The research team enrolled 30 patients whose pain had been refractory to medication for at least one year, including gabapentinoids, and whose daily morphine-equivalent dose remained below 120 mg. The cohort comprised 11 patients with diabetic peripheral neuropathy (DPN), 8 with chemotherapy-induced peripheral neuropathy (CIPN), 9 with chronic idiopathic axonal polyneuropathy (CIAP), and single patients with amyloidosis and Fabry disease. Mean age was 60 years, two-thirds were male, and mean pain duration was 8.2 years, underscoring how long these patients had endured severe symptoms before reaching advanced therapy.

Baseline characterization revealed striking clinical differences across etiologies that likely reflect distinct underlying disease mechanisms. Patients with CIAP reported the heaviest pain symptom burden, with higher levels of evoked pain such as hyperalgesia and allodynia, greater burning feet, and a more pronounced affective pain component, a pattern the authors interpret as greater central sensitization, possibly amplified by the prolonged diagnostic uncertainty these patients face. In contrast, patients with DPN carried more neurological deficits, with higher Utah Early Neuropathy Scale scores (20.3 versus 13.3 in CIAP), worse pin sensation, and lower intraepidermal nerve fiber density at both distal-leg and proximal-thigh biopsy sites, indicating a more aggressive neurodegenerative process affecting both small and large fibers. CIPN patients had notably shorter pain duration (3.8 years versus 10.2 in CIAP), consistent with the more acute onset that follows chemotherapy exposure.

Across the whole cohort, baseline disease burden was severe by every measure. Mean pain intensity on the visual analog scale was 8.6 out of 10, the Neuropathic Pain Symptom Inventory score was 61.1 out of 100, and the Short-Form McGill Pain Questionnaire-2 reached 115.5 out of 220, all within the severe range. Autonomic involvement was moderate, with abnormal sweating, orthostatic intolerance, gastrointestinal and urogenital disturbances evident on the Survey of Autonomic Symptoms and the Small Fiber Neuropathy Symptoms Inventory Questionnaire. Health-related quality of life was profoundly impaired, with a mean EQ-VAS of 38.8 out of 100, substantial pain-related sleep interference, and reduced global functioning.

All patients underwent implantation of two percutaneous epidural leads at the T10–T11 vertebral levels to target lower-limb pain, with a third cervical lead at C4–C7 added for the 40 percent of patients who also had upper-limb symptoms, reflecting the length-dependent pattern typical of polyneuropathy. Following a 7–14 day trial with an external stimulator, patients achieving at least 50 percent pain relief received a permanent implantable pulse generator. The trial-to-permanent ratio was 86 percent. Programming was individualized: 83 percent of patients selected a low-frequency (90 Hz) fast-acting sub-perception modality delivering stimulation below the perception threshold, while 17 percent chose combination therapy integrating supra-perception paresthesia-based stimulation with an anatomically guided sub-perception configuration designed to maximize modulation of dorsal horn elements.

The results were remarkable. Mean VAS pain intensity plummeted from 8.6 at baseline to 2.0 at 12 months, an approximate 75 percent reduction that was sustained across all follow-up visits (p < 0.001). Multidimensional pain severity on the SF-MPQ-2 fell from 115.5 to 23.0, and the NPSI neuropathic symptom score dropped from 61.1 to 11.1, far exceeding established minimal clinically important difference thresholds. Linear mixed-effects models confirmed significant improvements over time across every patient-reported outcome, with the largest effects in pain-related measures. Notably, the magnitude of response differed by etiology: estimated pain reductions were approximately 85 percent in DPN, 75 percent in CIPN, and 70 percent in CIAP, with the group effect significantly favoring DPN over CIAP (p < 0.001). Even the single patients with Fabry disease and amyloidosis experienced roughly 55 percent reductions in pain intensity, with the amyloidosis patient showing 70–80 percent reductions in overall pain and neuropathic symptom scores.

Beyond pain, the therapy produced unexpected benefits in autonomic and wellbeing domains. Autonomic symptom burden fell by roughly 40 percent across etiologies, with the SAS decreasing from 16.5 to 9.9 (p = 0.02) and the SFN-SIQ dropping 46 percent from 13.5 to 7.3 (p = 0.001). Item-level analyses revealed significant improvements in sensitive skin, hot flashes, dizziness on standing, diarrhea, cold feet, nausea and bloating, and lightheadedness, findings the authors suggest may reflect improved vasomotor regulation, peripheral perfusion and thermoregulatory activity, mechanisms previously described in peripheral vascular disease and spinal cord injury. Erectile dysfunction, particularly prevalent in DPN, showed limited response, indicating that further optimization of stimulation parameters may be needed to target this impairment specifically.

Quality of life transformed in parallel. The EQ-VAS rose from 38.8 to 77.9 and the EQ-index from 0.70 to 0.93, improvements that vastly exceeded the reported minimal clinically important difference of 0.05 and reached normative thresholds for age-matched Spanish populations. Pain-related sleep interference collapsed from severe to mild impairment, with CPSI-3 scores falling from 18.4 to 3.5 (p < 0.001). Global functioning improved from 63.9 to 86.1 on the GAF scale. Medication burden fell dramatically: 59 percent of patients completely discontinued analgesic medications and the remaining 41 percent reduced their use. At final follow-up, 96 percent of participants rated themselves as much or very much improved on the patient global impression of change.

Perhaps the most intriguing finding concerns small nerve fiber integrity. Intraepidermal nerve fiber density, the gold standard for quantifying small-fiber involvement, was assessed through skin punch biopsies at baseline and 12 months. Given that IENFD is expected to decline by approximately 11 percent annually in these conditions, the overall stability observed over 12 months, with proximal values changing from 5.0 to 4.8 fibers/mm and distal values remaining unchanged at 3.1 fibers/mm, suggests attenuation or stabilization of small-fiber degeneration following SCS. Increases outnumbered decreases in the non-parametric analysis, although changes were modest and not statistically significant. The authors caution that larger controlled studies are needed to establish causality, particularly in CIPN, where the natural history of fiber loss remains uncertain.

Neurological signs themselves, including sensory and motor tests on the UENS, remained largely unchanged (17.3 to 16.4; p = 0.96), with only the allodynia subscore showing significant group-level improvement. The authors attribute this discrepancy between symptom relief and sign stability to the distinction between rapid modulation of neural activity and central pain processing versus the slower processes of axonal regeneration and remyelination required for structural recovery. The complication rate was low, with one explantation due to infection, one lead revision, and one exclusion for atypical clinical evolution. The study’s main limitations include its small sample size, single-center design, and etiological heterogeneity, which constrain subgroup comparisons. Nevertheless, the authors argue that their findings begin to fill a critical evidence gap for CIAP, a subtype potentially accounting for up to one-third of polyneuropathy cases, and extend support for SCS in CIPN, whose incidence is expected to rise with improving cancer survival rates. For patients trapped in the cycle of failed medications and escalating pain, the message is clear: neuromodulation deserves consideration far earlier and across far more diagnostic categories than convention has allowed.

Subject of Research: Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies

Article Title: Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies

Article References: Canós, Á., Castel, B., Bermejo, A., Izquierdo Aguirre, R. M., Robledo, R., Gallach, E., Sevilla, T., Argente, P., & Huertas, I. (2026). Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies. Frontiers in Pain Research, 7, Article 1954493. https://doi.org/10.3389/fpain.2026.1954493

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1954493

Keywords: Clinical, phenotypes, outcomes, spinal, cord, stimulation, painful, peripheral, polyneuropathy, cohort, including, diabetic