Combination of waveforms in modern spinal cord stimulation

Background After the surge of burst stimulation, different waveforms were developed to optimize results in spinal cord stimulation. Studies have shown higher responder rates for multiwave therapy, but since the launch of such multiwave systems, little is known about the patients’ preference regarding waveforms in the long-term follow-up. No study connected particular waveforms to specific pain etiologies or required stimulation parameters so far. Method Thirty-four patients with refractory chronic neuropathic pain were treated with spinal cord stimulation systems providing multiwave therapy between September 2018 and October 2019. Patients with a follow-up of at least 6 months were selected; 10 subjects were excluded due to revision surgery, infection, and loss to follow-up. Data regarding pain intensity and preferred waveform for the trial, the implantation, 3-month and 6-month follow-up were recorded. Results During the trial phase, 10 patients (43.5%) achieved significant pain relief using tonic stimulation, 5 using burst (21.7%), 3 using microburst (13.0%), and 4 using a combination of tonic and microburst (17.4%). One single patient preferred Contour stimulation during the trial. After 3 months, 6 patients preferred microburst (25%), 6 preferred tonic (25%), 5 used a combination of tonic and microburst (20.8%), and 5 patients used burst (20.8%). After 6 months, similar results were obtained. Contour and Whisper were used in complex cases failing to other waveforms. Conclusions Tonic stimulation, isolated or in combination, remains an important component in spinal cord stimulation, being used by almost half of the patients. Over time, the usage of microburst increased considerably. Whisper and Contour, although battery-consuming, are good salvage options in complex cases.

Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain

Patients with chronic neuropathic pain (CNP) often complain about their terrible memory, especially the speed of information processing. Accumulating evidence suggests a possible link between gut microbiota and pain processing as well as cognitive function via the microbiota-gut-brain axis. This study aimed at exploring the fecal microbiome and plasma metabolite profiles in middle-aged spared nerve injury (SNI) mice model with cognitive dysfunction (CD) induced by CNP. The hierarchical cluster analysis of performance in the Morris water maze test was used to classify SNI mice with CD or without CD [i.e., non-CD (NCD)] phenotype. 16S rRNA sequencing revealed a lower diversity of gut bacteria in SNI mice, and the increase of Actinobacteria, Proteus, and Bifidobacterium might contribute to the cognitive impairment in the CNP condition. The plasma metabolome analysis showed that the endocannabinoid (eCB) system, disturbances of lipids, and amino acid metabolism might be the dominant signatures of CD mice. The fecal microbiota transplantation of the Sham (not CD) group improved allodynia and cognitive performance in pseudo-germ-free mice via normalizing the mRNA expression of eCB receptors, such as cn1r, cn2r, and htr1a, reflecting the effects of gut bacteria on metabolic activity. Collectively, the findings of this study suggest that the modulation of gut microbiota and eCB signaling may serve as therapeutic targets for cognitive deficits in patients with CNP.

Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain–A Biomedical Mechanism of Action

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg2+), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg2+ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg2+ (40 mg/kg intraperitoneally). Mg2+ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg2+ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.

Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment

Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients’ welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.

The Identification of Blood Biomarkers of Chronic Neuropathic Pain by Comparative Transcriptomics

In this study, we recruited 50 chronic pain (neuropathic and nociceptive) and 43 pain-free controls to identify specific blood biomarkers of chronic neuropathic pain (CNP). Affymetrix microarray was carried out on a subset of samples selected 10 CNP and 10 pain-free control participants. The most significant genes were cross-validated using the entire dataset by quantitative real-time PCR (qRT-PCR). In comparative analysis of controls and CNP patients, WLS (P = 4.80 × 10–7), CHPT1 (P = 7.74 × 10–7) and CASP5 (P = 2.30 × 10–5) were highly significant, whilst FGFBP2 (P = 0.00162), STAT1 (P = 0.00223), FCRL6 (P = 0.00335), MYC (P = 0.00335), XCL2 (P = 0.0144) and GZMA (P = 0.0168) were significant in all CNP patients. A three-arm comparative analysis was also carried out with control as the reference group and CNP samples differentiated into two groups of high and low S-LANSS score using a cut-off of 12. STAT1, XCL2 and GZMA were not significant but KIR3DL2 (P = 0.00838), SH2D1B (P = 0.00295) and CXCR31 (P = 0.0136) were significant in CNP high S-LANSS group (S-LANSS score > 12), along with WLS (P = 8.40 × 10–5), CHPT1 (P = 7.89 × 10–4), CASP5 (P = 0.00393), FGFBP2 (P = 8.70 × 10–4) and FCRL6 (P = 0.00199), suggesting involvement of immune pathways in CNP mechanisms. None of the genes was significant in CNP samples with low (< 12) S-LANSS score. The area under the receiver operating characteristic (AUROC) analysis showed that combination of MYC, STAT1, TLR4, CASP5 and WLS gene expression could be potentially used as a biomarker signature of CNP (AUROC − 0.852, (0.773, 0.931 95% CI)).

Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

Background Neuropathic pain in neuroimmunological disorders refers to pain caused by a lesion or disease of the somatosensory system such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are autoimmune disorders of the central nervous system, and ≥ 50% of patients with these disorders experience chronic neuropathic pain. The currently available medications for the management of neuropathic pain have limited effectiveness in patients with MS and NMOSD, and there is an unmet medical need to identify novel therapies for the management of chronic neuropathic pain in these patients. In this review article, we summarize the role of interleukin-6 (IL-6) in the pathogenesis of MS and NMOSD and the ameliorative effects of anti–IL-6 therapies in mouse models of experimental autoimmune encephalomyelitis (EAE). Main body Intraperitoneal injection of MR16-1, an anti–IL-6 receptor (IL-6R) antibody, reduced mechanical allodynia and spontaneous pain in EAE mice, which was attributed to a reduction in microglial activation and inhibition of the descending pain inhibitory system. The effect of anti–IL-6 therapies in ameliorating neuropathic pain in the clinical setting is controversial; a reduction in pain intensity has been reported with an anti–IL-6 antibody in four studies, namely a case report, a pilot study, a retrospective observational study, and a case series. Pain intensity was evaluated using a numerical rating scale (NRS), with a lower score indicating lesser pain. A reduction in the NRS score was reported in all four studies. However, in two randomized controlled trials of another anti–IL-6R antibody, the change in the visual analog scale pain score was not statistically significantly different when compared with placebo. This was attributed to the low mean pain score at baseline in both the trials and the concomitant use of medications for pain in one of the trials, which may have masked the effects of the anti–IL-6R antibody on neuropathic pain. Conclusion Thus, anti–IL-6 therapies might have a potential to reduce neuropathic pain, but further investigations are warranted to clarify the effect of inhibition of IL-6 signaling on neuropathic pain associated with MS and NMOSD.

Connectivity-based thalamus parcellation and surgical targeting of somatosensory subnuclei

OBJECTIVE The anatomy of the posterolateral thalamus varies substantially between individuals, presenting a challenge for surgical targeting. Patient-specific, connectivity-based parcellation of the thalamus may effectively approximate the ventrocaudal nucleus (Vc). This remains to be robustly validated or assessed as a method to guide surgical targeting. The authors assessed the validity of connectivity-based parcellation for targeting the Vc and its potential for improving clinical outcomes of pain surgery. METHODS A cohort of 19 patients with regional, chronic neuropathic pain underwent preoperative structural and diffusion MRI, then progressed to deep brain stimulation targeting the Vc based on traditional atlas coordinates. Surgical thalami were retrospectively segmented and then parcellated based on tractography estimates of thalamocortical connectivity. The location of each patient’s electrode array was analyzed with respect to their primary somatosensory cortex (S1) parcel and compared across patients with reference to the thalamic homunculus. RESULTS Ten patients achieved long-term pain relief. Sixty-one percent of an average array (interquartile range 42%–74%) was located in the S1 parcel. In patients who achieved long-term benefit from surgery, array location in the individually generated S1 parcels was medial for face pain, centromedial for arm pain, and centrolateral for leg pain. Patients who did not benefit from surgery did not follow this pattern. Standard stereotactic coordinates of electrode locations diverged from this pattern. CONCLUSIONS Connectivity-based parcellation of the thalamus appears to be a reliable method for segmenting the Vc. Identifying the Vc in this way, and targeting mediolaterally as appropriate for the region of pain, merits exploration in an effort to increase the yield of successful surgical procedures.