Introduction

Complex regional pain syndrome (CRPS) has been associated with a pro-inflammatory state driven by different circulating mediators. Dorsal root ganglion stimulation (DRG_STIM) suppressed pain levels and improved functional capacity in intractable CRPS in observational and randomized-controlled studies. However, in-human studies evaluating the impact of selective DRG stimulation on the neuro-immune axis in CRPS patients remains under-investigated.

Methods/Materials

This pilot study performed molecular inflammatory phenotyping (saliva/serum), gene expression assay of neuroinflammatory genes (Panther^TM pathway enrichment analysis), quantitative sensory profiling and score-based assessment of pain, mood and sleep in 24 subjects (12 CRPS patients - 12 healthy controls) before and after 3 months of selective L4-DRG_STIM.

Results

After L4-DRG_STIM CRPS pain significantly decreased with improved sleep and mood. Elevated levels were found pre- and post L4-DRG_STIM for high-mobility group box 1, tumor-necrosis factor α, IL-6 and leptin indicating a pro-inflammatory state in CRPS patients. IL-1β was elevated pre-L4 DRG_STIM, but not post-treatment. IL-10 decreased after 3 months in serum, while saliva oxytocin increased after L4-DRG_STIM (Fig.1). Gene expression analysis demonstrated down-regulated TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 and upregulated CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 (Fig.2). CRPS subjects showed significantly increased thresholds for warmth, tactile and vibration detection (WDT, MDT and VDT) and exaggerated pain summation (WUR). After 3 months of unilateral L4-DRG_STIM all pain parameters exhibited trends towards normalization of sensitivity accumulating to a significant overall normalization for pain sensitivity (effect size: 0.91, p<0.01). Reduction of pain summation (WUR) correlated significantly with pain reduction after 3 months of L4-DRG_STIM (Fig.3).

Figure 1. Interleukin-1ß, interleukin 6, interleukin 10, TNF-α, high-mobility group box 1 protein (HMGB1), Leptin, adiponectin and ghrelin serum analysis and saliva concentrations of oxytocin at baseline, after 1 week L4-DRG_STIM trial and after 3 months.

Figure 2

Baseline and post L4-DRG stimulation changes of gene expression demonstrating significant upregulation (green) for CXCL2 - CCL11 - IL36G – CRP – SCGB1A1 – IL-17F – TNFRSF4 - PLA2G2A - CREB3L3 - ADAMTS12 - IL1F10 - NOX1 - CHIA - BDKRB1 and downregulation (red) TLR1 – FFAR2 – IL1RAP – IL1RN – C5 – PKB – IL18. P value <0.05 was considered significant.

Figure 3
Aggregated somatosensory parameters (somatosensory principal components) in the CRPS-affected knee before (“Pre”) and after L4-DRG stimulation (“Post”) normalized to QST from the contralateral control knee. Sensitivity normalized for all pain components, but not for thermal and mechanical detection. Pressure pain/pain summation (PPT/WUR), thermal pain (CPT/HPT), punctate mechanical pain (MPT/MPS), thermal detection (CDT/WDT/TSL) and mechanical detection (MDT/VDT).
Open circles - Non-nociceptive components “(detection”); Black circles - Nociceptive components (“pain”)
* p<0.05 pre vs. post L4-DRG stimulation.

Discussion

Although of preliminary character, L4-DRG_STIM evoked pain relief and improved functional impairment in CRPS patients revealing a pro-inflammatory molecular pattern associated with an impaired sensory profile. Serum IL-10 significantly declined, while saliva oxytocin increased after L4-DRG_STIM. Sub-group analysis demonstrated either upregulated or downregulated genes involved in immune host response and neural pain circuits.

Conclusions

Large biobank-based approaches are recommended to re-evaluate genetic phenotyping as a quantitative outcome measure for neurostimulation therapy in CRPS patients. The concept of a personalized and predictive neurostimulation therapy based on a comprehensive, preimplant mapping represents the next pivotal step in clinical neuromodulation research for pain.