Table 1.
In-human neurostimulation trials for chronic pain disorders addressed to molecular phenotyping, including markers relevant for immunometabolism.
| Year/Study Design | Pain Disorder | Stimulation Target | Patients | Score-Based Parameter | Stimulation Paradigm | Immunometabolic Parameter | Treatment Duration |
|---|---|---|---|---|---|---|---|
| 2019/RCT [4] | Migraine | Cervical branch vagus nerve (nVNS) | [48] | Head pain Severity-Frequency, BMI, PSQI, MIDAS, BDI | 120 sec dose bilateral vagus nerve applied 2 times/day (1 ms bursts of 5 kHz sine waves every 40 ms (25 Hz)) | ELISA serum (leptin, ghrelin, adiponectin, IL-1β, IL-6, IL-10, TNF-α, HMGB-1) | 2 months |
| 2019/pPS [52] | Migraine | Cervical branch vagus nerve (nVNS) | [24] | Head pain Severity -Frequency, BMI, PSQI, MIDAS, BDI, EQ-5D-5L | 120 sec dose bilateral vagus nerve applied 2 times/day (1 ms bursts of 5 kHz sine waves every 40 ms (25 Hz)) | ELISA saliva (IL-1β – oxytocin) | 10 weeks |
| 2019/pPS [5] | CRPS | DRG (L4-DRGSTIM) | [24] | Neuropathic pain Severity, BMI, PSQI, BDI | Chronic stimulation, bipolar, 20 Hz, 200-300 µsec, 300–1600 µA | ELISA serum-saliva (leptin, ghrelin, adiponectin, IL-1β, IL-6, IL-10, TNF-α, HMGB-1, BDNF, oxytocin) | 3 months |
| 2019/pPS [79] | CRPS | DRG (L4-DRGSTIM) | [12] | Neuropathic pain Severity, BMI, PSQI, BDI | Chronic stimulation, bipolar, 20 Hz, 200–300 µsec, 300–1600 µA | Gene expression blood cells (FFAR2, ILRN, IL-17F, PLA2G2, NOX1 (metabolic function)) | 3 months |
| 2018/pPS [6] | FBSS CLBP | Spinal Cord dorsal column level Th10-11 | [24] | FBSS-CLBP Severity, BMI, PSQI, BDI | BurstDR chronic stimulation, bipolar, 40 Hz burst rate, 500 Hz intraburst rate, 1 msec, 2.05–2.45 mA | ELISA-serum (leptin, adiponectin, ghrelin) | 3 months |
| 2017/pPS [7] | FBSS CLBP | Spinal Cord dorsal column level Th10-11 | [24] | FBSS-CLBP Severity, BMI, PSQI, BDI | BurstDR SCS chronic stimulation, bipolar, 40 Hz burst rate, 500 Hz intraburst rate, 1 msec, 2.05–2.45 mA | ELISA-serum (IL-1β, IL-10, TNF-α, HMGB-1) | 3 months |
| 2017/RCT [78] | CRPS | Spinal Cord dorsal column level Th10-11 | [24] | CRPS Severity – Phenotype FBSS – CLBP Severity, BMI, PSQI, BDI | SCS chronic stimulation, bipolar, BurstDR vs 40 Hz vs 500 Hz vs 1200 Hz vs sham | ELISA-artificial skin blister (IL-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, Eotaxin, G-CSF, GM-CSF, IFN-g, IP-10, MCP-1, MIP-1a, MIP-1b, PDGF-BB, TNF-a, VEGF, T cells) | 3 months |
| 2016/pPS [75] | NP Phantom pain |
Spinal Cord dorsal column level Th10-11 | [14] | Pain Severity BMI | Chronic stimulation, bipolar, tonic SCS mode with 50 Hz SCS on vs off | Proteomic Mass Spectrometry-CSF (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein, gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein, VGF and dickkopf-related protein 3) | 12 months |
| 2014/pPS [77] | FBSS | Spinal Cord dorsal column level Th10-11 | [9] | Pain Severity, SF-36 | Chronic stimulation, bipolar, tonic SCS mode with 40–100 Hz, 210–360 µsec, 3–7.4 Volt | ELISA-CSF (GDNF) | |
| 2013/pPS [76] | NP Phantom pain |
Spinal Cord dorsal column level Th10-11 | [14] | Pain Severity, SF-36 | Chronic stimulation, bipolar, tonic SCS mode with 40–100 Hz, 210–360 µsec, 3–7.4 Volt | ELISA-CSF (VEGF, BDNF, MCP-1, chemokines) |
CM = chronic migraine; EM = episodic migraine; HFEM = high frequency episodic migraine; FBSS = failed back surgery syndrome; CLBP = chronic lower back pain; CRPS = complex regional pan syndrome; NP = neuropathic pain; VAS = visual analogue scale; HIT = Headache Impact Test; m = month; MIDAS = migraine disability score; BDI = beck depression inventory, PSQI = Pittsburgh Sleep Quality Index; BMI = body mass index; EQl = Quality of life; nVNS = cervical non-invasive vagus nerve stimulation; SCS = tonic spinal cord stimulation; BurstDR-SCS = burst spinal cord stimulation; DRG-SCS = dorsal root ganglion stimulation; CSF = cerebrospinal fluid; IL = interleukines, HMGB-1 = high-mobility group box-1; DAMP´S = damage-associated molecular pattern; free fatty acid receptor 2 (FFAR2); interleukine receptor 1 antagonist (ILRN), interleukine 17-F (IL-17F); phospholipase A2, group IIA (PLA2G2); NADPH oxidase (NOX1); VEGF = vascular endothelial growth faxtor; GDNF = glial cell-derived neurotrophic factor; ELISA = enzyme-linked immune assay; pPS = prospective pilot study; rCS = retrospective case series; RCT = randomized, double-blind sham-controlled study; w = week; y = year.