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Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic., Competing Interests: CC is an equity holder of Convergent Medical Technologies, Inc., reports personal fees from electroCore Inc., and Spark Biomedical, and has issued and pending patents related to vagus nerve stimulation to control bleeding and inflammation. MB reports personal fees from Soterix Medical, grants from Google X, personal fees from Halo Neuroscience, outside the submitted work; in addition, he has a patent Brain Stimulation issued. MFr reports pending patent applications describing injectable electrode structures for Neuronoff, Inc., and is an employee and equity holder of Neuronoff, Inc. He further reports issued patents for selective Vagus nerve stimulation and selective electrical vagal block for regulation of autonomic functions such as heart rate and blood pressure for Boston Scientific. MFu reports personal fees from Axon Therapies, CVRx, Daxor, Edwards Life Sciences, Galvani, and Respicardia, outside the submitted work. SH is an employee and equity holder of Cala Health. NK reports a patent devices and methods for reducing inflammation using electrical stimulation pending. BS reports personal fees from electroCore, and reports patents issued and pending related to transcutaneous cervical vagus nerve stimulation. PS is an employee and equity holder of electroCore, and reports patents issued and pending related to transcutaneous cervical vagus nerve stimulation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Czura, Bikson, Charvet, Chen, Franke, Fudim, Grigsby, Hamner, Huston, Khodaparast, Krames, Simon, Staats and Vonck.)

Objective : In the treatment of chronic diseases, remission is commonly used as a meaningful treatment goal, synonymous with the absence of significant clinical signs and symptoms of a disease, but not representing a cure. The objective of this paper is to propose a definition for remission for use as an outcome to evaluate the long-term efficacy of therapies for chronic pain. Methods : Data from a randomized clinical trial (NCT01609972) testing the efficacy of spinal cord stimulation in low back and leg pain subjects was used to evaluate the association between pain and functional outcomes and identify the cut-off value to predict remission. Available data over 24-month assessment period included visual analog score (VAS), disability (Oswestry Disability Index [ODI]), patient and clinician global impression of change (PGIC and CGIC), and patient satisfaction. Cluster analysis, Pearson's correlation coefficients, sensitivity, and specificity analyses were used to evaluate its utility in predicting higher patient functionality and satisfaction. Results : Though the term remission has been used in the chronic pain field, a consistent definition has not been previously established. Based on the analysis of the clinical data, we propose that a sustained (≥6 months) pain score of ≤3.0 cm out of 10 cm on VAS be defined as remission. Applying this definition to the clinical trial data: subjects in remission at 24 months versus non-remitters were significantly more likely to be in the highest functional category of minimally disabled according to the ODI (31.5 vs. 8.2%, respectively, p = 0.001), and be 'very satisfied' (75.7 vs 22.6%, respectively, p < 0.001). Conclusions : The validity of the proposed definition of remission is supported by the persistence of remission in this study group, and its correspondence with patient satisfaction, and reduced disability. Further evaluation of the definition using clinical data from other long-term studies is needed.

Introduction: Pain treatment is best performed when a patient-centric, safety-based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice., Methods: The current PACC update was designed to address the deficiencies and innovations emerging since the previous PACC publication of 2012. An extensive literature search identified publications between January 15, 2007 and November 22, 2015 and authors contributed additional relevant sources. After reviewing the literature, the panel convened to determine evidence levels and degrees of recommendations for intrathecal therapy. This meeting served as the basis for consensus development, which was ranked as strong, moderate or weak. Algorithms were developed for intrathecal medication choices to treat nociceptive and neuropathic pain for patients with cancer, terminal illness, and noncancer pain, with either localized or diffuse pain., Results: The PACC has developed an algorithmic process for several aspects of intrathecal drug delivery to promote safe and efficacious evidence-based care. Consensus opinion, based on expertise, was used to fill gaps in evidence. Thirty-one consensus points emerged from the panel considerations., Conclusion: New algorithms and guidance have been established to improve care with the use of intrathecal drug delivery., (© 2017 International Neuromodulation Society.)

Introduction: The International Neuromodulation Society (INS) has determined that there is a need for guidance regarding safety and risk reduction for implantable neurostimulation devices. The INS convened an international committee of experts in the field to explore the evidence and clinical experience regarding safety, risks, and steps to risk reduction to improve outcomes., Methods: The Neuromodulation Appropriateness Consensus Committee (NACC) reviewed the world literature in English by searching MEDLINE, PubMed, and Google Scholar to evaluate the evidence for ways to reduce risks of neurostimulation therapies. This evidence, obtained from the relevant literature, and clinical experience obtained from the convened consensus panel were used to make final recommendations on improving safety and reducing risks., Results: The NACC determined that the ability to reduce risk associated with the use of neurostimulation devices is a valuable goal and possible with best practice. The NACC has recommended several practice modifications that will lead to improved care. The NACC also sets out the minimum training standards necessary to become an implanting physician., Conclusions: The NACC has identified the possibility of improving patient care and safety through practice modification. We recommend that all implanting physicians review this guidance and consider adapting their practice accordingly., (© 2014 International Neuromodulation Society.)

Introduction: The International Neuromodulation Society (INS) has determined that there is a need to provide an expert consensus that defines the appropriate use of neuromodulation technologies for appropriate patients. The Neuromodulation Appropriateness Consensus Committee (NACC) was formed to give guidance to current practice and insight into future developments., Methods: The INS executive board selected members of the international scientific community to analyze scientific evidence for current and future innovations and to use clinical experience to fill in any gaps in information. The NACC used PubMed and Google Scholar to obtain current evidence in the field and used clinical and research experience to give a more complete picture of the innovations in the field., Results: The NACC has determined that currently approved neurostimulation techniques and technologies have expanded our ability to treat patients in a more effective and specific fashion. Despite these advances, the NACC has identified several additional promising technologies and potential applications for neurostimulation that could move this field forward and expand the applicability of neuromodulation., Conclusions: The NACC concludes that the field of neurostimulation is an evolving and rapidly changing one that will lead to improved patient access, safety, and outcomes., (© 2014 International Neuromodulation Society.)

Introduction: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications., Methods: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar., Results: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated., Conclusions: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation., (© 2014 International Neuromodulation Society.)

Introduction: The International Neuromodulation Society (INS) has identified a need for evaluation and analysis of the practice of neurostimulation of the brain and extracranial nerves of the head to treat chronic pain., Methods: The INS board of directors chose an expert panel, the Neuromodulation Appropriateness Consensus Committee (NACC), to evaluate the peer-reviewed literature, current research, and clinical experience and to give guidance for the appropriate use of these methods. The literature searches involved key word searches in PubMed, EMBASE, and Google Scholar dated 1970-2013, which were graded and evaluated by the authors., Results: The NACC found that evidence supports extracranial stimulation for facial pain, migraine, and scalp pain but is limited for intracranial neuromodulation. High cervical spinal cord stimulation is an evolving option for facial pain. Intracranial neurostimulation may be an excellent option to treat diseases of the nervous system, such as tremor and Parkinson's disease, and in the future, potentially Alzheimer's disease and traumatic brain injury, but current use of intracranial stimulation for pain should be seen as investigational., Conclusions: The NACC concludes that extracranial nerve stimulation should be considered in the algorithmic treatment of migraine and other disorders of the head. We should strive to perfect targets outside the cranium when treating pain, if at all possible., (© 2014 International Neuromodulation Society.)

Background: Spinal cord stimulation (SCS), by virtue of its historically described up-front costs and level of invasiveness, has been relegated by several complex regional pain syndrome (CRPS) treatment algorithms to a therapy of last resort. Newer information regarding safety, cost, and efficacy leads us to believe that SCS for the treatment of CRPS should be implemented earlier in a treatment algorithm using a more comprehensive approach., Methods: We reviewed the literature on pain care algorithmic thinking and applied the safety, appropriateness, fiscal or cost neutrality, and efficacy (S.A.F.E.) principles to establish an appropriate position for SCS in an algorithm of pain care., Results and Conclusion: Based on literature-contingent considerations of safety, efficacy, cost efficacy, and cost neutrality, we conclude that SCS should not be considered a therapy of last resort for CRPS but rather should be applied earlier (e.g., three months) as soon as more conservative therapies have failed., (© 2013 International Neuromodulation Society.)

Currently accepted chronic pain treatment algorithms have positioned therapies according to levels of invasiveness and up-front costs. After reviewing updated literature on efficacy and cost outcomes of care for patients with chronic pain that include interventional implantable technologies, we offer a new model of thinking when formulating algorithms of care that might include more invasive and costly interventions such as spinal cord stimulation, the SAFE principles. These SAFE principles include "safety,""appropriateness,""fiscal neutrality," and "efficacy.", (© 2009 International Neuromodulation Society.)

Objective: The objective of this study was to evaluate current practice characteristics, treatment choices, clinical experiences, and economic concerns associated with intrathecal therapy., Design: Health care professionals in the United States, who were known to actively use intrathecal therapy in their practices, were recruited to participate in an online survey; contact information was obtained via Internet searches, university Websites, association memberships, industry databases, and personal contacts. Survey responses were summarized descriptively., Results: Of the 329 practitioners who were contacted, 87 participated in the survey. Most participants specialized in anesthesiology (77.0%), worked in a private practice or private hospital (74.7%), and had been practicing pain management for more than 10 years (64.4%). Morphine was the most frequently used opioid for the initiation of intrathecal therapy (80.7% of practitioners), and 81.9% had used ziconotide in their practice. Most practitioners (63.9%) had treated at least one patient who developed a granuloma, and 66.0% of those practitioners had a patient experience permanent or temporary neurological injury due to a granuloma. Fewer than half of practitioners were satisfied with reimbursement from private insurance companies (25.3%) or workers compensation (34.9%), and 90.5% believed reimbursement rates for filling, refilling, and programming patient pumps are not adequate to cover practice costs. The majority of practitioners (56.6%) use fewer pumps in their practices because of reimbursement issues., Conclusions: Intrathecal pain management practices continue to evolve as the options for treatment increase, and the body of applicable scientific literature grows; however, economic considerations can influence clinical decisions and may interfere with treatment choice and patient access to therapy.

Objectives.  Although the load impedance of a pulse generator has a significant effect on battery life, the electrical impedance of contact arrays in spinal cord stimulation (SCS) has not been extensively studied. We sought to characterize the typical impedance values measured from common quadripolar percutaneous SCS contact arrays. Methods.  In 36 patients undergoing percutaneous trial stimulation for various chronic pain conditions, bipolar impedance between adjacent contacts of 64 leads with 9 mm center-to-center spacing was measured in two different vertebral level regions, cervical (C3-C7) and lower-thoracic (T7-T12). Multiple linear regression was applied to analyze the contribution of six variables to the biological tissue portion of the impedance (excluding the resistance of the lead wires). Results.  The median impedance in the cervical region (351 ± 90 Ω) was significantly lower (36%, p < 0.001) than in the lower-thoracic region (547 ± 151 Ω). In addition, time since implant had a weaker but still significant effect on tissue impedance. Conclusions.  Results from finite-difference mathematical modeling of SCS suggest that the difference in tissue impedance related to vertebral level may be due to the dorsoventral position of the lead in the epidural space. The presence of a larger space between the triangularly shaped dorsal part of the vertebral arch and the round shape of the dural sac in the lower-thoracic region increases the likelihood that the stimulating lead will not make dural contact, and thus "see" an increased impedance from the surrounding epidural fat. This implies that the energy requirements for stimulation in the thoracic region will be higher than in the cervical region, at least during the acute phase of implant.

It is known that, in spite of meeting appropriate clinical criteria for spinal cord stimulation (SCS) and having undergone flawless procedures, a significant number of patients who fail the therapy continues to exist. It is the purpose of this article to focus on the development of psychosocial indicators of success for SCS, if any. Referring to specialist literature authors present a review of what is known, what is not known, and what remains controversial on this topic. After reading this article we hope the reader will understand the importance of a psychological evaluation as part of the development of standards for identifying appropriate patients for this therapy. To improve treatment outcomes of SCS, seems to be essential to perform psychosocial evaluations on all persons clinically indicated for SCS to exclude those patients, who most probably, on a psychosocial level, will fail the procedure. To maximize treatment efficacy, authors believe spinal cord stimulation for chronic pain control must be part of a comprehensive program. An accurate preoperative psychosocial assessment and a course of psychological assistance both before and after therapy seems to be crucial for improving outcomes.

We present data collected from a multicenter study using a new neurostimulation system. This new system uses a current-shifting programming technique for spinal cord stimulation. The system maintains a continuous, suprathreshold stimulation field while adjusting the distribution of anodic and cathodic current among contacts along a multi-contact array. The changing distribution of current shifts the electric field along the spinal cord, resulting in real-time, dynamic paresthesia steering. This process of adjusting the stimulation field has been termed continuous electric field adjustment (CEFA). This technique has been used to assess paresthesia coverage for patients undergoing implantation of stimulation contact arrays for chronic pain. This multicenter study evaluated the performance of the CEFA technique. The results of the study showed that paresthesia coverage could be shifted in real-time to different regions on the patient's body in a comfortable fashion, with the patient always feeling paresthesia during the adjustment process. The results of the study also show that the process was time-efficient: intraoperatively, the median time to assess 71 combinations on a single 8-contact lead across 18 patients was 4.1 (3.6-5.0) minutes.

Irritable Bowel Syndrome (IBS) is a functional gastrointestinal (GI) disorder, characterized by abdominal pain, altered bowel habit (diarrhea and/or constipation), and bloating in the absence of demonstrable organic pathology. It is the most common GI disorder seen in primary care and gastroenterology practices. Conservative therapies for IBS are directed at both pain and correction of altered GI motility. A small proportion of patients with IBS have severe or refractory symptoms and report constant pain. IBS is no longer considered solely a disorder of motility, but rather its clinical expression is viewed as dysregulation of CNS-enteric function. Symptoms of IBS cannot be explained entirely by changes in motility alone and may also arise from complex feedback and feed-forward interactions between supraspinal circuits, the spinal cord, and the periphery, in effect, a neuropathic process, that might be amenable to neuromodulation, that is, spinal cord stimulation. We present here a single case report of a patient with IBS who responded positively to SCS after failing all conservative therapies to alleviate or manage her abdominal pain and diarrheal episodes. Our discussion is focused on the reasons why SCS might work in patients with IBS.

Untreated chronic pain is costly to society and to the individual suffering from it. The treatment of chronic pain, a multidimensional disease, should rely on the expertise of varying health care providers and should focus not only on the neurobiological mechanisms of the process but also on the psychosocial aspects of the disease. Implantable devices are costly and invasive, and such efficacious therapies should be used only when more conservative and less costly therapies have failed to provide relief of pain and suffering. Spinal cord stimulation provides neuromodulation of neuropathic, but not nociceptive, pain signals and when used for appropriate indications in the right individuals provides approximately 60-80% long-term pain relief in 60-80% of patients trialled for efficacy. Intrathecal therapies with opioids such as morphine, fentanyl, sufentanil or meperidine--or non-opioids such as clonidine or bupivacaine--provide analgesia in patients with nociceptive or neuropathic pain syndromes. Baclofen, intrathecally, provides profound relief of muscle spasticity due to multiple sclerosis, spinal cord injuries, brain injuries or cerebral palsy.

Objectives: In a companion article, we synthesized current clinical and preclinical data to formulate hypotheses about the etiology of drug administration catheter-tip inflammatory masses. In this article, we communicate our recommendations for the detection, treatment, mitigation, and prevention of such masses., Methods: We reviewed published and unpublished case reports and our own experiences to find methods to diagnose and treat catheter-tip inflammatory masses in a manner that minimized adverse neurological sequelae. We also formulated hypotheses about theoretical ways to mitigate, and possibly, prevent the formation of such masses., Results: Human cases have occurred only in patients with chronic pain who received intrathecal opioid drugs, alone or mixed with other drugs, or in patients who received agents that were not labeled for long-term intrathecal use. Most patients had noncancer pain owing to their large representation among the population with implanted pumps. Such patients also had a longer life expectancy and exposure to intrathecal drugs, and they received higher daily doses than patients with cancer pain. Clues to diagnosis included the loss of analgesic drug effects accompanied by new, gradually progressive neurological symptoms and signs. When a mass was diagnosed before it filled the spinal canal or before it caused severe neurological symptoms, open surgery to remove the mass often was not required. Anecdotal reports and the authors' experiences suggest that cessation of drug administration through the affected catheter was followed by shrinkage or disappearance of the mass over a period of 2-5 months., Conclusions: Attentive follow-up and maintenance of an index of suspicion should permit timely diagnosis, minimally invasive treatment, and avoidance of neurological injury from catheter-tip inflammatory masses. Whenever it is feasible, positioning the catheter in the lumbar thecal sac and/or keeping the daily intrathecal opioid dose as low as possible for as long possible may mitigate the seriousness, and perhaps, reduce the incidence of such inflammatory masses.

Objectives. To examine the performance and reliability of a redesigned implantable intrathecal catheter. Materials and Methods. A total of 212 catheters were implanted in 202 patients in this 22-center prospective study of an implantable catheter/pump system used to deliver intrathecal drugs for the treatment of pain and spasticity. Along with physician assessments of ease of use, the rates of common catheter complications (dislodgments, disconnections, fractures, and kinks) experienced during the study were analyzed in relation to implant conditions (catheter entry site, tip position, and anchoring method). Results. A cumulative total of 3112.8 months of patient experience (average: 15.4 months; range: 0-30.2 months per catheter) revealed an overall catheter-caused complication rate of 0.3% per patient month. Physician assessments were favorable with 89% rating this catheter as better than previously used intraspinal catheters. A measure of catheter survival estimates (Kaplan-Meier) at nine months was 89% including all complications. Comparison of data relating to implant techniques demonstrated a variety of catheter implant techniques (entry, positioning, anchoring) with no correlation between any one technique and the common complications. Conclusions. Performance data and physician assessments indicate that this catheter is an improvement over the previously available catheter.

Unrelieved chronic pain is costly to patients and society. Noninvasive and less costly therapies should be used before more invasive and more costly therapies. Therapies for pain control should be used according to a pain treatment continuum. Nerve-blocking techniques, neurolytic techniques, and implantable neuromodulatory technologies, such as SCC and spinal delivery of analgesics, are cost-effective when less invasive therapies fail to provide adequate analgesia.

The pharmacologic tailoring guidelines of the World Health Organization represent the accepted treatment algorithm for the management of cancer-related pain syndromes. Unfortunately, the guidelines are only effective in 70% to 90% of patients, leaving a substantial population with intractable pain. In fact, recent surveys have shown that, in the United States, only 50% of hospitalized terminally ill patients die comfortably. When patients do not respond to the WHO guidelines, practitioners should abandon the therapy and not the patient. Interventional pain management approaches including intraspinal delivery of analgesics may be an effective alternative. Before a more permanent system for intraspinal therapy is implemented, a trial must be performed to assure efficacy, rule out toxicity, and establish that the positive response to the intrathecal agent trialed is not due to placebo effects. An external drug delivery system is appropriate if the patient has less than 3 months to live. If the patient is expected to survive more than 3 months, a totally implanted system is appropriate and cost-effective. Although morphine remains the gold standard for intrathecal pain therapy, other opioids such as fentanyl, hydromorphone, sufentanil, and meperidine are now being used in patients who do not tolerate morphine. Nonopioid agents for intrathecal use in patients who have pain syndromes that are poorly responsive to opioids include local anesthetics, such as bupivacaine, and clonidine.

Due to successful use of intrathecal drug delivery in the management of refractory pain and spasticity, new agents and indications are now being investigated. Preclinical studies of neurotrophic factors, molecules necessary for neuroneal survival and development, suggest that these agents may be beneficial for patients with neurologic disorders. Because neurotrophic factors do not cross the blood-brain barrier following systemic administration, local delivery routes, including intrathecal, intracerebroventrical, and intraparenchymal routes, are being studied; research is being conducted on intrathecal delivery for amyotrophic lateral sclerosis (ALS), intracerebroventricular delivery for Parkinson's disease and Alzheimer's disease, and intrahippocampal delivery for seizure disorders. Treatment of other neurologic disorders, such as brain tumors and HIV-related viral infections, also may be optimized by methods of local drug delivery, including intratumoral and intraparenchymal administration of potentially effective agents. Intraspinal, intratumoral, and intraparenchymal routes of administration are speculated to become critical components of treatment for a variety of neurological indications.

Unrelieved pain is costly to the economic fabric of our society; its direct costs to patients and their families is staggering. Spinal cord stimulation for the treatment of chronic pain is cost-effective when used in the context of a pain treatment continuum. Many theories on the mechanism of action of spinal cord stimulation have been suggested, including activation of gate control mechanisms, conductance blockade of the spinothalamic tracts, activation of supraspinal mechanisms, blockade of supraspinal sympathetic mechanisms, and activation or release of putative neuromodulators. Whatever theory or theories of mechanism are correct, spinal cord stimulation has efficacy in the treatment of failed back surgery syndrome, complex regional pain syndromes, intractable pain due to peripheral vascular disease, and intractable pain due to angina.