Differential Target Multiplexed Spinal Cord Stimulation in Persistent Spinal Pain Syndrome Type II: A Multicenter Prospective Study

Neuromodulation. 2026 Apr 13:S1094-7159(26)00079-6. doi: 10.1016/j.neurom.2026.03.016. Online ahead of print.

ABSTRACT

OBJECTIVES: Differential target multiplexed spinal cord stimulation (DTM-SCS) is a novel neuromodulation paradigm designed to modulate neuroglial interactions involved in chronic pain. This study tested the hypothesis that in a real-world clinical setting, DTM-SCS is associated with sustained improvements in pain intensity and related clinical outcomes in patients with persistent spinal pain syndrome type II (PSPS-II) and that early inflammatory biomarker modulation may reflect interindividual heterogeneity in treatment response.

MATERIALS AND METHODS: This was a prospective, multicenter, observational cohort study conducted across eight Italian pain management centers. Adult patients with PSPS-II and severe low back pain (Numeric Rating Scale [NRS] > 5) were consecutively enrolled. All participants underwent a DTM-SCS stimulation. Clinical outcomes included pain intensity (NRS), functional disability (Oswestry Disability Index [ODI]), neuropathic pain symptoms (Douleur Neuropathique 4 [DN4]), pain catastrophizing (PCS), and health-related quality of life (Patient-Reported Outcomes Measurement Information System [PROMIS]). Assessments were performed at baseline and at four, 12-, and 24 weeks. Peripheral inflammatory cytokines were measured at baseline and four weeks, and exploratory cluster analysis was applied. Longitudinal changes were analyzed using repeated-measures comparisons and mixed-effects models.

RESULTS: A total of 71 patients were enrolled, with 67 evaluable at the primary end point (12 weeks). Mean NRS decreased significantly from baseline (8.35 ± 1.39) to 12 weeks (5.34 ± 2.03; mean difference -3.01, p < 0.0001), with sustained improvement at 24 weeks. At 12 weeks, 51.47% of patients achieved a ≥50% reduction in pain. Significant improvements also were observed in ODI, DN4, PCS, and selected PROMIS domains (all p < 0.0001). Exploratory cytokine analysis identified three clusters; one cluster characterized by coordinated cytokine modulation showed greater pain reduction at 12 weeks (p = 0.025). The safety profile was consistent with established SCS therapy.

CONCLUSIONS: In routine clinical practice, DTM-SCS was associated with sustained improvements in pain, function, and patient-reported outcomes in PSPS-II, with an acceptable safety profile. Exploratory biomarker findings suggest biological heterogeneity that may influence treatment trajectories, supporting further controlled and biomarker-informed studies.

PMID:42159521 | DOI:10.1016/j.neurom.2026.03.016