This was a prospective, randomized, double-masked (participant and investigators/outcomes assessor) pilot research study comparing hfTENS to a lfTENS control/comparison intervention, conducted between October 3, 2022, and November 30, 2024. All study procedures and the Informed Consent form and consent processes were approved by the Miami VA Institutional Review Board (IRB, #1 668 339), and the study was registered via ClinicalTrials.gov (NCT05531643), prior to commencing the study. The study was conducted in accordance with the principles of the Declaration of Helsinki and adhered to the requirements of the United States Health Insurance Portability and Accountability Act.

Potential participants were recruited from the Miami VA Medical Center and from Bascom Palmer Eye Institute (University of Miami; Miami, FL) with moderate to severe chronic ocular pain with neuropathic/nociplastic features (NOP). Target enrollment was set at 50 participants in order to include an adequate sample to evaluate the feasibility of an at home TENS protocol and the safety and tolerability of the hfTENS. Individuals were randomized in a 2:1 ratio to treatment with hfTENS and lfTENS, respectively. Randomization assignments were concealed using numbered, identical devices with stimulation programs pre-set according to the randomization schedule; the treatment code linking device number to intervention assignment was maintained by the study statistician. Devices were distributed in numeric order based on the participant’s chronological order of enrollment. Participants and all study staff involved in participant evaluations, including investigators assessing pain outcomes and ocular surface parameters, were blinded to treatment allocation. Participants in both groups completed four study visits at the Miami VA: Visit 1) screening; Visit 2) baseline ocular pain symptom assessments, quantitative sensory testing (QST), ocular examination, and an in-clinic TENS trial; Visits 3 and 4) follow-up (at 3 and 6 months after treatment initiation, respectively) ocular pain symptom assessments, QST, and ocular examination.

Study participants were informed about the opportunity to participate in this study by their medical providers during appointments. Individuals who expressed interest in participating were contacted and pre-screened over the phone or in person based on the following inclusion criteria: 1) older than 18 years of age; 2) persistent ocular pain for 6 months or longer; 3) average eye pain intensity of ≥ 4 on a 0-10 numerical rating scale (NRS); 4) presence of NOP-like symptoms (characterized by burning, wind/light sensitivity, and/or persistent pain after topical anesthesia); 5) on a stable medication regimen for the past 3 months; and 6) no prior use of TENS for orofacial conditions. Patients were excluded if they had pre-existing ocular diseases that may contribute to their pain (eg, corneal or conjunctival scarring, corneal edema, uveitis) or contraindications to TENS (eg, pacemaker, implantable defibrillator).

Written informed consent was obtained, and participants completed full screening procedures, including questionnaires regarding comorbidities and medications, as well as ocular symptom scales to confirm moderate-severe ocular pain severity and endorsement of NOP-like symptoms (eg, “burning” eye pain; allodynia or hyperalgesia to light or wind). ^,, An ocular examination was conducted to exclude participants with evidence of tear dysfunction in either eye (tear break up time (TBUT) <5 seconds, corneal fluoresceine staining > 3, or Schirmer’s test < 5 mm/5minutes; see below for ocular examination details). Participants meeting all study criteria were randomized to the hfTENS intervention or lfTENS comparison intervention.

Randomization was performed according to a computer-generated randomization schedule, using a variable ( n = 6) blocked randomization sequence. Each device had the stimulation program pre-set according to the randomization assignment by the manufacturer before delivery and the hf and lf devices appeared identical. Participants and all study staff involved in participant evaluations were blinded to treatment allocation, with the study statistician being the only person with access to the randomization code linking the stimulus condition to devices.

Visit 2 was scheduled within 2 months of the Screening Visit. Participants completed ocular symptom questionnaires to assess baseline severity of symptoms, QST procedures to assess evoked sensitivity, and an ocular examination to record baseline levels of tear parameters. Participants then underwent an initial in-lab 20-minute TENS session according to their randomization assignment. Current ocular pain intensity rating (NRS, 0-10) and side effects were recorded at 5-, 30-, 60-, and 120-minutes post-treatment. QST procedures were repeated after the 120-minute pain report. At the end of the visit, participants received instructions for self-administering TENS at home and were made to demonstrate the proper procedure to study staff who used a checklist to ensure participant understanding. The following day, participants were called to assess symptoms and side effects.

The follow-up visits occurred at 3- and 6-months (± 30 days) after Visit 2. Participants completed the same set of questionnaires, QST protocol, and ocular examination as at baseline (Visit 2). At the end of each visit, participants completed the Patient Global Impression of Change (PGIC) questionnaire and were asked to demonstrate how they used their device while study staff observed for proper technique. At the end of Visit 4, devices were collected to download data indicating the dates and time/duration of device use, and participants were offered to continue treatment with a hfTENS device. For any participant who did not attend a Visit 3 and/or 4 within the specified time frame, data from the closest ocular pain questionnaires completion from bi-weekly phone calls (see below), within 30 days of the scheduled visit date, were used for analysis purposes.

From Visit 2 to Visit 4, participants were called every-other week to assess device use, ocular symptoms, and side effects.

QST was performed at the site of pain (cornea) and at sites near to (forehead), and remote (forearm) from, the site of clinical pain (eyes) to quantify sensitivity to noxious and non-noxious stimuli as an assessment of somatosensory (dys)function.

The ocular examination included an evaluation of the cornea, tear film, and tear production. Corneal sensitivity was tested clinically using a cotton-tipped applicator (Q-tip). A wisp was made from the tip of Q-tip and applied centrally to the cornea to evaluate blink response. Responses were graded on a 4-point scale: 0 = no (no blink, patient does not feel the touch), 1 = reduced (minimal response, patient barely feels the touch), 2 = normal (appropriate blink response with feeling the touch), and 3 = increased (robust blink response and withdrawal movement away from Q-tip) sensitivity. Corneal surface damage was assessed by applying fluorescein dye to the surface of the eye, which highlights areas of epithelial disruption. The stained areas were then examined under a specialized blue light using on the slitlamp microscope. Damage was graded using a standard 0-15 point scale, based on the extent of damage to the regions of the cornea (0-3 points per region: central, inferior, superior, nasal, and temporal), with higher scores indicating more severe epithelial injury. Tear film stability was assessed using TBUT, which measures how long the eye’s tear layer remains intact after a blink. After instillation of fluorescein dye, the time between a complete blink and the first appearance of a dry spot on the cornea was recorded in seconds. Shorter TBUT values indicated greater tear film instability. Tear production was evaluated using Schirmer’s test (mm/5mins), in which small strips of filter paper were placed under the lateral third of the lower eyelid of each eye for 5 minutes. The length of tear migration (wetting on the strip) was measured in millimeters. Lower values reflect reduced aqueous tear production.

The primary outcome measure of analgesic effectiveness in this pilot trial was change in rating of ocular pain intensity measured using the 0-10 NRS. For acute effects, the primary outcome was change in ratings of the intensity of your eye pain “right now,” assessed immediately before and after the initial in-lab TENS treatment session (Session 2). For long-term effects (eg, baseline compared to 3 months and baseline compared to 6 months), the primary outcomes considered were: “eye pain right now,” “worst eye pain intensity during the past week,” and “average eye pain intensity during the past week”. Secondary outcomes examined included PGIC, and changes in other measures of ocular symptom severity (scores on NPSI-Eye, DEQ-5, and OSDI), assessments of evoked sensitivity (mechanical detection thresholds and pain and unpleasantness ratings to a standard stimulus at the cornea, VDT, and HPT with corresponding pain and unpleasantness ratings at the forehead and forearm), and ocular signs (clinical corneal sensation, corneal staining, TBUT, Schirmer score).

Data were analyzed using non-parametric tests performed in SPSS 29. Wilcoxon signed-rank tests were used to assess pre- vs post-treatment outcomes within subjects for each group (hfTENS and lfTENS). Fischer’s Exact tests and Mann-Whitney U tests were used to assess differences between the hfTENS and lfTENS groups across outcome variables. Any participants who dropped out before 3 months were excluded for the 3- and 6-month analyses.

To identify potential factors that could predict treatment response, independent of hf or lfTENS assignment, participants were categorized as responders or non-responders, based on achieving at least a 30% decrease in “worst eye pain” or “average eye pain during the past week,” at 3 months. Potential predictors of response evaluated included demographics (age, sex (queried by open-ended self-report, data categorized as male or female)), comorbidities, baseline neuropathic pain characteristics (NPSI-Eye), baseline somatosensory testing (Belmonte, VDT, HPT), and baseline ocular surface signs (clinical corneal sensation, corneal staining, TBUT, tear production).

P values less than 0.05 were considered statistically significant.

Thirty-seven participants were enrolled and randomized to treatment ( Figure 1 ). Our study sample included a nearly equal distribution of males and females (male: 49%, n = 18; female: 51%, n = 19), with an average age of 58 ± 12 years, and the majority identified as White (70%, n = 26) and non-Hispanic (54%, n = 20). A significant proportion of participants reported co-morbid psychological and non-ocular pain conditions, but no significance differences in the prevalence of these comorbidities at baseline was found between hfTENS and lfTENS groups. (Supplemental Table 1).

CONSORT Flow Diagram. This flow diagram illustrates participant progression through the pilot study. It details enrollment, intervention allocation, follow-up completion at 3 and 6 months, and inclusion in analysis. Reasons for exclusion and attrition are noted, and group-level demographic characteristics are shown.

Twenty-four participants received the hfTENS device and 13 received the lfTENS device at the start of the pilot study. Three devices had to be replaced due to report of malfunction by participants. In consultation with the study statistician, devices were replaced with another device with the same stimulus parameters, except in the case of one individual who was given the hfTENS device at the start of the study and then mistakenly replaced with the lfTENS device at Visit 3. This error was not realized until the end of the study. Data from this individual was therefore analyzed as part of the hfTENS group up to the 3-month visit (Visit 3) and was included in the lfTENS group after. Eighteen of 24 people in the hfTENS group and ten of 13 in the lfTENS group were included in the final 6-month analysis. Fourteen of the hfTENS and five of the lfTENS devices were available for data download at the end of the intervention period. Participant self-reported weekly use was much higher in both groups (median three sessions/week) compared to recorded data from the devices (median of one session/week) for the first 3 months. (Detailed device usage by hf and lfTENS groups are reported in Supplemental Table 2).

A total of 19 individuals reported an adverse effect with TENS use at some point during the study, with the most common being headaches or migraines ( n = 10) (Supplemental Table 3). Other noted adverse effects included forehead rash, forehead symptoms (eg, pain, numbness), ear sensitivity, and head “fullness” or an unbalanced sensation. While six participants reported temporarily discontinuing device use due to an adverse effect, none withdrew from the study for this reason.

After the initial in-lab TENS session, ratings of eye pain intensity “right now” were significantly reduced compared to pre-TENS ratings for both the hfTENS and lfTENS groups at all time points (5, 30, 60, 120mins; Table 1 ), with sustained therapeutic effects at 1 day after the in-lab treatment for hfTENS (median [IQR]: 4.00[4.00] at baseline to 2.00[4.00] one-day post, p =.03) but not lfTENS (4.00[5.00] at baseline to 3.50[4.00] one-day post, p =.59,). Both groups demonstrated decreases in NPSI-Eye total scores (hfTENS: 32.50[29.00] at baseline to 16.50[19.00] one-day post, p =.003; lfTENS: 40.00[64.00] to 38.00[57.00], p =.02), though the lfTENS group only had a significant reduction in the paresthesia/dysesthesia subscore, while the hfTENS group exhibited significant reductions across all NPSI-Eye subscores ( Table 1 ).

Assessment of longer-term analgesic effects at the 3-month time point, showed that both the hfTENS and lfTENS group had no significant changes in “eye pain now”, “worst eye pain during the past week”, or “average eye pain during the past week”. However, the hfTENS group had a significant reduction in NOP symptom report for the pressing (2.50[5.50] at baseline to 1.50[2.50] at 3 months, p =.03) and paroxysmal pain (1.50 [3.50] to 0.00 [1.50], p =.02) subscores of the NPSI-Eye, whereas the lfTENS group did not have significant symptom reductions for any NPSI-Eye subscores ( Table 2 ). OSDI scores similarly improved in the hfTENS group, with total scores significantly decreasing from 52.08[27.08] at baseline to 37.50[22.92] at 3 months ( p =.03) but not in the lfTENS group (68.18[45.83] to 66.67 [64.58], p =.24). While no significant changes in NOP-like symptoms were noted from baseline to the 6-month time point in the hfTENS or lfTENS groups, a significant decrease in ratings of worst eye pain during the past week was noted in the hfTENS group (6.00[4.00] at baseline to 4.50 [6.00] at 6 months, p =.049) (Supplemental Table 4).

Table 2

Effects of Hf and lfTENS on Ocular Pain and Dry Eye Symptoms After 3 Months of at-Home Use.

		hfTENS			lfTENS
		Median[IQR]		P value (n)	Median[IQR]		P value (n)
		Baseline	3 months		Baseline	3 months
Eye Pain “right now” (NRS, 0-10)		4.00[3.00]	3.00[3.00]	.32 (19)	4.00[5.00]	5.00[3.00]	.51 (11)
Eye Pain “worst over past week” (NRS, 0-10)		5.00[4.00]	5.00[5.00]	.65 (19)	8.00[4.00]	6.00[4.00]	.10 (11)
Eye Pain “average over past week” (NRS, 0-10)		4.00[4.00]	4.00[5.00]	.60 (19)	6.00[4.00]	6.00[4.00]	.39 (11)
Total NPSI-Eye (0-100)		26.00[26.00]	19.00[16.00]	.10 (19)	50.00[46.00]	39.00[50.00]	.24 (11)
NPSI-Eye Subscores	Burning (0-10)	2.00[6.00]	2.00[5.00]	.21 (19)	6.00[5.00]	5.00[7.00]	.61 (11)
	Pressing (0-10)	2.50[5.50]	1.50[2.50]	.03 (19)	3.50[4.00]	3.50[4.00]	.31 (11)
	Paroxysmal (0-10)	1.50[3.50]	0.00[1.50]	.02 (19)	4.00[3.00]	3.00[7.00]	.78 (11)
	Evoked (0-10)	3.67[2.67]	3.67[3.67]	.60 (19)	5.33[4.00]	5.33[6.00]	.23 (11)
	Paresthesia/dysesthesia (0-10)	2.50[2.50]	1.00[3.50]	.20 (19)	5.00[5.00]	4.50[7.00]	.80 (11)
Total DEQ-5 (0-22)		13.00[6.00]	12.00[8.00]	.11 (17)	16.00[6.00]	16.00[7.00]	.61 (11)
Total OSDI (0-100)		52.08[27.08]	37.50[22.92]	.03 (9)	68.18[45.83]	66.67[64.58]	.24 (7)

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