The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for Spinal Cord Stimulation Long-term Outcome Optimization and Salvage Therapy.

INTRODUCTION: The International Neuromodulation Society (INS) has recognized a need to establish best practices for optimizing implantable devices and salvage when ideal outcomes are not realized. This group has established the Neurostimulation Appropriateness Consensus Committee (NACC)® to offer guidance on matters needed for both our members and the broader community of those affected by neuromodulation devices. MATERIALS AND METHODS: The executive committee of the INS nominated faculty for this NACC® publication on the basis of expertise, publications, and career work on the issue. In addition, the faculty was chosen in consideration of diversity and inclusion of different career paths and demographic categories. Once chosen, the faculty was asked to grade current evidence and along with expert opinion create consensus recommendations to address the lapses in information on this topic. RESULTS: The NACC® group established informative and authoritative recommendations on the salvage and optimization of care for those with indwelling devices. The recommendations are based on evidence and expert opinion and will be expected to evolve as new data are generated for each topic. CONCLUSIONS: NACC® guidance should be considered for any patient with less-than-optimal outcomes with a stimulation device implanted for treating chronic pain. Consideration should be given to these consensus points to salvage a potentially failed device before explant.

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control.

OBJECTIVES: Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms - both sub- and supra-threshold - are programmed relative to the patient's perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems. METHODS: ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed. RESULTS: ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT (r = 0.93; p < 0.0001) and DT (r = 0.93; p < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture. CONCLUSION: We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.

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.

Novel Intermittent Dosing Burst Paradigm in Spinal Cord Stimulation.

INTRODUCTION: Intermittent dosing (ID), in which periods of stimulation-on are alternated with periods of stimulation-off, is generally employed using 30 sec ON and 90 sec OFF intervals with burst spinal cord stimulation (SCS). The goal of this study was to evaluate the feasibility of using extended stimulation-off periods in patients with chronic intractable pain. MATERIALS AND METHODS: This prospective, multicenter, feasibility trial evaluated the clinical efficacy of the following ID stimulation-off times: 90, 120, 150, and 360 sec with burst waveform parameters. After a successful trial (≥50% pain relief) using ID stimulation, subjects were titrated with OFF times beginning with 360 sec. Pain, quality of life, disability, and pain catastrophizing were evaluated at one, three, and six months after permanent implant. RESULTS: Fifty subjects completed an SCS trial using ID stimulation settings of 30 sec ON and 90 sec OFF, with 38 (76%) receiving ≥50% pain relief. Pain scores were significantly reduced from baseline at all time points (p < 0.001). Improvements in quality of life, disability, and pain catastrophizing were aligned with pain relief outcomes; 45.8% of the subjects that completed the six-month follow-up visit used an OFF period of 360 seconds. CONCLUSIONS: ID burst SCS effectively relieved pain for six months. The largest group of subjects used IDB settings of 30 sec ON and 360 sec OFF. These findings present intriguing implications for the optimal "dose" of electricity in SCS and may offer many advantages such as optimizing the therapeutic window, extending battery life, reducing recharge burden and, potentially, mitigating therapy habituation or tolerance.

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.

Psychosocial characteristics of candidates for implantable pain devices: validation of an assessment model.

Aim: To provide a detailed profile of Veteran and community patients with chronic pain who completed preprocedural psychological evaluations for implantable pain devices. Patients & methods: A total of 157 candidates completed a preimplantable pain device evaluation between June 2018 and October 2019 with a pain psychologist that included a structured interview, elicitation of patient-centered goals for the implantable device, and psychometric testing. Results: Candidates demonstrated moderate to high rates of sleep impairment (73%), depressive symptoms (62%), anxiety symptoms (61%), pain catastrophizing (37%), cognitive impairment screen (30%) and somatic symptoms (24%). Conclusion: Candidates for implantable pain devices report high rates of mood, sleep and cognitive impairment, reinforcing the value of preprocedural psychological evaluations.

Single arm prospective multicenter case series on the use of burst stimulation to improve pain and motor symptoms in Parkinson's disease.

BACKGROUND: In this study we analyze new clinical data in the use of spinal cord stimulation (SCS) for the treatment of pain and motor symptoms in patients with Parkinson's Disease (PD), as both a singular bioelectric therapy and as a salvage therapy after deep brain stimulation (DBS). METHODS: Fifteen patients were recruited and had percutaneous electrodes implanted at the level of the thoracic or cervical spine. Participants were set to one of three stimulation modes: continuous tonic stimulation, continuous Burst stimulation (40 Hz, 500 Hz, 1000 µs), or cycle mode (on time of 10-15 s, off time of 15-30 s) with Burst (40 Hz, 500 Hz, 1000 µs). Patients completed the Visual Analogue Scale (VAS), Unified Parkinson's Disease Rating Scale, Self-Rating Depression Scale, Hamilton Depression Rating Scale, Profile of Mood State, 10-meter walking test, and the Timed Up and Go (TUG). RESULTS: All patients experienced significant improvement in VAS scores with a mean reduction of 59% across all patients. Patients who chose the cycling burst stimulation parameter had an average 67% reduction in VAS scores, as compared to the continuous burst parameter group, which had an average 48% reduction in VAS scores. Seventy-three percent of patients experienced improvement in the 10-meter walk, with an average improvement of 12%. Sixty-four percent of patients experienced clinically relevant improvements in the TUG, with an average improvement of 21%. CONCLUSIONS: This study points to the potential utility of SCS to address both pain and certain aspects of motor symptoms in PD patients who have and have not received DBS therapy.

Emergence From the COVID-19 Pandemic and the Care of Chronic Pain: Guidance for the Interventionalist.

BACKGROUND: The current coronavirus disease 2019 (COVID-19) pandemic led to a significant disruption in the care of pain from chronic and subacute conditions. The impact of this cessation of pain treatment may have unintended consequences of increased pain, reduced function, increased reliance on opioid medications, and potential increased morbidity, due to the systemic impact of untreated disease burden. This may include decreased mobility, reduction in overall health status, and increase of opioid use with the associated risks. METHODS: The article is the study of the American Society of Pain and Neuroscience (ASPN) COVID-19 task force to evaluate the policies set forth by federal, state, and local agencies to reduce or eliminate elective procedures for those patients with pain from spine, nerve, and joint disease. The impact of these decisions, which were needed to reduce the spread of the pandemic, led to a delay in care for many patients. We hence review an emergence plan to reinitiate this pain-related care. The goal is to outline a path to work with federal, state, and local authorities to combat the spread of the pandemic and minimize the deleterious impact of pain and suffering on our chronic pain patients. RESULTS: The article sets forth a strategy for the interventional pain centers to reemerge from the current pandemic and to set a course for future events. CONCLUSIONS: The COVID-19 pandemic represents an overwhelming challenge to interventional pain physicians and their patients. In addition to urgent actions needed for disease mitigation, the ASPN recommends a staged return to pain management professionals' workflow.

Spinal cord stimulation in Parkinson's disease: a review of the preclinical and clinical data and future prospects.

Parkinson's disease (PD) is a progressive neurodegenerative disease with an incidence of 0.1 to 0.2% over the age of 40 and a prevalence of over 1 million people in North America. The most common symptoms include tremor, bradykinesia, rigidity, pain, and postural instability, with significant impact in quality of life and mortality. To date there is ongoing research to determine the optimum therapy for PD. In this review we analyze the current data in the use of spinal cord stimulation (SCS) therapy for treatment for Parkinsonian symptoms. We specifically address waveform pattern, anatomic location and the role of spinal cord stimulation (SCS) as a salvage therapy after deep brain stimulation (DBS) therapy. We also outline current experimental evidence from preclinical research highlighting possible mechanisms of beneficial effects of SCS in this context. Though the use of SCS therapy is in its infancy for treatment of PD, the data points to an exciting area for ongoing research and exploration with positive outcomes from both cervical and thoracic tonic and BURSTDR spinal cord stimulation.

A Review of Clinical Data on Salvage Therapy in Spinal Cord Stimulation.

BACKGROUND: Since its introduction in 1967, neuromodulation through spinal cord stimulation (SCS) or dorsal root ganglion stimulation (DRGs) has advanced significantly in both the technology and indications for use. There are now over 14,000 SCS implants performed worldwide every year. This review focuses on mechanisms behind the loss of efficacy in neuromodulation and current data on salvage therapy, defined as the conversion of a neuromodulation device to an alternative SCS or DRG stimulation, in the event of loss of efficacy or failure of a trial. STUDY DESIGN: A narrative review of clinical studies regarding habituation, explant data, and salvage therapy with SCS. METHODS: Available literature was reviewed on spinal cord stimulation technology and salvage therapy. 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. OUTCOME MEASURES: The primary outcome measures were to understand the mechanisms of loss of efficacy, provide a review of explants due to failure in treatment, and summarize the data on current salvage therapy in SCS. RESULTS: A total of eight studies and four abstracts/poster presentations were identified and reviewed. Of the eight studies, only one was a randomized controlled trial. CONCLUSIONS: There is limited evidence for the appropriate treatment alternatives, but from data currently available the conversion from conventional tonic stimulation to burst, high frequency (10 kHz), multiple wave forms, and/or DRGs may be appropriate in select patients and will require further research to determine the most appropriate first line salvage in the context of the underlying pain pathology.

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.

Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain.

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.

A Comprehensive Algorithm for Management of Neuropathic Pain.

BACKGROUND: The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. METHODS: Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. RESULTS: The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. CONCLUSIONS: The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.

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.

Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study.

BACKGROUND: Rising evidence indicate that oxytocin and IL-1ß impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls. METHODS: 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS. RESULTS: nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p < 0.01). Inter-ictal saliva oxytocin and IL-1ß were significantly elevated pre- as well as post-nVNS compared to healthy controls (p < 0.01) and similarly showed changes that may reflect the observed clinical effects. CONCLUSIONS: Our results add to accumulating evidence for a therapeutic efficacy of adjunct cervical non-invasive vagus nerve stimulation in migraine patients. This study failed to provide an evidence-derived conclusion addressed to the predictive value and usefulness of saliva assays due to its uncontrolled study design. However, saliva screening of mediators associated with trigemino-nociceptive traffic represents a novel approach, thus deserve future targeted headache research. Trial registration This study was indexed at the German Register for Clinical Trials (DRKS No. 00011089) registered on 21.09.2016.

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.