The role of endogenous opioids in mindfulness and sham mindfulness-meditation for the direct alleviation of evoked chronic low back pain: a randomized clinical trial.

Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.Trial Registration: ClinicalTrials.gov identifier: NCT04034004.

Application of the novel Nalu™ Neurostimulation System for peripheral nerve stimulation.

Peripheral nerve stimulation is an established treatment modality for chronic neuropathic pain. Over the last decade, with the advent of innovative devices and delivery platforms, peripheral nerve stimulation has evolved from invasive open surgeries to image-guided, minimally invasive percutaneous procedures. The authors hereby present a novel device, the Nalu™ Neurostimulation System (Nalu Medical, CA, USA), which has established its advantages in providing predictable and reliable peripheral nerve stimulation therapy for chronic neuropathic pain management. This novel device is effective in treating chronic pain conditions such as post-herniorrhaphy pain syndrome, intercostal neuralgia, post-laminectomy syndrome, and complex regional pain syndrome and holds great promise for the treatment of peripheral neuropathic pain.

Chronic nerve pain is a debilitating condition that can affect quality of life and functioning. The Nalu™ Neurostimulation System (Nalu Medical, CA, USA) provides long-term pain relief without medications. There are numerous devices currently available that can be utilized to block pain signals using small wires. This system is unique because the wires placed over affected nerves are powered by an external battery that does not require permanent surgical implantation. Pain after hernia surgery, back surgery, hip surgery and knee surgery, as well as nerve pain can be effectively managed by this system.

Recommendations for anesthetic management for intraoperative neuromodulation cases.

This paper performs a review of current literature as well as uses our single-center experience to discuss pre-operative, intra-operative and, briefly, postoperative management for dorsal column stimulators (DCSs), dorsal root ganglion (DRG) stimulators, peripheral nerve stimulators (PNSs) and intrathecal pumps. Generally, pre-operative antibiotics are recommended with discontinuation within 24 h postoperatively. For dorsal column and DRG stimulation, monitored anesthesia care or general anesthesia with intra-operative neuromonitoring is recommended; for peripheral nerve stimulation and intrathecal pump implementation, monitored anesthesia care is preferred. There is little information on appropriate anesthetic management during these forms of neuromodulation. More research is necessary to articulate specific pre-operative, intra-operative and postoperative management guidelines and recommendations for dorsal column stimulator, DRG stimulation, PNS and intrathecal pump implantation.

Neuromodulation is a procedure wherein the nerves that are responsible for pain are stimulated, for example with electrical pulses, to reduce the pain signals originating from that nerve. The implantation of neuromodulation devices requires surgery. This paper reviews current literature and provides guidelines based on our single center experience to discuss anesthetic management of patients before surgery, during surgery and after the surgery. We review management for different forms of neuromodulation including dorsal column stimulators (DCSs), dorsal root ganglion (DRG) stimulators, peripheral nerve stimulators and intrathecal pumps. We searched various online databases to find papers that discussed anesthetic management around these surgeries. Generally, starting antibiotics before the surgery and then stopping the antibiotics within 24 h after the surgery is recommended. For dorsal column and DRG stimulation, monitored anesthesia care, where patients are awake but very relaxed, or general anesthesia with neuromonitoring during the operation (so that surgeons can check the function of the nerves in real time) is recommended. For peripheral nerve stimulation and intrathecal pump implementation, monitored anesthesia care is preferred. There is little information in the literature on appropriate anesthetic management during these forms of neuromodulation. More research is necessary to articulate specific management guidelines before surgery, during surgery and after surgery for DCSs, DRG stimulation, peripheral nerve stimulator and intrathecal pump implantation.

Peripheral Nerve Stimulation in Pain Management: A Systematic Review.

BACKGROUND: Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear. OBJECTIVES: To assess the clinical evidence of PNS in the treatment of acute or chronic pain. STUDY DESIGN: A systematic review of the efficacy and safety of PNS in managing acute or chronic pain. METHODS: Data sources were PubMed, Cochrane Library, Scopus, CINAHL Plus, Google Scholar, and reference lists. The literature search was performed up to December 2019. Study selection included randomized trials, observational studies, and case reports of PNS in acute or chronic pain. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. Data syntheses: 227 studies met inclusion criteria and were included in qualitative synthesis. RESULTS: Evidence synthesis based on randomized controlled trials (RCTs) and observational studies showed Level I and II evidence of PNS in chronic migraine headache; Level II evidence in cluster headache, postamputation pain, chronic pelvic pain, chronic low back and lower extremity pain; and Level IV evidence in peripheral neuropathic pain, and postsurgical pain. Peripheral field stimulation has Level II evidence in chronic low back pain, and Level IV evidence in cranial pain. LIMITATIONS: Lack of high-quality RCTs. Meta-analysis was not possible due to wide variations in experimental design, research protocol, and heterogeneity of study population. CONCLUSIONS: The findings of this systematic review suggest that PNS may be effective in managing chronic headaches, postamputation pain, chronic pelvic pain, and chronic low back and lower extremity pain, with variable levels of evidence in favor of this technique.

A review of the StimRouter® peripheral neuromodulation system for chronic pain management.

The StimRouter® peripheral nerve stimulation system created by Bioness, Inc., (CA, USA) is US FDA-approved for the treatment of peripheral mononeuropathy refractory to conservative medical management. StimRouter is a minimally invasive system that utilizes a subcutaneously implanted lead with integrated anchor and electrodes, and an external pulse generator to produce peripheral neuromodulation and achieve pain relief. Multiple published clinical trials reviewed here have shown the StimRouter system to have a high margin of safety, differentiating it from other existing peripheral neuromodulation systems requiring open surgical electrode placement and implantable pulse generators. These studies have also shown the StimRouter system to be efficacious in the treatment of multiple peripheral mononeuropathies; improving patient pain, activity levels and quality of life. StimRouter represents a feasible option for management of chronic peripheral mononeuropathy.

A Comprehensive Practice Guideline for Magnetic Resonance Imaging Compatibility in Implanted Neuromodulation Devices.

OBJECTIVES: The evolution of neuromodulation devices in order to enter magnetic resonance imaging (MRI) scanners has been one of understanding limitations, engineering modifications, and the development of a consensus within the community in which the FDA could safely administer labeling for the devices. In the initial decades of neuromodulation, it has been contraindicated for MRI use with implanted devices. In this review, we take a comprehensive approach to address all the major products currently on the market in order to provide physicians with the ability to determine when an MRI can be performed for each type of device implant. MATERIALS AND METHODS: We have prepared a narrative review of MRI guidelines for currently marketed implanted neuromodulation devices including spinal cord stimulators, intrathecal drug delivery systems, peripheral nerve stimulators, deep brain stimulators, vagal nerve stimulators, and sacral nerve stimulators. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles, as well as manufacturer-provided information. RESULTS: Guidelines and recommendations for each device and their respective guidelines for use in and around MR environments are presented. CONCLUSIONS: This is the first comprehensive guideline with regards to various devices in the market and MRI compatibility from the American Society of Pain and Neuroscience.

Prospective case series on the use of peripheral nerve stimulation for focal mononeuropathy treatment.

Aim: This case series looks at outcomes in 39 patients implanted using the Bioness Stimrouter system on various isolated mononeuropathies. Patients & methods: A case series of 39 patients with a total of 42 implants were enrolled starting August 2017 at various pain management centers. Results: Of 39 patients studied, 78% of the participants noticed an improvement in their pain. There was a 71% reduction in pain scores with the average preprocedure score of 8 improving to 2 post-implant. Participants noted on average a 72% improvement in activity with the greatest observed in the brachial plexus (80%) and suprascapular nerve (80%) and smallest in the intercostal nerve (40%). Approximately 89% of those implanted with a peripheral nerve stimulator experienced a greater than 50% reduction in opioid consumption. Conclusion: Peripheral nerve stimulators are a new, minimally invasive neuromodulation modality that shows promising early results in our 39-patient case series.

Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling.

BACKGROUND: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. METHODS: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. RESULTS: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. CONCLUSIONS: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

A revised psychosocial assessment model for implantable pain devices to improve their evidence basis and consensus with updated pain management guidelines.

Although psychosocial evaluations for implantable pain devices have been consensus recommendations since the 1990s, there is an inconsistent support regarding their ability to identify suitable pain device candidates or to predict clinical outcomes. With the emergence of evidence-based practices and the recent release of pain management guidelines emphasizing functional improvements and safety, the disparity between the recommendations for implantable pain device psychosocial evaluations and the evidence supporting them has only grown. In this special report, we describe a revised model for conducting psychosocial evaluations among implantable pain device candidates. This model includes changes to increase the evidence-basis of the psychosocial evaluations, incorporate patient-centered care standards and harmonize the evaluation structure with the most current pain management guidelines.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

A Review of Spinal and Peripheral Neuromodulation and Neuroinflammation: Lessons Learned Thus Far and Future Prospects of Biotype Development.

BACKGROUND: There is increasing literature evidence both clinically and experimentally on the existence of potent, adaptive interactions between the central and peripheral aspects of the neuroimmune system in the genesis and maintenance of chronic neuropathic extremity pain and nociceptive back pain. The neuroinflammatory pathways are modulated by the interaction of pro- and anti-inflammatory cytokines and chemokines, which are released by peripheral immune system-derived cell species (macrophages and leukocytes). This review examines the possible impact of spinal and peripheral neurostimulation on the inflammatory response in the context of acute and chronic pain pathologies of different origin. STUDY DESIGN: A narrative review of preclinical and clinical studies addressed to the spinal cord and peripheral nerve stimulation and neuroinflammation. METHODS: Available literature was reviewed on neurostimulation technologies and both acute and chronic low-grade inflammation to identify primary outcome measures and to provide an overview of postulated mechanisms of action of neurostimulation on host inflammatory responses. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles. RESULTS: A comprehensive review of the literature indicates an alternate or synergistic mechanism of action of neurostimulation, beyond modulating somatosensory pain pathways, in modifying inflammatory response associated with chronic pain, by promoting a systemic anti-inflammatory state with upregulation of anti-inflammatory mediators. CONCLUSIONS: These preliminary findings may have important implications on the potential applications of neurostimulation as an anti-inflammatory therapy and the role of molecular profiling as a preimplant screening modality and post-implant outcome validation. Thus, future targeted clinical and experimental research is highly warranted in this particular novel field of neuromodulation.

The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes. METHODS: The NACC performed a comprehensive literature search of articles about DRG published from 1995 through June, 2017. A total of 2538 article abstracts were then reviewed, and selected articles graded for strength of evidence based on scoring criteria established by the US Preventive Services Task Force. Graded evidence was considered along with clinical experience to create the best practices consensus and recommendations. RESULTS: The NACC achieved consensus based on peer-reviewed literature and experience to create consensus points to improve patient selection, guide surgical methods, improve post-operative care, and make recommendations for management of patients treated with DRG stimulation. CONCLUSION: The NACC recommendations are intended to improve patient care in the use of this evolving therapy for chronic pain. Clinicians who choose to follow these recommendations may improve outcomes.

Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), Schwann cells, fibroblasts, dorsal root ganglia, and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.

Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

BACKGROUND: Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. STUDY DESIGN: A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. METHODS: We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. RESULTS: HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. CONCLUSIONS: To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology.

Review of Recent Advances in Peripheral Nerve Stimulation (PNS).

Peripheral nerve stimulation (PNS) for the treatment of chronic pain has become an increasingly important field in the arena of neuromodulation, given the ongoing advances in electrical neuromodulation technology since 1999 permitting minimally invasive approaches using an percutaneous approach as opposed to implantable systems. Our review aims to provide clinicians with the recent advances and studies in the field, with specific emphasis on clinical data and indications that have been accumulated over the last several years. In addition, we aim to address key basic science studies to further emphasize the importance of translational research outcomes driving clinical management.