Regulatory Framework for Implantable Neurostimulation Devices: Comparison of Systems in the US and European Union.

BACKGROUND: Implantable neurostimulation devices must be authorized before they are placed on the market. For this purpose, requirements, and processes for assessing their fulfillment, have been defined in different jurisdictions. OBJECTIVE: In this study, we aimed to address differences between the US and European Union (EU) regulatory systems and their relationship to innovation. MATERIALS AND METHODS: A literature review and analysis were conducted using legal texts and guidance documents. RESULTS: The US system has one central body, the Food and Drug Administration, whereas the EU system has several bodies with different responsibilities. The devices themselves are divided into risk classes, which are based on the vulnerability of the human body. This risk class determines the intensity of the review by the market authorization body. In addition to the requirements for development, manufacture, and distribution, the device itself must meet technical and clinical requirements. Compliance with technical requirements is indicated by nonclinical laboratory studies. Proof of efficacy is provided by means of clinical investigations. Procedures are defined for reviewing these elements. Once the market authorization process has been completed, the devices can be placed on the market. In the postmarketing phase, the devices must continue to be monitored, and measures must be initiated, if necessary. CONCLUSIONS: Both US and EU systems are intended to ensure that only safe and effective devices find their way to and remain on the market. The basic approaches of the two systems are comparable. In detail, however, there are differences in ways these goals are achieved.

A Definition of Neuromodulation and Classification of Implantable Electrical Modulation for Chronic Pain.

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.

Five-Year Longitudinal Follow-up of Restorative Neurostimulation Shows Durability of Effectiveness in Patients With Refractory Chronic Low Back Pain Associated With Multifidus Muscle Dysfunction.

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).

The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for the Mitigation of Complications of Neurostimulation.

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.

4. Painful diabetic polyneuropathy.

INTRODUCTION: Pain as a symptom of diabetic polyneuropathy (DPN) significantly lowers quality of life, increases mortality and is the main reason for patients with diabetes to seek medical attention. The number of people suffering from painful diabetic polyneuropathy (PDPN) has increased significantly over the past decades. METHODS: The literature on the diagnosis and treatment of diabetic polyneuropathy was retrieved and summarized. RESULTS: The etiology of PDPN is complex, with primary damage to peripheral nociceptors and altered spinal and supra-spinal modulation. To achieve better patient outcomes, the mode of diagnosis and treatment of PDPN evolves toward more precise pain-phenotyping and genotyping based on patient-specific characteristics, new diagnostic tools, and prior response to pharmacological treatments. According to the Toronto Diabetic Neuropathy Expert Group, a presumptive diagnosis of "probable PDPN" is sufficient to initiate treatment. Proper control of plasma glucose levels, and prevention of risk factors are essential in the treatment of PDPN. Mechanism-based pharmacological treatment should be initiated as early as possible. If symptomatic pharmacologic treatment fails, spinal cord stimulation (SCS) should be considered. In isolated cases, where symptomatic pharmacologic treatment and SCS are unsuccessful or cannot be used, sympathetic lumbar chain neurolysis and/or radiofrequency ablation (SLCN/SLCRF), dorsal root ganglion stimulation (DRGs) or posterior tibial nerve stimulation (PTNS) may be considered. However, it is recommended that these treatments be applied only in a study setting in a center of expertise. CONCLUSIONS: The diagnosis of PDPN evolves toward pheno-and genotyping and treatment should be mechanism-based.

Radiofrequency for chronic lumbosacral and cervical pain: Results of a consensus study using the RAND/UCLA appropriateness method.

BACKGROUND: Despite the routine use of radiofrequency (RF) for the treatment of chronic pain in the lumbosacral and cervical region, there remains uncertainty on the most appropriate patient selection criteria. This study aimed to develop appropriateness criteria for RF in relation to relevant patient characteristics, considering RF ablation (RFA) for the treatment of chronic axial pain and pulsed RF (PRF) for the treatment of chronic radicular pain. METHODS: The RAND/UCLA Appropriateness Method (RUAM) was used to explore the opinions of a multidisciplinary European panel on the appropriateness of RFA and PRF for a variety of clinical scenarios. Depending on the type of pain (axial or radicular), the expert panel rated the appropriateness of RFA and PRF for a total of 219 clinical scenarios. RESULTS: For axial pain in the lumbosacral or cervical region, appropriateness of RFA was determined by the dominant pain trigger and location of tenderness on palpation with higher appropriateness scores if these variables were suggestive of the diagnosis of facet or sacroiliac joint pain. Although the opinions on the appropriateness of PRF for lumbosacral and cervical radicular pain were fairly dispersed, there was agreement that PRF is an appropriate option for well-selected patients with radicular pain due to herniated disc or foraminal stenosis, particularly in the absence of motor deficits. The panel outcomes were embedded in an educational e-health tool that also covers the psychosocial aspects of chronic pain, providing integrated recommendations on the appropriate use of (P)RF interventions for the treatment of chronic axial and radicular pain in the lumbosacral and cervical region. CONCLUSIONS: A multidisciplinary European expert panel established patient-specific recommendations that may support the (pre)selection of patients with chronic axial and radicular pain in the lumbosacral and cervical region for either RFA or PRF (accessible via https://rftool.org). Future studies should validate these recommendations by determining their predictive value for the outcomes of (P)RF interventions.

Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial.

Importance: Opioid use for chronic nonmalignant pain can be harmful. Objective: To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care. Design, Setting, and Participants: Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020. Intervention: Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months. Main Outcomes and Measures: The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report. Results: Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt). Conclusions and Relevance: In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities. Trial Registration: isrctn.org Identifier: ISRCTN49470934.

Gradation of Clinical Holistic Response as New Composite Outcome to Evaluate Success in Spinal Cord Stimulation Studies for Pain.

INTRODUCTION: The most prominent outcome measurement in the field of neuromodulation is pain relief. Nevertheless, the number of studies that rely on composite outcomes has increased. The aims of this study are twofold: (1) to evaluate which measures are important to include in a composite outcome and (2) to develop this new composite outcome to evaluate the degree of being a clinical holistic responder with a corresponding minimal clinical important difference (MCID). MATERIALS AND METHODS: Data from patients with persistent spinal pain syndrome type 2 treated with High-Dose Spinal Cord Stimulation (HD-SCS) were used. Pain intensity for low back and leg pain, disability, health-related quality of life, medication use, and patient satisfaction were measured at baseline and after 12 months of HD-SCS. Exploratory and Confirmatory Factor Analyses were used to evaluate which measures should be included in the composite outcome. Anchor-based and distribution-based methods were applied to determine the MCID of the newly developed outcome measurement. RESULTS: A three-factor model was the most appropriate for this data set, in which leg pain intensity, EQ5D VAS, and disability had the largest loading on these factors. A clinical holistic outcome was created with a total score ranging from 0 (=better [no pain, no disability, and perfect health status]) to 300 (=worse [maximal pain, maximal disability, and worst health status]). The MCID value based on an absolute change score from baseline up to 12 months of HD-SCS was 87.97. When calculating with percentage changes, a MCID value of 48.4% was revealed. CONCLUSIONS: This new composite outcome evaluating the degree of deviation from being a holistic responder is a step toward a meaningful, overall outcome assessment for patients who are treated with SCS. Further studies to evaluate the psychometric properties and the generalizability toward other patient populations still need to be performed.

Cross-Country Differences in Pain Medication Before and After Spinal Cord Stimulation: A Pooled Analysis of Individual Patient Data From Two Prospective Studies in the United Kingdom and Belgium.

OBJECTIVES: Spinal cord stimulation (SCS) can reduce the need for opioids; however, the influence on the full spectrum of pain medication is less known. The aims of this study were to explore general prescription practices for patients scheduled for SCS, potential differences in prescriptions between Belgium and United Kingdom, and the influence of SCS on pain medication. MATERIALS AND METHODS: Individual patient data from the TRIAL-STIM study in the United Kingdom and DISCOVER in Belgium were pooled. Medication use was collected before SCS and three months after SCS from 180 chronic pain patients. The Medication Quantification Scale III (MQS) was used to calculate a total score for medication use, as well as subscores for several classes. Differences in prescription practices between United Kingdom and Belgium were evaluated with two-sided Wilcoxon tests. To evaluate differences in medication use after three months of SCS between United Kingdom and Belgium, Tweedie-generalized linear models were calculated. RESULTS: There was a statistically significant difference (-6.40 [95% CI from -3.40 to -9.10]) between the median total MQS score in United Kingdom and Belgium before SCS. Additionally, a significant difference was found for nonsteroidal anti-inflammatory drugs (NSAIDs) (-3.40 [95% CI -3.40 to -6.80]), neuropathic agents (-2.30 [95% CI -0.40 to -3.80]), and benzodiazepines (1.83e-05 [95% CI 2.64-05 to 7.45-05]) between United Kingdom and Belgium, before SCS. Tweedie-generalized models revealed a statistically significant interaction between country and time for MQS, neuropathic agents, and opioids. CONCLUSIONS: Our combined analysis revealed differences in prescription practice in patients scheduled for SCS implantation between Belgium and United Kingdom. NSAIDs and neuropathic mood agents are more frequently used in the United Kingdom, presumably due to easier access to repeat prescriptions and over the counter medications. After three months of SCS, a decrease in medication use is observed in both countries, with higher reductions in Belgium, presumably due to strict regulations concerning reimbursement criteria.

Effectiveness and Safety of Intrathecal Drug Delivery Systems for the Management of Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVES: Intrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS) have been proposed and assessed for the management of cancer pain; however, such treatments remain underused. We conducted a systematic review to evaluate the effectiveness and safety of IDDS and SCS for cancer pain. MATERIALS AND METHODS: Electronic databases MEDLINE, CENTRAL, EMBASE, and WikiStim were searched from 1988 to March 2021. Randomized controlled trials and observational studies of adults with pain related to cancer or its treatment who received an implantable IDDS or SCS were eligible for inclusion. The primary outcome of the review was change in pain intensity from baseline to the last available follow-up, measured using a visual analog scale or numerical rating scale. The protocol for this review is registered on PROSPERO (CRD42021240717). RESULTS: A total of 22 studies (24 reports) included a total of 3043 participants who received either IDDS or SCS for cancer pain. Eight studies reporting data for 405 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest posttreatment follow-up time compared with baseline (mean difference [MD], -3.31; 95% CI, -4.18 to -2.45; p < 0.001). Six studies reporting data for 325 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment compared with baseline (MD, -3.53; 95% CI, -4.06 to -3.00; p < 0.001). A meta-analysis including studies of participants with either an IDDS or an SCS device showed similar results. Improvements in other outcomes following implantation of IDDS also were observed. Postdural puncture headache was the most reported complication, whereas urinary retention, nausea, and vomiting were commonly reported side effects. CONCLUSION: Our findings suggest that IDDS is effective in reducing pain intensity for patients with cancer pain when compared with pretreatment.

Systematic Review to Identify Predictors of Treatment Response to Neuromodulation in Patients With Neuropathic Pain-Protocol.

OBJECTIVES: Patients who suffer from long-term, neuropathic pain that proves refractory to conventional medical management are high consumers of health care resources and experience poorer physical and mental health than people with other forms of pain. Pharmacologic treatments have adverse effects; nonpharmacologic interventions have limitations. Spinal cord stimulation (SCS) is an effective treatment for neuropathic pain, although 30% to 40% of patients fail to achieve acceptable levels of pain relief. There are currently no objective methods to predict the success of SCS to treat neuropathic pain, and therefore, it is important to understand which patient factors may be predictive of a lack of response to SCS, to inform future patient treatment options. This study proposes a protocol for a systematic review and meta-analysis of published studies to examine these predictive factors. MATERIALS AND METHODS: Several bibliographic databases will be searched to identify relevant studies published since 2012 that provide data on patient characteristics (eg, age, gender, pain severity) as predictors of SCS outcomes of pain, function, and health-related quality of life. Two independent reviewers will screen citations; data will be extracted after full-text screening. Risk of bias will be assessed using the Quality In Prognosis Studies tool. RESULTS: A formal quantitative synthesis is planned in which data from studies with the same predictive factors are available; this will be considered for pooling into separate meta-analyses. In cases of high heterogeneity or inconsistency in the data, subgroup analysis will be conducted. CONCLUSIONS: This study seeks to provide a contemporary review of patient predictors of success of neuromodulation for neuropathic pain. We anticipate that findings may guide the use of neuromodulation in patient subgroups and the design and reporting of future clinical studies in this field.

A Clinical Evaluation of the Accuracy of an Intrathecal Drug Delivery Device.

INTRODUCTION: Implantable intrathecal drug delivery (ITDD) devices are used to treat severe pain and spasticity refractory to conventional medical management. Although off-label medications and drug admixtures are commonly used in clinical practice and recommended by international guidelines, manufacturers state that this practice can result in device failure. The impact of off-label drugs and drug combinations on pump accuracy has hitherto never been assessed. MATERIALS AND METHODS: A multinational, three-center, retrospective review of patient records was undertaken. The inclusion criterion was the presence of an ITDD device implantation in adult patients, with the pump in situ for the expected battery lifespan. Residual drug volumes at each refill, drug mixtures and concentrations, and rate and flow pattern of the pump (simple or flex) were recorded. A normalized flow rate ratio was calculated (actual to theoretical flow rate). The impact of nonapproved drugs, battery life, pump size, and flow program on drug delivery accuracy was assessed. RESULTS: Data from 1402 pump refills were collected (73 patients). The overall mean accuracy ratio was 0.995 (95% CI = 0.986-1.004). The ratio for approved drug status was 0.990 vs 0.997 in nonapproved, with a difference of -0.007 (-0.032 to 0.017). At the tenth centile for remaining battery life (14 months), the ratio was 0.983 vs 1.009 for the 90th centile (69 months), with a difference of -0.026 (-0.038 to -0.014). The ratio for flex administration was 0.982 vs 1.006 for simple, with a difference of -0.024 (-0.040 to -0.008). For pump size of 40 mL, the ratio was 0.975 vs 1.010 for 20 mL, with a difference of -0.035 (-0.063 to -0.008). The 95% prediction interval for individual refill ratios was ±0.15. CONCLUSION: In a clinical setting, the ITDD pumps retained high levels of accuracy and acceptable precision across their lifespan despite using unapproved drugs or admixtures and under various flow modes and rates.

Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis.

OBJECTIVES: Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain. MATERIALS AND METHODS: An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios. RESULTS: Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England. CONCLUSIONS: The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options.

Spinal Cord Stimulation for Neuropathic Pain in England From 2010 to 2020: A Hospital Episode Statistics Analysis.

OBJECTIVES: Spinal cord stimulation (SCS) is a recognized intervention for the management of chronic neuropathic pain. The United Kingdom National Institute of Health and Care Excellence has recommended SCS as a management option for chronic neuropathic pain since 2008. The aim of this study is to undertake an assessment of SCS uptake across the National Health Service in England up to 2020. MATERIALS AND METHODS: Hospital Episode Statistics were obtained for patients with neuropathic pain potentially eligible for SCS and patients receiving an SCS-related procedure. Data were retrieved nationally and per region from the years 2010-2011 to 2019-2020. RESULTS: There were 50,288 adults in England attending secondary care with neuropathic pain in 2010-2011, increasing to 66,376 in 2019-2020. The number of patients with neuropathic pain with an SCS procedure increased on a year-to-year basis until 2018-2019. However, less than 1% of people with neuropathic pain received an SCS device with no evidence of an increase over time when considering the background increase in neuropathic pain prevalence. CONCLUSION: Only a small proportion of patients in England with neuropathic pain potentially eligible for SCS receives this intervention. The recommendation for routine use of SCS for management of neuropathic pain has not resulted in an uptake of SCS over the last decade.

Applicability and Validity of an e-Health Tool for the Appropriate Referral and Selection of Patients With Chronic Pain for Spinal Cord Stimulation: Results From a European Retrospective Study.

OBJECTIVES: To support rational decision-making on spinal cord stimulation (SCS), a European expert panel developed an educational e-health tool using the RAND/University of California at Los Angeles Appropriateness Method. This retrospective study aimed to determine the applicability and validity of the tool using data from patients for whom SCS had been considered. MATERIALS AND METHODS: A total of 12 European implant centers retrieved data from 25 to 50 consecutive patients for whom SCS was considered in 2018-2019. For each patient, data were captured on the clinical and psychosocial variables included in the e-health tool, center decisions on SCS, and patient outcomes. Patient outcomes included global perception of effect by the patient and observer, and pain reduction (numeric pain rating scale) at six-month follow-up. RESULTS: In total, 483 patients were included, of whom 133 received a direct implant, 258 received an implant after a positive trial, 32 had a negative trial, and 60 did not receive SCS for reasons other than a negative trial. The most frequent indication was persistent spinal pain syndrome type 1 and type 2 (74%), followed by neuropathic pain syndromes (13%), complex regional pain syndrome (12%), and ischemic pain syndromes (0.8%). Data on the clinical and psychosocial variables were complete for 95% and 93% of patients, respectively, and missing data did not have a significant impact on the study outcomes. In patients who had received SCS, panel recommendations were significantly associated with patient outcomes (p < 0.001 for all measures). Substantial improvement ranged from 25% if the e-health tool outcome was "not recommended" to 83% if SCS was "strongly recommended". In patients who underwent a trial (N = 290), there was 3% of trial failure when SCS was "strongly recommended" vs 46% when SCS was "not recommended". CONCLUSIONS: Retrospective application of the e-health tool on patient data showed a strong relationship between the panel recommendations and both SCS trial results and treatment outcomes.

Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial.

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.

Holistic Treatment Response: An International Expert Panel Definition and Criteria for a New Paradigm in the Assessment of Clinical Outcomes of Spinal Cord Stimulation.

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.

Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction.

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.

Reporting Guidelines for Clinical Trial Protocols and Reports of Implantable Neurostimulation Devices: Protocol for the SPIRIT-iNeurostim and CONSORT-iNeurostim Extensions.

OBJECTIVES: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) statements have been shown to improve the quality of reporting of trial protocols and randomized controlled trials. Extensions to the SPIRIT and CONSORT statements specific to certain interventions have the potential to address methodological considerations that would otherwise be overlooked. The aim of this protocol is to describe the methods to develop reporting guidelines for clinical trial protocols and reports of implantable neurostimulation devices. MATERIALS AND METHODS: The SPIRIT-iNeurostim and CONSORT-iNeurostim extensions will be developed through a staged consensus process involving literature review and expert consultation. The initial list of candidate items will be informed by findings from previous systematic reviews and published protocols and clinical trials of implantable neurostimulation devices. The candidate items will be included in a two-round Delphi survey. In the first round, participants will be invited to vote on the importance of each item and to suggest additional relevant items. In the second round, participants will be invited to re-score the items considering feedback received and the suggested additional items. A consensus meeting will then take place to discuss the results of the Delphi survey and reach consensus on the items to include in the extensions. DISCUSSION: Development of the SPIRIT-iNeurostim and CONSORT-iNeurostim extensions has the potential to lead to improvements and increase in transparency of the reporting of clinical trial protocols and reports of implantable neurostimulation devices.

Cauda equina syndrome after unilateral medial branch blocks of the lower lumbar zygapophyseal joints.

Medial branch blockade of the lumbar facet joints is widely performed and generally accepted as a safe intervention. We present a case of neurological damage following a medial branch blockade with local anesthetic and steroid. A patient suffering from chronic low back pain radiating to the buttocks and thighs underwent nine medial branch blockades over a few years. Three months after successful back surgery to remove a herniated L2-3 disk, the pain recurred, and left L3-4 , L4-5, and L5 -S1  medial branch blocks were performed under fluoroscopy. Immediately following the procedure, the patient developed paraparesis in both legs, loss of pinprick but preserved fine touch sensation, proprioception, and sphincter sensory and motor function. MRI showed ischemic lesions of the cauda equina. Direct needle trauma was discounted as a cause, due to the bilateral neurological deficit, plus the lack of pain during the procedure. Particulate steroid preparations can form aggregates, which may embolize and block small terminal arteries, causing neurological damage. Although the patient received nine sets of injections uneventfully during the previous 36 months, this procedure took place 3 months following spinal surgery. This rare, but catastrophic case of cauda equina syndrome occurred following L3-4 , L4-5 , and L5 -S1  medial branch blockades 3 months after spinal surgery, which is believed to be caused by accidental intra-arterial injection of particulate methylprednisolone, with consequent aggregates causing blockage and ensuing ischemia. Therefore we suggest particulate steroid preparations should not be used in axial spinal injection.