; p=0.608).²⁴ For treatment, 109 subjects (mean age 40 years) were randomized to either active (100 Hz) or sham stimulation for 1 hour. Pain was significantly reduced in the active treatment group compared to the sham group: −3.46±2.32 vs −1.78±1.89 or −59% vs −30%, p<0.0001.²⁵

TENS has also been studied in temporomandibular disorder. In one study, participants (n=40, age 20–55, 16 male) were randomly assigned to two groups, medication only (n=20, group A) or medication plus TENS (n=10, group B) (TENS, Bharat Medical Systems; frequency not reported). Both groups received the same medication schedule (combination of analgesics and muscle relaxants), and after two 30-minute TENS sessions, 5 days apart, group B was found to have significantly more pain reduction (69%) compared to group A (64%) (p=0.019).²⁶

In trigeminal neuralgia (TN), one prospective open label study (n=30) utilized 20-minutes daily TENS (Waves technologic, New Delhi; frequency not specified) for 20–40 days. Electrodes were placed along the individual distribution of pain (inferior alveolar, infra orbital, supra orbital, and lingual nerve branches) in addition to a temporal electrode to complete the circuit. Overall, patients reported an average 65% reduction in pain at 1 month (8.9 to 3.1 on a 0–10 NRS), and an average 85% reduction (8.9 to 1.3) at 3 months.²⁷

In our retrospective study, ocular pain was reduced by 27% after a minimum 3-month span. Compared to other studies on facial pain, we observed a smaller degree of pain reduction in our cohort. However, most of our assessed time points were at greater than 3 months and there is a paucity of data on whether effects of TENS are sustained or wane with time in individuals with chronic facial pain.

There is biologic plausibility that TENS may affect eye pain. The pathway of noxious sensation from the cornea to the brain starts along primary afferent unmyelinated C and lightly myelinated Aδ fibers of the nasociliary branch of V1 to the trigeminal ganglion.²⁸ Afferents from the periphery then enter the spinal tract of trigeminal nerve and synapse within the spinal trigeminal nucleus. Second order neurons decussate and ascend via the trigeminal-thalamic tract to the thalamus, and third order neurons continue to the postcentral somatosensory gyrus and other projection sites.²⁹

TENS may interact with these pathways at multiple points through both peripheral and central mechanisms.^17,30 One study identified that TENS (Eclipse+; EMPI Inc.; 100 Hz) works as an anti-hyperalgesic by stimulating deep tissue large diameter afferents as opposed to cutaneous afferents. In regards to ocular pain, TENS could modulate ocular pain by stimulating deep Aβ afferent fibers within V1 and possibly V2, thus blocking pain signals arising from unmyelinated C and lightly myelinated Aδ fibers, as described in the gate control theory (Figure 3).^30,31 High-frequency TENS (>60 Hz) has also been found to have effects at the level of the spinal cord through activation of supraspinal δ-opioid and cholinergic receptors, modifying the release of gamma-Aminobutyric acid (GABA) and enkephalins.^32–34 This mechanism is proposed to modulate ocular pain ultimately through an inhibitory effect on interneurons within the trigeminal-thalamic tract, preventing the further propagation of facial pain.²² Supraspinal effects of TENS have also been investigated. High-frequency TENS has been found to activate μ- and δ-opioid receptors within the rostral ventral medulla (RVM). The RVM is crucial in mediating descending modulation of pain, and there is evidence that this mechanism applies to the trigeminal pathway to inhibit further pain propagation, as both trigeminal input to the RVM and projections from RVM to spinal trigeminal nuclei have been shown in mammalian species^35–37.

Figure 3:

Nociceptive pathway in ocular pain and TENS modulation on pathway

TENS=transcutaneous electrical nerve stimulation; TG=trigeminal ganglion; SP=stellate ganglion; CA=carotid artery; NCV1=nasociliary branch of V1; STT=spinal-thalamic tract; SN=spinal trigeminal nucleus; TGTT=trigeminal-thalamic tract; TH=thalamus; C=cortex; 1=1^st order neuron; 2=2^nd order neuron; 3=3^rd order neuron

The nociceptive pathway from corneal nerves travel along the nasociliary nerve of the ophthalmic branch of trigeminal (V1). Cell bodies are located within the trigeminal ganglion. These nerve fibers course through the spinal-thalamic tract within the medulla and synapse within the spinal trigeminal nucleus, nucleus caudalis, in the medulla. From here, second order neurons decussate and cross over to the contralateral medulla. Nerve fibers course anteriorly and synapse within the thalamus. Third order neurons then synapse within the somatosensory cortex. The proposed locations of TENS modulation of this pathway are in three main areas. A) TENS fiber stimulation of Aβ deep afferent fibers, as opposed to cutaneous Aβ fibers, within the nasociliary nerve. Through the Gate Control theory³¹, it is proposed that they prevent the propagation of electrical signals through lightly myelinated and unmyelinated Aδ/C fibers.^30,31 B) TENS is proposed to stimulate delta-opioid and cholinergic receptors within the spinal nucleus of the medulla, which have an inhibitory effect on ascending nociceptive fibers.^32,33 C) Within the cortex, TENS has been found to eliminate hypometabolism within the orbitofrontal cortex and rostral angular cingulate cortex, which has been identified in humans via PET scans and fMRI.^38,39 D) TENS may also have effects on sympathetic efferent hyperactivity. The stellate ganglion contains postganglionic sympathetic fibers that project fibers around the carotid artery. TENS may act as a sympatholytic accounting for part of its analgesic clinical effects.⁴³

Additional central mechanisms of TENS have been identified in human models with the use of PET and fMRI. In 14 patients with episodic migraines, patients at baseline were found to have hypometabolism within the orbitofrontal (OFC), rostral anterior cingulate (rACC), and middle temporal lobe cortices, compared to healthy controls. After 3 months of Cefaly use, there was a significant reduction in hypometabolism of the OFC and rACC of the migraine patients in addition to a significant reduction of monthly migraines.³⁸ Additionally, TENS (Cefaly) has been studied with fMRI in migraine patients: it was identified that there is functional modulation in the ACC which may be related to its anti-nociceptive effects.³⁹ These findings indicate that TENS may have an additional central neuromodulatory effects within human subjects, in addition to the peripheral and spinal mechanisms of chronic pain control previously discussed that were identified in animal models.

Furthermore, it should be noted that, not infrequently, sympathetic efferent hyperactivity may be a prominent feature in the pathogenesis and maintenance of neuropathic syndromes⁴⁰, including trigeminal pain⁴¹, and possibly eye pain.⁴² In this context, TENS has been shown to modulate sympathetic activity by a sympatholytic effect and this may also partially account for its analgesic clinical effects in eye pain.⁴³

Finally, it is important to mention that in patients with established ocular pain, it is likely that adjacent nerve fibers in the supraorbital, supratrochlear or infraorbital nerves, not directly exposed to noxious insults, may contribute to the painful manifestations, and TENS may interact along these additional activated nerve pathways through similar mechanisms described above for its analgesic effects.⁴⁴

As with all studies, our study’s findings must be considered in light of its limitations which included a retrospective methodology on a specific patient population. In addition, given small numbers, we were not able to evaluate whether specific baseline factors predict a more robust effect of TENS on ocular pain. Furthermore, TENS was used as part of a multimodal approach and we therefore cannot determine the isolated effect of TENS on ocular pain. Future studies are thus needed to prospectively evaluate the effect of TENS in various ocular pain populations, at multiple time points, with appropriate control groups, and examine the effect of TENS on other aspects of eye pain, such as inflammation and tear film parameters. Despite these limitations, the novel contribution of the study is that similar to pain outside the eye, we demonstrate that TENS can safely be used for the long-term management of ocular pain. Ultimately, we found that all individuals continued treatment for at least 3 months, and for up to 14 months, and most of them indicated that they felt their pain was better managed than prior to using the device. However, it is important to remember that there are many neuromodulation approaches to treat chronic pain, such as percutaneous electrical nerve stimulation (PENS), peripheral nerve stimulation (PNS), and peripheral nerve field stimulation (PNFS) and we do not know whether these approaches will be better than TENS for the treatment of ocular pain. Yet, we found that TENS is a simple, effective and safe treatment that was used by patients in the context of self-management of their ocular pain.