This pilot RCT examined the effectiveness of daily wearable TENS therapy in alleviating pain, fatigue, and gait alterations in individuals with PASC. High-dose TENS participants experienced greater reduction in functional interference due to pain compared to low-dose TENS participants. Additionally, objective assessment of gait parameters revealed significant improvement in stride time and cadence at 4 weeks from baseline in the high-dose TENS group across various walking tasks. Moreover, both groups exhibited high compliance rates (≥ 3 hours per day) and reported device acceptability above 70% during the blinded study phase.
Previous RCTs utilizing FDA-approved pharmacological treatment for FM (i.e., duloxetine48, milnacipran49) have shown improvement in functional interference from pain when compared to placebo, with a BPI-I between-group mean difference ranging from 0.58–1.74 in a 12-week timeframe; however, accompanied by notable side effects including nausea (> 36%), constipation (> 14.7%), and dizziness (> 10.5%), amongst others48,49. The present study explored TENS as a safer pain management intervention with known minimal side effects50. We acknowledge the IG had less severe functional baseline pain scores than the PG, thus, evidence suggests this cohort would have had lesser improvement post-intervention 51. However, after 4-weeks of TENS therapy, the IG showed significantly greater reduction of BPI-I scores compared to the PG (mean difference = 2.61 points, p = 0.008, Table 2).
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) suggests a 1-point mean change from baseline to the targeted endpoint as a meaningful clinically significant difference (MCID)52. In our study, the FM subgroup undergoing high-dose TENS showed a trend for reaching this MCID as early as 4-weeks (mean change = 1.06 points, p = 0.080). This magnitude of reduction in BPI-I scores with high-dose TENS mirrors the improvements noted by Kong et al.53 and Jamison et al.34 in non-PASC patients with FM after 60-days and 3-months therapy, respectively. Our study uniquely demonstrates the benefit of high-dose TENS over low-dose in individuals with PASC and FM-like symptoms within a short timeframe. Despite a small sample size, the substantial effect size compared to low-dose TENS at 4-weeks (d = 2.26) indicates the potential of high-dose TENS for larger, longer-term studies.
Functional interference from fatigue is crucial to assess in PASC patients given its prolonged and severe nature54. Similarly to FM, the origin of fatigue in PASC patients has been linked to persistent inflammatory biomarkers55.Therefore, we used the GFI to assess functional interference from fatigue, a reliable tool that has shown significant fatigue reduction (1.4 to 1.6 points) in FM patients taking mild-moderate pregabalin doses (300mg to 450mg) over 14-weeks 56, with further improvement when increasing doses (600mg) over 32 weeks57. Interestingly, other pregabalin trials identified that substantial fatigue reduction, such as 10-point GFI decrease, was only seen in FM patients experiencing a 30% of pain reduction58. This trend was echoed in a recent study employing 4-week TENS therapy in women with FM59, which demonstrated a significant GFI improvement of 4.6-points correlated with reduced pain evoked by movement. Similarly, our study showed a significant 6.08-point GFI improvement in the sub-group of FM patients receiving high-dose TENS at 4-weeks from baseline. However, this mean change did not correlate with the observed changes in BPI-I scores, suggesting that PASC patients with FM may experience significant functional improvement from fatigue without necessarily needing concurrent pain relief.
In a recent systematic review, significant gait alterations were found in FM patients60. Utilizing instrumented walkway systems, observational studies revealed FM patients have significantly shorter cadence and longer double support phases compared to healthy individuals in 61. The present study exhibited that PASC patients with widespread pain undergoing 4-week high-dose TENS significantly improved their cadence by 5.6% and 9.5% in the single- and dual-tasks, respectively, and 3.9% in the fast-walking task. Moreover, studies have incorporated cognitive elements (dual-task) in walking assessments to predict risk-of-fall caused by fatigue in FM patients62, showing a notable impact on double-support phase during such tasks63. In the present study, the double-support phase of PASC patients undergoing 4-weeks high-dose TENS significantly improved by 11.6% in the dual-task. While no MCID is established for gait via wearables in FM patients, Kaleth et al.64 established an anchor-based MCID for walking distance, indicating clinically meaningful fatigue improvement. Our findings suggest that reducing functional interference from fatigue may aid fall prevention in PASC patients with chronic pain; however, further risk-of-fall assessment is needed for confirmation.
To date, the objective assessment of gait improvement in FM patients has been limited to studies focusing on interventions like aerobic exercise and physical therapy65–67. Moreover, the effectiveness of TENS in enhancing gait has only been investigated in stroke patients, however incorporating exercise therapy into the treatment regimen therapy as well68. This modality is often unsuitable for PASC patients given their high-risk for post-exertional malaise69. Consequently, they are generally advised to refrain from moderate physical exertion70. In this context, high-dose TENS offers a promising alternative for improving gait parameters in PASC patients with FM-like symptoms. Nevertheless, further research with a larger sample size is essential to substantiate this potential benefit.
The adherence to analgesic drugs among FM patients can be influenced by intermittent pain and adverse events71. In a duloxetine 12-week trial, up to 21% participants discontinued therapy due to adverse events72. The present study showed no discontinuations at 4-weeks, despite 6 patients reporting mild fatigue, pain, and skin irritation. These issues were resolved with advice from the research team. Compliance resulted in a median of > 3.5 therapy sessions per day and > 26 days of device usage. High compliant (≥ 21 of days used) patients’ rate was 100% in the IG and 81.8% in the CG. However, compliance decreased in the unblinded study phase (week-4 to 8). We attribute this to disengagement from placebo devices, depression, brain fog, and multiple hospital visits encountered by our patients during the study73.
A key factor contributing to high compliance may be high acceptability and perceived benefit of the wearable TENS device. The high-dose TENS group showed slightly higher perceived usefulness compared to the low-dose group (~ 71.2% vs ~ 61.4%), consistent with a previous RCT in FM patients undergoing TENS therapy for 3 weeks74. Moreover, all other acceptability items were similar to our previous trial involving PASC individuals undergoing electrical stimulation for musculoskeletal sequelae75.