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The article discusses the systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain.

Following publication of the original article [1], the authors reported an error in Figure 4 as the wrong figure was used. [ABSTRACT FROM AUTHOR]

Background: Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.Methods: We characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis.Results: We have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation.Conclusions: These findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS. [ABSTRACT FROM AUTHOR]

Purpose: Intractable upper limb and neck pain has traditionally been a challenging pain condition to treat, with conventional spinal cord stimulation (SCS) often inducing positional variation in paraesthesia and/or inadequate coverage of axial neck pain. The purpose of this Australian multi-centre prospective, clinical trial was to assess the safety and effectiveness of paraesthesia-independent 10 kHz SCS for the treatment of upper limb and neck pain. Methods: Subjects with chronic, intractable neck and/or upper limb pain of ≥ 5 cm (on a 0–10-cm visual analogue scale) were enrolled (ACTRN12614000153617) following human research ethics committee approval. Subjects were implanted with two epidural leads spanning C2–C6 vertebral bodies. Subjects with successful trial stimulation were implanted with a Senza® system (Nevro Corp., Redwood City, CA, USA) and included in the safety and effectiveness evaluation at 3 months post-implant (primary endpoint assessment, PEA) and followed to 12 months. Results: Overall, 31/38 (82.6%) subjects reported a successful 10 kHz SCS trial and proceeded to a permanent implant. Twenty-three of 30 subjects (76.7%) met the PEA. Subjects reported a reduction in neck pain and upper limb pain from baseline at the PEA (8.1 ± 0.2 cm vs. 2.9 ± 0.5 cm, 7.3 ± 0.3 cm vs. 2.5 ± 0.5 cm, respectively, p ≤ 0.0001). Disability, as measured by pain disability index score, decreased from 42.6 ± 2.6 at baseline to 22.7 ± 3.2 at PEA. Results were maintained 12 months post-implant. No neurological deficits, nor reports of paraesthesia, were observed. Conclusions: Stable, long-term results demonstrated that 10 kHz SCS is a promising therapy option for intractable chronic upper limb and neck pain. [ABSTRACT FROM AUTHOR]

Um die Qualität von Arznei- und Gewürzpflanzen langfristig sichern zu können, ist eine genauere Kenntnis der sie beeinflussenden Faktoren von Interesse. Am Beispiel der Zitronenmelisse (Melissa officinalis L.) wurden in zwei Feldversuchen an unterschiedlichen Standorten die Einflüsse der Faktoren Lichtintensität, Sorte und Erntezeitpunkt auf Ertragsparameter sowie sekundäre Pflanzeninhaltsstoffe untersucht. Es konnten teilweise deutliche Effekte der unterschiedlichen Lichtbedingungen auf die Gesamtphenole und die antioxidative Kapazität beobachtet werden, die zum Teil signifikanten Wechselwirkungen zwischen den Prüffaktoren unterlagen.

We believe that these methodological flaws invalidate the broad conclusions made about the effectiveness of spinal cord stimulation therapy, which has numerous high-quality studies with level 1 data, thus demonstrating efficacy across multiple stimulation waveforms or parameters. As a result, this trial did not compare sham spinal cord stimulation vs validated spinal cord stimulation, but rather, demonstrated that a previously unpublished set amplitude of stimulation therapy did not provide relief. [Extracted from the article]

Introduction: During the last decade, the complementary value of real-world data (through registries or medical records) and data from randomized clinical trials has been recognized as increasingly important. In the field of neuromodulation, only a few industry-independent nationwide neuromodulation registries are available. The interest in creating a European registry has increased but without a successful result. The goal of this online survey is to gain further insights into the need for and burden of a European registry for neuromodulation., Materials and Methods: An online survey was developed and distributed during the 3rd Joint Congress of the International Neuromodulation Society European Chapters in September 2023 (Hamburg, Germany). Healthcare professionals were asked to indicate the need for a European registry, the items that should be collected, and the restrictions to access of a European registry., Results: In total, 125 respondents opened the link to the survey, of whom 104 completed (at least partly) the survey. Of the 104 responses, 91% indicated that there is a need for a European registry, whereas 6% indicated there is no need. The main reasons for establishing a registry on a European level were the possibility of collecting real-world evidence (84%), the potential to collect big data from European patients (82%), to evaluate safety in neuromodulation (70%), and the possibility of reporting yearly on European activity in neuromodulation (51%). Indications for neuromodulation, patient characteristics, and follow-up assessments were most often stated as items that should be collected. Access should not only be granted to implanters but also to nurses, the assessment team, and other physicians, as agreed on by 64%, 52%, and 51%, respectively., Discussion: More than 90% of the respondents believed that a European registry for neuromodulation is needed, mainly to obtain real-world (big) data about the effectiveness and safety of this therapy. This survey clearly pointed to the need for a European registry for which it seems key to ensure financial and logistical support, in addition to in-depth legal guidance in developing this registry., Competing Interests: Conflict of Interest Lisa Goudman is a postdoctoral research fellow funded by the Research Foundation Flanders, Belgium (project number 12ZF622N). Philippe Rigoard reports grants and consultant fees from Medtronic, Abbott, and Boston Scientific, outside the submitted work. Marc Russo has stock options from Presidio Medical and Saluda Medical and a minor equity holding in SPR Therapeutics obtained before 2019 and now in a noncontrolled escrow account for the duration of his International Neuromodulation Society presidency. Konstantin Slavin reports institutional grants and consulting income from Medtronic, Abbott, Boston Scientific, Neuros, Integer, Biotronik, Saluda, Varian, and WISE, and minor ownership of Neuramodix, Thermaquil, Vycor Medical, and Higgs Boson. Maarten Moens has received speaker fees from Medtronic, Nevro, and Saluda Medical. STIMULUS received independent research grants from Medtronic. The remaining authors report no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Conflict of Interest Timothy R. Deer consults for Abbott, Saluda, Painteq, Cornorloc, Spinal Simplicity, Spinethera, Nervonik, Biotronik, and SPR Therapeutics. Dawood Sayed reports personal fees from Abbott, Medtronic, Flowonix, Nevro, and Boston Scientific, outside the submitted work. David M. Dickerson reports research support from SPR Therapeutics and Abbott; consulting fees from Abbott, Vertos, SPR, and Biotronik; speaker’s fees from Abbott, Vertos, Biotronik, and SPR Therapeutics; and meeting and travel support from Vertos, SPR, and Abbott. He is a committee chair for the North American Neuromodulation Society and the American Society of Anesthesiologists, and a board member of the Midwest Pain Society. He serves as a clinical advisory member for National Median Arcuate Ligament Syndrome Advisory and National Rx and Drug Abuse Summit. Erika A. Petersen reports research support from Mainstay, Medtronic, Nalu, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda, in addition to personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda, and Vertos, outside the submitted work. She holds stock options from SynerFuse and neuro42. Michael A. Fishman reports honoraria from Abbott, Biotronik, Medtronic, and Mainstay Medical; consults and advises for Biowave, Biotronik, Medtronic, and Thermaquil; conducts funded research for Abbott, Biowave, Biotronik, and Medtronic; receives royalties/patent from Brixton Biosciences, Medtronic, and Vyrsa (acq Nevro); and has stock options from Brixton Biosciences and Thermaquil, an equity position in Celeri Health, and ownership in Brixton Biosciences. James Fitzgerald reports personal fees from Medtronic and Abbott, and grants from Abbott, outside the submitted work. Ganesan Baranidharan reports grants and personal fees from Nevro Corporation, Abbott, and Boston Scientific; and personal fees from Nalu Medical, outside the submitted work. Dirk De Ridder reports other from Abbott during the conduct of the study, and he has a patent pending with Abbott. Krishnan V. Chakravarthy reports other from Medtronic, Mainstay Medical, Vertos, NXTSTIM, Accufix Medical, Newrom Biomedical, and Douleur Therapeutics, outside the submitted work. Corey W. Hunter reports other from Saluda Medical Pty Ltd; grants, personal fees, and other from Abbott; and grants from Biotronik, outside the submitted work. Eric Buchser reports personal fees from Medtronic, Switzerland, outside the submitted work. Chris Gilligan reports other from Mainstay Medical and Sollis Therapeutics; and personal fees from Medtronic, Saluda, and Abbott, outside the submitted work. Simon Thomson reports consulting agreements with Boston Scientific Neuromodulation, Galvani Bioelectronics, Mainstay Medical, and Saluda Medical. Jessica Jameson reports personal fees from Nevro, Boston Scientific, and Abbott, outside the submitted work. Thomas T. Simopoulos reports personal consultant fees from Nevro Corp, outside the submitted work. Robert M. Levy is an uncompensated consultant for Nalu, Saluda Medical, and Mainstay Medical; and has stock options from Nalu and Saluda Medical obtained before 2019 and not exercisable through the duration of his term as International Neuromodulation Society president and editor-in-chief of the journal Neuromodulation: Technology at the Neural Interface. The remaining authors reported no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise and international representation to establish evidence-based guidance on the mitigation of neuromodulation complications. This Neurostimulation Appropriateness Consensus Committee (NACC)® project intends to update evidence-based guidance and offer expert opinion that will improve efficacy and safety., Materials and Methods: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to October 2023. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant., Results: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The NACC recommends best practices regarding the mitigation of complications associated with neurostimulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate., Competing Interests: Conflict of Interest Timothy R. Deer consults for Abbott, Saluda, Ethos, Nalu, PainTeq, and Cornorloc; holds a patent pending with Abbott; is on the advisory board of Abbott and Nalu; has stock options with Saluda, Spinethera, and Nalu; and has institutional research grants from Abbott, Saluda, Vertiflex, and Mainstay. Dawood Sayed consults for Abbott, Saluda, PainTeq, and Surgentec and holds stock in PainTeq, Surgentec, Neuralace, Vertos, SPR, and Mainstay. Jason E. Pope serves as a consultant, on the advisory board, and conducts research for Ethos Labs, Flowonix, Saluda, PainTeq, Aurora Spine, Mainstay, Thermaquil, Abbott, Vertiflex, Vertos, and SPR Therapeutics; owns stock in PainTeq, Aurora Spine, Thermaquil, Spine Thera, Saluda, Abbott, AGR, NIS, Vertos, Celeri Health, and SPARK; receives royalties from Aurora Spine; consults for Biotronik, Medtronic, Boston Scientific, and WISE; conducts research for Ethos, Celeri Health, and Boston Scientific; and serves on the advisory board of Spine Thera. Steven M. Falowski consults for Abbott, Medtronic, Boston Scientific, Vertos, and Saluda. Research is performed with Abbott, Medtronic, Biotronik, Saluda, and Vertiflex. Equity positions are held in Saluda, CornerLoc, SPR Therapeutics, Thermaquil, Stimgenics, SpineThera, Neural Integrative Solutions, and AGR. Konstantin V. Slavin reports grants from Medtronic, Abbott, and Boston Scientific; personal fees from Medtronic, Abbott, Boston Scientific, MSEI, Nuvectra, and Stimwave; and nonfinancial support from Neuramodix, Thermaquil, Higgs Boson, and Stimwave, outside the submitted work. Sean Li consults for Abbott, Avanos, Averitas Pharma, Biotronik, Nalu, NeuroOne, PainTeq, Saluda, SPR Therapeutics, and Vertos Medical; and has research grants from Avanos, Averitas Pharma, Biotronik, Nevro, PainTeq, Saluda, and SPR Therapeutics and equity in Nalu and NeuroOne. Lawrence R. Poree reports personal fees and other from Saluda Medical Inc, personal fees and other from Nalu Inc, personal fees from Medtronic, and personal fees from Gimer, outside the submitted work. Sam Eldabe reports personal fees from Medtronic, Mainstay Medical, Saluda Medical, and Boston Scientific; and grants from Medtronic, during the conduct of the study. Kaare Meier reports teaching fees from Abbott, outside the submitted work; his institution has received travel support from Abbott and Boston Scientific. Julie G. Pilitsis is a consultant for Boston Scientific, Nevro, TerSera, Medtronic, Saluda, and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, TerSera, and National Institutes of Health (NIH) 2R01CA166379-06 and NIH U44NS115111. She is medical advisor for Aim Medical Robotics and Karuna and has stock equity. Alexios G. Carayannopoulos’ institution has received grant/research money in his name from Medtronic, Abbott, Nevro, Boston Scientific, Asahi, Aspen Medical, NIH, and the Defense Advanced Research Projects Agency. Christophe Perruchoud reports grants and personal fees from Medtronic and Boston Scientific during the conduct of the study; and advisory board membership for Medtronic and Boston Scientific. Amir Hadanny reports consulting fees and stock options from Aviv Scientific and EEG-Sense, and travel support from Aviv Scientific. Eric Lee consults with Abbott, Nalu and Boston Scientific. Mehul J. Desai consults for Medtronic, Nalu Medical, and SPR Therapeutics, and has stock options in SPR Therapeutics, SynerFuse, Virdio Health, and VRYSA Technologies. Ajay Antony consults for Saluda, Vertos, Abbott, Boston Scientific, and PainTeq. Fabian Piedimonte reports personal fees from Medtronic and Abbott outside the submitted work and divested as of June 2020. Robert M. Levy is an uncompensated consultant for Nalu, Saluda Medical, Mainstay Medical; and has stock options from Nalu and Saluda Medical obtained before 2019 and not exercisable through the duration of his terms as INS president and editor-in-chief of the journal, Neuromodulation: Technology at the Neural Interface. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Adults with refractory, mechanical chronic low back pain associated with impaired neuromuscular control of the lumbar multifidus muscle have few treatment options that provide long-term clinical benefit. This study hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology., Materials and Methods: In this prospective five-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (N = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic low back pain, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. Low back pain intensity (10-cm visual analog scale [VAS]), disability (Oswestry Disability Index), and quality of life (EuroQol's "EQ-5D-5L" index) were compared with baseline and following the intent-to-treat principle, with a supporting mixed-effects model for repeated measures that accounted for missing data., Results: At five years (n = 126), low back pain VAS had improved from 7.3 to 2.4 cm (-4.9; 95% CI, -5.3 to -4.5 cm; p < 0.0001), and 71.8% of participants had a reduction of ≥50%. The Oswestry Disability Index improved from 39.1 to 16.5 (-22.7; 95% CI, -25.4 to -20.8; p < 0.0001), and 61.1% of participants had reduction of ≥20 points. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95% CI, 0.195-0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a five-year visit, 46% discontinued, and 23% decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed., Conclusion: Over a five-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic low back pain associated with multifidus muscle dysfunction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354; registration date: October 15, 2016; principal investigator: Christopher Gilligan, MD, Brigham and Women's Hospital, Boston, MA, USA. The study was conducted in Australia (Broadmeadow, New South Wales; Noosa Heads, Queensland; Welland, South Australia; Clayton, Victoria), Belgium (Sint-Niklaas; Wilrijk), The Netherlands (Rotterdam), UK (Leeds, London, Middlesbrough), and USA (La Jolla, CA; Santa Monica, CA; Aurora, CO; Carmel, IN; Indianapolis, IN; Kansas City, KS; Boston, MA; Royal Oak, MI; Durham, NC; Winston-Salem, NC; Cleveland, OH; Providence, RI; Spartanburg, SC; Spokane, WA; Charleston, WV)., Competing Interests: Conflict of Interest Christopher Gilligan reports stock options received from Mainstay, personal fees from Mainstay, Saluda, Persica, and Iliad Lifesciences, expert witness testimony personal fees, and serving as editor-in-chief of Pain Practice; Willem Volschenk reports personal fees from Mainstay; Marc Russo reports personal fees from Mainstay; Matthew Green reports personal fees from Mainstay; Christopher Gilmore reports personal fees and other from SPR, and personal fees from Nevro, Nalu, Biotronik, Boston Scientific, and Saluda; Vivek Mehta reports grants and honoraria from Mainstay and Abbott, personal fees from Boston Scientific, personal fees and honoraria from Medtronic, patent fees from EEPIN-Executive Education Program in Neuromodulation, and leadership/fiduciary role as Chair, Faculty of Pain Medicine UK; Kris De Smedt reports personal fees from Mainstay; Usman Latif reports personal fees from Hydrocision, Spinal Simplicity, Omnia Medical, SPR Therapeutics, and Vertos, and honoraria and personal fees from Nevro and Nalu; Dawood Sayed reports personal fees from Abbott, Boston Scientific, Flowonix, Medtronic, Nevro, Saluda, and Vertiflex, personal fees and stock options from Mainstay, SPR Therapeutics, PainTEQ, and Vertos, and stock options from Neuralace and Surgentec; Peter Georgius reports personal fees from Boston Scientific and Medtronic, lecture support and personal fees from Tilray, lecture support from CSL Seqirus, patent pending personal fees for Arch Bar Wire Application, and personal fees and data safety monitoring/advisory board membership for Presidio; Jonathan Gentile reports personal fees from Mainstay; Bruce Mitchell reports personal fees from Mainstay; Meredith Langhorst reports personal fees from Mainstay and Vivex; Frank Huygen reports grants, personal fees, and honoraria from Abbott and personal fees and honoraria from Saluda; Ganesan Baranidharan reports a grant from Mainstay, grants and personal fees from Nevro, Abbott, Boston Scientific, and personal fees from Nalu and Stryker; Vivek Patel reports personal fees from Mainstay, grants from Orthofix, Pfizer, Premia Spine, Medicrea, Globus, 3-Spine, and Spinal Kinetics, contracts and grants from Aesculap and Medtronic, contracts from Zimmer Biomet Spine, Inc, J&J Medical Device Business Services, NCS America, Simplify Medical, SI Bone, Orthobond Corp, and Cerapedics, consulting fees from Spine Welding, SI Bone, expert testimony for Ogborn Mihm, LLP—Expert Witness Deposition, and support attending meetings from Ecential Robotics and Johnson & Johnson Medical; Alexios Carayannopolous reports consulting fees from Pain Spine and Rehabilitation Consulting, Inc, royalties from Springer Press, grants from Aspen Medical, National Institutes of Health, Defense Advanced Research Projects Agency, and Medtronic, expert testimony as PSR Consulting, Inc, meeting/travel support from American Society of Regional Anesthesia and Pain Medicine, National Board of Osteopathic Medical Examiners, American Alliance of Orthopaedic Executives (AAOE), and American Orthopedic Association, and leadership/fiduciary roles for AAOE, and Rhode Island Society of Pain Physicians; Salim Hayek reports data safety/advisory board membership as immediate past president of North American Neuromodulation Society; Adish Gulve reports personal fees, honoraria, and data safety/advisory board membership from Medtronic, grants and honoraria from Boston Scientific and Abbott, honoraria from Mainstay Medical, grants, honoraria, and safety/advisory board membership from Nevro, and other services from Medtronic and Abbott; Jean-Pierre Van Buyten reports personal fees from Mainstay and grants and personal fees from Medtronic, Nevro, Boston Scientific, and Abbott; Antoine Tohmeh reports stock ownership and personal fees with two spine companies; Jeffrey Fischgrund reports personal fees from Stryker, Relievant, FzioMed, and Asahi Kasei, expert testimony from multiple sources, and data safety/advisory board personal fees for OssDesign; Shivanand Lad reports personal fees from Mainstay; Farshad Ahadian reports institutional grants from Mainstay Medical, Sollis Therapeutics, Boston Scientific, Semnur Pharma, and SI Bone, consulting fees for PainScan, expert testimony for the US Department of Justice, patent personal fees from US Patent 62/949,876, data safety/advisory board personal fees and institutional grant from SKK, institutional payments for leadership/fiduciary roles with the AAMP as Director at Large, Treasurer, President-Elect, as President; Timothy Deer reports grants from, Boston Scientific, PainTEQ; grants, personal fees, and stock from Saluda, grants, personal fees, and data safety/monitoring board membership from SPR Therapeutics, grants, patent pending, data safety/monitoring board membership, and personal fees from Abbott, personal fees from Boston Scientific, SpineThera, Cornerloc, PainTeq, and Spinal Simplicity, personal and institution fees from Mainstay Medical, data safety monitoring/advisory board and personal fees from Biotronik and Vertos, leadership/fiduciary role with American Society of Pain and Neuroscience, and stock (personal) from SpineThera; William R. Klemme reports personal fees, meeting support, and data safety/advisory board membership with Mainstay Medical and Sollis Therapeutics; Richard Rauck reports grants from SPR, Nalu, and Nevro, personal fees from Presidio, and grants and personal fees from Boston Scientific and Saluda; James Rathmell reports a leadership/fiduciary role on the editorial board from American Society of Anesthesiology; Greg Maislin provides biostatistical consulting services concerning statistical analysis methods and presentation for Mainstay Medical; Jan Pieter Heemels provides full-time executive consultancy receiving monthly retainer and stock options from Mainstay Medical; Sam Eldabe reports personal fees and nonfinancial support from Mainstay, personal fees from Saluda, institutional grants and personal fees from Medtronic, institutional grants from Boston Scientific, leadership/fiduciary roles as chair of European Diploma of Pain Medicine and European Society of Regional Anaesthesia and Pain Therapy, examination faculty, chair of neuromodulation device Expert Working Group at National Health Service England, and chair International Association for the Study of Pain Neuromodulation Special Interest Group. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The author reports no conflicts of interest in this communication.

Objectives: Neuromodulation therapies use a variety of treatment modalities (eg, electrical stimulation) to treat chronic pain. These therapies have experienced rapid growth that has coincided with escalating confusion regarding the nomenclature surrounding these neuromodulation technologies. Furthermore, studies are often published without a complete description of the effective stimulation dose, making it impossible to replicate the findings. To improve clinical care and facilitate dissemination among the public, payors, research groups, and regulatory bodies, there is a clear need for a standardization of terms., Approach: We formed an international group of authors comprising basic scientists, anesthesiologists, neurosurgeons, and engineers with expertise in neuromodulation. Because the field of neuromodulation is extensive, we chose to focus on creating a taxonomy and standardized definitions for implantable electrical modulation of chronic pain., Results: We first present a consensus definition of neuromodulation. We then describe a classification scheme based on the 1) intended use (the site of modulation and its indications) and 2) physical properties (waveforms and dose) of a neuromodulation therapy., Conclusions: This framework will help guide future high-quality studies of implantable neuromodulatory treatments and improve reporting of their findings. Standardization with this classification scheme and clear definitions will help physicians, researchers, payors, and patients better understand the applications of implantable electrical modulation for pain and guide informed treatment decisions., Competing Interests: Conflict of Interest Richard B. North holds >30 patents in the field of neuromodulation and currently receives royalties from Abbott. Marc A. Russo reports research activities (paid to research institution) for Boston Scientific, Mainstay Medical, Medtronic, Nevro, Presidio Medical, and Saluda Medical, historical equity interest in Lungpacer and SPR Therapeutics, and stock options in Saluda Medical and Presidio Medical. Marc A. Russo is President of the International Neuromodulation Society and Director-at-Large of the Neuromodulation Society of Australia and New Zealand. Robert M. Levy is an uncompensated consultant for Biotronik, Abbott, Nalu, Saluda Medical, and Mainstay Medical and has stock options from Nalu and Saluda Medical obtained before 2019, not exercisable through the duration of his term as International Neuromodulation Society President and editor-in-chief of the journal Neuromodulation: Technology at the Neural Interface. Salim M. Hayek is the immediate past president of the North American Neuromodulation Society. Sam Eldabe consults for Mainstay Medical, Medtronic, and Saluda Medical. Sam Eldabe’s department research is funded by Boston Scientific, Saluda Medical, and Horizon Europe. Scott F. Lempka has equity in CereGate, Hologram Consultants, LLC, and Presidio Medical, Inc, is a member of the scientific advisory board, and receives consulting fees from Abbott Neuromodulation, CereGate, and Presidio Medical, Inc, and receives research support from Abbott Neuromodulation, Medtronic, plc, Neuromodulation Specialists, LTD, and Presidio Medical, Inc. All other authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Neuromodulation has been successfully used globally to address severe refractory chronic pain for over five decades. Compared to the wide acceptance that it enjoys in United States and Europe, it is fairly underutilized in Asia, including India., Objectives: We conducted the first systematic nationwide survey to provide an overview of neuromodulation in the past 20 years to investigate the practice trends for severe refractory chronic pain and barriers for the uptake of neuromodulation therapies for pain in India., Design: A 20-point detailed questionnaire survey was sent out for online completion in August 2020 to practitioners in India involved in interventions for pain. The survey was completed by 112 practitioners (10% return rate). The response data collected were analyzed, tabulated, and presented as percentages., Results: The average duration of pain practice in India for the majority of respondents was less than a decade. About 70% of practitioners expressed that they manage severe refractory pain without neuromodulation. This survey confirms that neuromodulation is grossly underutilized for pain, comprising only 10% of total neuromodulation implants performed per annum in India. The most common indications were neuropathic pain (45%) and failed back surgery syndrome (42%). The respondents expressed the main barriers to be related to the cost (85%), lack of awareness (68%), and lack of good training (59%). More than 50% of respondents also expressed difficulty of access to neuromodulation therapies for pain and acceptance by patients., Conclusion: The younger generation of pain practitioners in India is becoming more aware and convinced about the role of neuromodulation to alleviate severe pain and suffering. An all-round approach combining improved training, awareness at various levels, more flexible options of newer technology and reimbursement approval can positively influence its use. This can be achieved with the collective efforts of physicians, insurers, industry, and focused academic activities of clinical societies., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this prospective, single-blinded, dose-response study was to evaluate the safety and efficacy of a novel, paresthesia-free (subperception) spinal cord stimulation (SCS) waveform designed to target dorsal horn dendrites for the treatment of chronic neuropathic low back pain (LBP)., Materials and Methods: Twenty-seven participants with chronic neuropathic LBP were implanted with a commercial SCS system after a successful trial of SCS therapy. Devices were programmed to deliver the investigative waveform (100 Hz, 1000 μs, T9/T10 bipole) at descending stimulation perception threshold amplitudes (80%, 60%, 40%). Programs were evaluated at six, ten, and 14 weeks, after which participants selected their preferred program, with more follow-up at 26 weeks (primary outcomes). Participants were blinded to the nature of the programming. Pain score (visual analog scale [VAS]), Brief Pain Inventory (BPI), quality of life (EQ-5D-5L), and health status (36-Item Short Form [SF-36]) were measured at baseline and follow-ups. Responder rate, treatment satisfaction, clinician global impression of change, and adverse events (AEs) also were evaluated., Results: Mean (± SD) baseline VAS was 72.5 ± 11.2 mm. At 26 weeks (n = 26), mean change from baseline in VAS was -51.7 mm (95% CI, -60.7 to -42.7; p < 0.001), with 76.9% of participants reporting ≥50% VAS reduction, and 46.2% reporting ≥80% VAS reduction. BPI, EQ-5D-5L, and SF-36 scores were all statistically significantly improved at 26 weeks (p < 0.001), and 100% of participants were satisfied with their treatment. There were no unanticipated AEs related to the study intervention, device, or procedures., Conclusions: This novel, paresthesia-free stimulation waveform may be a safe and effective option for patients with chronic neuropathic LBP eligible for SCS therapy and is deliverable by all current commercial SCS systems., Clinical Trial Registration: This study is registered on anzctr.org.au with identifier ACTRN12618000647235., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Pain score, functional disability, and health-related quality of life (HRQoL) are core outcome domains for chronic pain clinical trials. Although greater levels of pain reduction have been shown to be linked to larger gains in HRQoL, little is known of the association between HRQoL and disability in the setting of chronic pain. The aims of this study were to 1) investigate the association between functional disability and HRQoL and 2) estimate the utility values associated with levels of functional disability in patients treated with evoked compound action potential (ECAP) spinal cord stimulation (SCS) for chronic pain., Materials and Methods: Data on functional disability assessed using the Oswestry Disability Index (ODI) and HRQoL (EQ-5D-5L) were collected from 204 patients with an Evoke ECAP-SCS device and followed up to 12 months. SF-6D utility scores also were retrieved for 134 of these patients. Multivariable linear regression models adjusted for baseline utility values and patient demographics were used to compare differences in utility values across ODI categories., Results: Significant improvements in functional disability and HRQoL were observed at three- and 12-month follow-up after SCS. Patients reporting "minimum disability," "moderate disability," "severe disability," and "crippled" had mean EQ-5D scores of 0.82, 0.73, 0.59, and 0.45, respectively. The mean change in EQ-5D score was 0.007 per unit change in total ODI score. The R 2 statistic showed a moderate level association (49%-64% of variance in EQ-5D explained by ODI)., Conclusion: ECAP-SCS results in significant improvements in functional disability and HRQoL. This study shows that improvement in function of people with chronic pain before and after ECAP-SCS is associated with improvement in HRQoL., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Treatment response to spinal cord stimulation (SCS) is focused on the magnitude of effects on pain intensity. However, chronic pain is a multidimensional condition that may affect individuals in different ways and as such it seems reductionist to evaluate treatment response based solely on a unidimensional measure such as pain intensity., Aim: The aim of this article is to add to a framework started by IMMPACT for assessing the wider health impact of treatment with SCS for people with chronic pain, a "holistic treatment response"., Discussion: Several aspects need consideration in the assessment of a holistic treatment response. SCS device data and how it relates to patient outcomes, is essential to improve the understanding of the different types of SCS, improve patient selection, long-term clinical outcomes, and reproducibility of findings. The outcomes to include in the evaluation of a holistic treatment response need to consider clinical relevance for patients and clinicians. Assessment of the holistic response combines two key concepts of patient assessment: (1) patients level of baseline (pre-treatment) unmet need across a range of health domains; (2) demonstration of patient-relevant improvements in these health domains with treatment. The minimal clinical important difference (MCID) is an established approach to reflect changes after a clinical intervention that are meaningful for the patient and can be used to identify treatment response to each individual domain. A holistic treatment response needs to account for MCIDs in all domains of importance for which the patient presents dysfunctional scores pre-treatment. The number of domains included in a holistic treatment response may vary and should be considered on an individual basis. Physiologic confirmation of therapy delivery and utilisation should be included as part of the evaluation of a holistic treatment response and is essential to advance the field of SCS and increase transparency and reproducibility of the findings., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS., Materials and Methods: A comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science., Results: A total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively., Conclusions: This review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted., (Copyright © 2022. Published by Elsevier Inc.)

Background: Peripheral nerve stimulation (PNS) is an effective neuromodulation therapy for chronic neuropathic and nociceptive pain. Although the total number of PNS implantations has increased over the last decade, no curriculum exists to guide training and learning of this therapy. The goal of the North American Neuromodulation Society (NANS) education committee is to develop a series of competency-based curriculums for neuromodulation therapies. The PNS curriculum is the latest part of such series, following the curriculums for spinal cord stimulation and intrathecal drug delivery system., Materials and Methods: A multidisciplinary task force (anesthesiology, physical medicine and rehabilitation, neurosurgery, preventive medicine and public health, and neurology) was created by the educational committee of NANS to develop a PNS curriculum in accordance with the Accreditation Council for Graduate Medical Education (ACGME) milestones. The curriculum was created based on the best available evidence and expert knowledge (from our task force members) of available PNS systems. The final PNS curriculum was approved by the NANS board., Results: A PNS curriculum was developed by the task force. Milestones included professionalism, practice-based learning, interpersonal communication, medical knowledge, systems-based practice, procedural skills, and patient care. Each milestone was defined into three categories: early learner, advanced learner, and practitioner., Conclusions: This manuscript provides a PNS training curriculum developed by a multidisciplinary task force of the NANS educational committee in accordance with the milestones described by ACGME for basic learners, advanced learners, and practitioners. This curriculum will help provide a structured training and evaluation process for obtaining proficiency in PNS treatment(s)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration : NCT01719055 (ClinicalTrials.gov).

Abstract: Ambroxol is a multifaceted drug with primarily mucoactive and secretolytic actions, along with anti-inflammatory, antioxidant, and local anaesthetic properties. It has a long history of use in the treatment of respiratory tract diseases and has shown to be efficacious in relieving sore throat. In more recent years, ambroxol has gained interest for its potential usefulness in treating neuropathic pain. Research into this area has been slow, despite clear preclinical evidence to support its primary analgesic mechanism of action-blockade of voltage-gated sodium (Na v ) channels in sensory neurons. Ambroxol is a commercially available inhibitor of Na v 1.8, a crucial player in the pathophysiology of neuropathic pain, and Na v 1.7, a particularly exciting target for the treatment of chronic pain. In this review, we discuss the analgesic mechanisms of action of ambroxol, as well as proposed synergistic properties, followed by the preclinical and clinical results of its use in the treatment of persistent pain and neuropathic pain symptoms, including trigeminal neuralgia, fibromyalgia, and complex regional pain syndrome. With its well-established safety profile, extensive preclinical and clinical drug data, and early evidence of clinical effectiveness, ambroxol is an old drug worthy of further investigation for repurposing. As a patent-expired drug, a push is needed to progress the drug to clinical trials for neuropathic pain. We encourage the pharmaceutical industry to look at patented drug formulations and take an active role in bringing an optimized version for neuropathic pain to market., (Copyright © 2022 International Association for the Study of Pain.)

Background: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability., Objective: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery., Materials and Methods: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates., Results: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date., Conclusion: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02577354., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward., Objective: This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery., Materials and Methods: Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation., Results: At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake., Conclusions: At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction., Clinical Trial Registration: The study is registered on clinicaltrials.gov with identifier NCT02577354., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on the use of neurostimulation in the cervical region to improve outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for an often-overlooked area of neurostimulation practice., Materials and Methods: Authors were chosen based upon their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to the present. Identified studies were graded using the US Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant., Results: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The NACC recommends best practices regarding the use of cervical neuromodulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be utilized as a guide to assist decision making when clinically appropriate., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The field of neurostimulation for the treatment of chronic pain is a rapidly developing area of medicine. Although neurostimulation therapies have advanced significantly as a result of technologic improvements, surgical planning, device placement, and postoperative care are of equal importance to optimize outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for these often-overlooked areas of neurostimulation practice., Materials and Methods: Authors were chosen based on their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from the last NACC publication in 2017 to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on evidence strength and consensus when evidence was scant., Results: This NACC project provides guidance on preoperative assessment, intraoperative techniques, and postoperative management in the form of consensus points with supportive evidence. These results are based on grade of evidence, strength of consensus, and expert opinion., Conclusions: The NACC has given guidance for a surgical plan that encompasses the patient journey from the planning stage through the surgical experience and postoperative care. The overall recommendations are designed to improve efficacy and the safety of patients undergoing these neuromodulation procedures and are intended to apply throughout the international community., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)