Safety and Efficacy of Axon Therapy (SEAT Study), Utilizing Magnetic Peripheral Nerve Stimulation (mPNS) for Treatment of Neuropathic Pain.

Background: Many of the current treatments for chronic neuropathic pain have variable effectiveness and known side effects. Given the prevalence of this type of intractable pain (3-17% of general population), additional therapeutic non-invasive approaches are desired. Magnetic Peripheral Nerve Stimulation (mPNS) delivered at 0.5Hz provides an effective pain relief without side effects. The objective of this randomized, controlled, multi-site clinical trial was to compare long-term safety and efficacy of mPNS in patients with chronic, intractable, post-traumatic or post-surgical neuropathic pain to comprehensive Conventional Medical Management (CMM). Methods: A total of 65 patients with post-traumatic, post-surgical neuropathy were treated within a multicenter, randomized, clinical trial comparing the safety and effectiveness of mPNS + CMM to CMM alone. Patients were randomized 1:1 and followed through 90 days. The primary endpoint is a proportion of responders, 50% or greater reduction in pain at Day 90. The secondary endpoints included the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) and Patient Global Impression of Change (PGIC). Results: At 3 months, 71% of subjects were considered responders (>50% pain relief) in the mPNS + CMM group vs 13% of subjects in the CMM group. The mPNS + CMM group had a mean reduction in VAS scores at Day 90 of 3.8 points (>50% reduction), while CMM showed less than a 1-point (0.7 point) mean reduction or ~10% reduction (p < 0.0001). The EQ-5D-3L score increased in the mPNS + CMM study group, whereas the CMM group showed no improvement in EQ-5D-3L at Day 90. PGIC responder rates were 80.6% and 4.3% at Day 90 for mPNS + CMM and CMM groups, respectively. Conclusion: mPNS + CMM was superior to CMM in a randomized prospective study when used for treatment of post-traumatic, post-surgical neuropathy. Due to the lack of other effective non-invasive treatments for neuropathic pain, mPNS should be considered much earlier in the treatment algorithm.

Validation of a holistic composite outcome measure for the evaluation of chronic pain interventions.

Introduction: Chronic pain is a personal experience influenced by multiple biopsychosocial factors. Using a pain intensity measure alone to assess the effectiveness of a chronic pain intervention fails to fully evaluate its impact on the multifaceted chronic pain experience. The holistic minimal clinically important difference (MCID) is a composite outcome developed to provide a comprehensive assessment of chronic pain in response to intervention, across 5 outcome domains: pain intensity, health-related quality of life, sleep quality, physical, and emotional function. To focus on domains where the individual need is greatest, the holistic MCID reflects the cumulative MCID averaged over only the domains where subjects were impaired preintervention. Objectives: To assess the internal and construct validity of the Holistic MCID score to inform its future use as an evidence-based tool. Methods: This validation study was undertaken using data from the EVOKE trial with 111 patients up to 24-month follow-up. Internal consistency of the holistic MCID was assessed using Cronbach alpha statistic and dimensional exploration using principal component analysis. Results: The holistic MCID measure demonstrated strong internal consistency with Cronbach alpha >0.7 at all follow-ups. Principal component analysis showed one overarching holistic dimension to be present in the composite. Construct validity was demonstrated by an increase in the holistic MCID score being associated with both increased Patients' Global Impression of Change, EuroQol visual analogue scale score, and each of the outcome domains in a "leave-one-out" analysis (all P < 0.001). Conclusion: The holistic MCID provides a valid measure for the comprehensive, personalized assessment of response after a chronic pain intervention. The validity of the holistic MCID requires further confirmation in other chronic pain populations and with different interventions.

Long-Term Treatment of Chronic Postamputation Pain With Bioelectric Nerve Block: Twelve-Month Results of the Randomized, Double-Blinded, Cross-Over QUEST Study.

OBJECTIVE: The multicenter, randomized, double-blinded, active-sham controlled trial (high-freQUEncy nerve block for poST amputation pain [QUEST]) was conducted to show the safety and efficacy of a novel, peripherally placed high-frequency nerve block (HFNB) system in treating chronic postamputation pain (PAP) in patients with lower limb amputations. The primary outcomes from QUEST were reported previously. This study presents the long-term, single-cross-over, secondary outcomes of on-demand HFNB treatment for chronic PAP. MATERIALS AND METHODS: After the three-month randomized period, subjects in the active-sham group were crossed over to receive therapy for 12 months. Subjects self-administered HFNB therapy as needed and reported their pain (numerical rating scale [NRS]; range, 1-10) before and 30 and 120 minutes after each treatment. Pain medication use was reported throughout the study. Pain-days per week and quality of life (QOL) were assessed using the Brief Pain Inventory (BPI). Adverse events (AEs) were recorded for all subjects implanted for 12 months. RESULTS: Of 180 subjects implanted in QUEST, 164 (91%) were included in the cross-over period, and 146 (82%) completed follow-up. By month 12, average NRS pain in the combined cohort was reduced by 2.3 ± 2.2 points (95% CI, 1.7-2.8; p < 0.0001) 30 minutes after treatment and 2.9 ± 2.4 points (95% CI, 2.2-3.6; p < 0.0001) 120 minutes after treatment. Mean pain-days per week were significantly reduced (-3.5 ± 2.7 days; p < 0.001), and subject daily opioid use was reduced by 6.7 ± 29.0 morphine equivalent dose from baseline to month 12 (p = 0.013). Mean BPI-interference scores (QOL) improved by 2.7 ± 2.7 points from baseline (p < 0.001). The incidence of nonserious AEs and serious AEs was 72% (130/180) and 42% (76/180), respectively; serious device-related AEs occurred in 15 of 180 subjects (8%). CONCLUSION: Overall, HFNB delivered directly to the damaged peripheral nerve provided sustained, on-demand relief of acute PAP exacerbations, reduced opioid utilization, and improved QOL for patients with lower limb amputations with chronic PAP.

Twelve-month results from a randomized controlled trial comparing differential target multiplexed spinal cord stimulation and conventional spinal cord stimulation in subjects with chronic refractory axial low back pain not eligible for spine surgery.

Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

9. Chronic knee pain.

INTRODUCTION: Chronic knee pain is defined as pain that persists or recurs over 3 months. The most common is degenerative osteoarthritis (OA). This review represents a comprehensive description of the pathology, diagnosis, and treatment of OA of the knee. METHODS: The literature on the diagnosis and treatment of chronic knee pain was retrieved and summarized. A modified Delphi approach was used to formulate recommendations on interventional treatments. RESULTS: Patients with knee OA commonly present with insidious, chronic knee pain that gradually worsens. Pain caused by knee OA is predominantly nociceptive pain, with occasional nociplastic and infrequent neuropathic characteristics occurring in a diseased knee. A standard musculoskeletal and neurological examination is required for the diagnosis of knee OA. Although typical clinical OA findings are sufficient for diagnosis, medical imaging may be performed to improve specificity. The differential diagnosis should exclude other causes of knee pain including bone and joint disorders such as rheumatoid arthritis, spondylo- and other arthropathies, and infections. When conservative treatment fails, intra-articular injections of corticosteroids and radiofrequency (conventional and cooled) of the genicular nerves have been shown to be effective. Hyaluronic acid infiltrations are conditionally recommended. Platelet-rich plasma infiltrations, chemical ablation of genicular nerves, and neurostimulation have, at the moment, not enough evidence and can be considered in a study setting. The decision to perform joint-preserving and joint-replacement options should be made multidisciplinary. CONCLUSIONS: When conservative measures fail to provide satisfactory pain relief, a multidisciplinary approach is recommended including psychological therapy, integrative treatments, and procedural options such as intra-articular injections, radiofrequency ablation, and surgery.

Maximal Analgesic Effect Attained by the Use of Objective Neurophysiological Measurements With Closed-Loop Spinal Cord Stimulation.

OBJECTIVES: Spinal cord stimulation (SCS) has been challenged by the lack of neurophysiologic data to guide therapy optimization. Current SCS programming by trial-and-error results in suboptimal and variable therapeutic effects. A novel system with a physiologic closed-loop feedback mechanism using evoked-compound action potentials enables the optimization of physiologic neural dose by consistently and accurately activating spinal cord fibers. We aimed to identify neurophysiologic dose metrics and their ranges that resulted in clinically meaningful treatment responses. MATERIALS AND METHODS: Subjects from 3 clinical studies (n = 180) with baseline back and leg pain ≥60 mm visual analog scale and physical function in the severe to crippled category were included. Maximal analgesic effect (MAE) was operationally defined as the greatest percent reduction in pain intensity or as the greatest cumulative responder score (minimal clinically important differences [MCIDs]) obtained within the first 3 months of SCS implant. The physiologic metrics that produced the MAE were analyzed. RESULTS: We showed that a neural dose regimen with a high neural dose accuracy of 2.8µV and dose ratio of 1.4 resulted in a profound clinical benefit to chronic pain patients (MAE of 79 ± 1% for pain reduction and 12.5 ± 0.4 MCIDs). No differences were observed for MAE or neurophysiological dose metrics between the trial phase and post-implant MAE visit. CONCLUSION: For the first time, an evidence-based neural dose regimen is available for a neurostimulation intervention as a starting point to enable optimization of clinical benefit, monitoring of adherence, and management of the therapy.

Design of a Multicenter, Randomized Controlled Trial for the Treatment of Peripheral Neuropathic Pain (COMFORT Study) with a Micro-Implantable Pulse Generator.

Background: Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM). Methods/Design: This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study. Discussion: The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone.

Peripheral nerve stimulation (PNS) has been used for decades to treat neuropathic pain of peripheral origin. This therapy typically involves the placement small (~1 mm diameter) cylindrical electrodes (leads) near the nerve(s) in question, which is then followed by the delivery mild electrical pulses to the target, thereby blocking the pain signal from reaching the central nervous system. Despite the clinical success of this approach, there are few randomized controlled trials (RCTs) demonstrating PNS efficacy in the treatment of peripheral neuralgia/neuropathy. This may be, in large part, due to a paucity of PNS devices that are small enough to deliver this therapy at multiple locations in the extremities and the torso. For example, most implantable pulse generators (IPGs) range in size from 14 to 40 cm³ in volume. The purpose of this RCT is to demonstrate the safety and efficacy of an externally powered micro-IPG (<1.5 cm³ in volume), in the delivery of PNS to treat peripheral neuropathic pain. Active Arm subjects will receive therapy with the micro-IPG and continue to use conventional medical management (CMM); Control Arm subjects will be treated with CMM only. The primary endpoint is the responder rate at 3-months, in both arms, defined as the percentage of subjects with ≥50% pain reduction from baseline following implantation of the micro-IPG. Control Arm subjects will be given the option to crossover to the Active Arm at 3-months. Study subjects in both arms are followed out to 36 months.

Ten-kHz Spinal Cord Stimulation vs Radiofrequency Ablation of Splanchnic Nerves: A Single-Site Retrospective Comparison of 12-Month Outcomes.

OBJECTIVES: A prospective study on 10-kHz spinal cord stimulation (SCS) for various causes of chronic abdominal pain (CAP) showed robust improvements in subjects' pain and function. Radiofrequency ablation of splanchnic nerves (snRFA) has been used in advanced pain management treatment algorithms for CAP. This analysis was designed to provide what we believe is the first comparison of the efficacy of these two therapies. Propensity-score matched analysis (PMA) was performed to compare pain relief and decrease in medication usage in snRFA and SCS for treating refractory CAP. MATERIALS AND METHODS: Medical records were extracted for consecutive patients with CAP treated from June 2015 to June 2021 who underwent either snRFA or SCS at the Carolinas Pain Institute after positive diagnostic splanchnic block. The patients' diagnoses included gastroparesis, chronic pancreatitis, postsurgical CAP, and other dysmotility syndromes. PMA was performed to produce matched pairs in terms of baseline clinical status, reported pain, and opioid use over 12 months, after treatment was compared in the groups. RESULTS: PMA produced two well-balanced groups (n = 31) for SCS and snRFA. Analysis showed significant improvement in pain scores in both groups through 12 months, but the mean reduction in reported numerical rating scale points was significantly greater for the SCS group, averaging 4.7 vs 3.0 points for the snRFA group (p < 0.01). Responder rates (≥50% pain relief) similarly diverged at 12 months, with 67.7% vs 30.0% responders in the SCS and snRFA groups, respectively (p = 0.017). Opioid usage did not change in the snRFA group but was reduced in the SCS group at 12 months (p = 0.004). CONCLUSIONS: SCS provided longer pain relief than did snRFA in this propensity-matched study. Pain scores and opioid usage were significantly less at 12-month follow-up when SCS was used for control of CAP.

Primary 3-Month Outcomes of a Double-Blind Randomized Prospective Study (The QUEST Study) Assessing Effectiveness and Safety of Novel High-Frequency Electric Nerve Block System for Treatment of Post-Amputation Pain.

Purpose: This multicenter, randomized, double-blinded, active sham-controlled pivotal study was designed to assess the efficacy and safety of high-frequency nerve block treatment for chronic post-amputation and phantom limb pain. Patients and Methods: QUEST enrolled 180 unilateral lower-limb amputees with severe post-amputation pain, 170 of whom were implanted with the Altius device, were randomized 1:1 to active-sham or treatment groups and reached the primary endpoint. Responders were those subjects who received ≥50% pain relief 30 min after treatment in ≥50% of their self-initiated treatment sessions within the 3-month randomized period. Differences between the active treatment and sham control groups as well as numerous secondary outcomes were determined. Results: At 30-min, (primary outcome), 24.7% of the treatment group were responders compared to 7.1% of the control group (p=0.002). At 120-minutes following treatment, responder rates were 46.8% in the Treatment group and 22.2% in the Control group (p=0.001). Improvement in Brief Pain Inventory interference score of 2.3 ± 0.29 was significantly greater in treatment group than the 1.3 ± 0.26-point change in the Control group (p = 0.01). Opioid usage, although not significantly different, trended towards a greater reduction in the treatment group than in the control group. The incidence of adverse events did not differ significantly between the treatment and control groups. Conclusion: The primary outcomes of the study were met, and the majority of Treatment patients experienced a substantial improvement in PAP (regardless of meeting the study definition of a responder). The significant in PAP was associated with significantly improved QOL metrics, and a trend towards reduced opioid utilization compared to Control. These data indicate that Altius treatment represents a significant therapeutic advancement for lower-limb amputees suffering from chronic PAP.

Clinical study of a micro-implantable pulse generator for the treatment of peripheral neuropathic pain: 3-month and 6-month results from the COMFORT-randomised controlled trial.

BACKGROUND: We report the results from the first large, postmarket, multicentre, randomised controlled trial (RCT) evaluating peripheral nerve stimulation (PNS) for the treatment of chronic peripheral pain with a micro-implantable pulse generator (micro-IPG). METHODS: Subjects meeting eligibility were randomised (2:1) to either the active arm receiving PNS and conventional medical management (CMM) or the control arm receiving CMM alone. Treatments were limited to the following areas: lower back, shoulder, knee and foot/ankle. RESULTS: At 6 months, the active arm achieved an 88% responder rate with a 70% average reduction in pain. At the 3-month primary endpoint, the active arm achieved an 84% responder rate with an average pain reduction of 67% compared with the control arm, which achieved a 3% responder rate with an average pain reduction of 6%. Both responder rate and pain reduction in the active arm were significantly better than in the control arm (p<0.001). A majority of patient-reported outcomes also reached statistical significance. There have been no reports of pocket pain and no serious adverse device effects. 81% of subjects found the external wearable component of the PNS system to be comfortable. CONCLUSIONS: This study successfully reached its primary endpoint-the active arm achieved a statistically significant superior responder rate as compared with the control arm at 3 months. These RCT results demonstrated that PNS, with this micro-IPG, is efficacious and safe. This ongoing study will follow subjects for 3 years, the results of which will be reported as they become available.

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET.

Introduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Chronic Abdominal Discomfort Syndrome (CADS): Defining and Discussing a Novel Diagnosis.

In this article, we propose a new diagnostic paradigm known as Chronic Abdominal Discomfort Syndrome (CADS). Patient's presentation centers around chronic abdominal pain not explained by acute pathology with or without accompanying dyspepsia, bloating, nausea and vomiting among other symptoms. The pathophysiology is noted to be neurogenic, possibly stemming from visceral sympathetic nerves or abdominal wall afferent nerves. Diagnosis is supported by signs or symptoms traversing clinical, diagnostic and functional criteria. Included is a tool which can assist clinicians in diagnosing patients with CADS per those domains. We hope to facilitate primary care physicians' and gastroenterologists' utilization of our criteria to provide guidance for selecting which patients may benefit from further interventions or evaluation by a pain physician. The pain physician may then offer interventions to provide the patient with relief.

Demographics and PainDETECT as Predictors of 24-Month Outcomes for 10 kHz SCS in Nonsurgical Refractory Back Pain.

BACKGROUND: Nonsurgical refractory back pain (NSRBP) is broadly defined as chronic refractory back pain in patients who have not had previous spine surgery and, because they are deemed inappropriate candidates for surgery, are reliant on conventional medical management (CMM), which often provides poor long-term outcomes. High-frequency spinal cord stimulation (10kHz SCS) has demonstrated high rates of pain relief and improvements in functioning in patients with NSRBP. However, despite the use of temporary trial stimulation to select patients who will respond to therapy, some patients fail to achieve long-term therapy response with permanent implants. Prediction analysis founded on patients' baseline characteristics may enrich the appropriate selection of patients for permanent implantation. OBJECTIVES: To examine baseline patient characteristics to predict long-term pain and functional responses to treatment with 10 kHz SCS for NSRBP. STUDY DESIGN: A retrospective analysis of baseline patient characteristics as predictors of 24-month pain and functional outcomes from a previous multicenter randomized controlled trial of 10 kHz SCS in patients with NSRBP. PATIENTS: Patients diagnosed with chronic, neuropathic, axial, low back pain refractory to CMM who had had no previous spine surgery, were deemed unsuitable candidates for it according to a spine surgeon, were implanted with 10kHz SCS and continued with CMM for up to 24 months. METHODS: The baseline characteristics of and 24-month outcomes in the 125 implanted patients who participated in the NSRBP randomized controlled trial (RCT) were included in this analysis. The baseline characteristics included demographics, baseline pain on the visual analog scale (VAS), baseline function based on the Oswestry Disability Index (ODI), mental health according to the patient health questionnaire-9 (PHQ-9), neuropathic pain as measured by PainDETECT, and each patient's temporary trial response. Patient response at 24 months was defined as absolute change from the baseline on the VAS and ODI, and each patient was also classified as a pain responder (achieving at least a 50% decrease in VAS pain score from the baseline) and a function responder (at least a 10-point decrease in ODI or a 24-month score of no more than 20 points). Multivariate prediction models based on regression and classification and regression tree (CART) techniques were developed using the response variables discussed above as the dependent variables and the baseline characteristics as the independent variables. RESULTS: Different factors contributed to pain and functional outcomes. Patients presenting with neuropathic pain (PainDETECT >= 19) and female gender had higher odds of being pain responders to 10 kHz SCS therapy than did males and those without neuropathic pain. Both higher age and depression score (PHQ-9) independently reduced the odds that a patient would be an ODI responder. Years since diagnosis, the reason the patient was deemed unsuitable for spine surgery, and pain etiology were not predictive of pain or functional outcomes. LIMITATIONS: A retrospective sub-analysis of a single pragmatic randomized controlled trial. CONCLUSIONS: There may be an opportunity to increase pain relief and functional improvement if additional patient screening accompanies the temporary lead trial. The presence of neuropathic pain, female gender, age, and depression had some predictive value, but this analysis demonstrates the treatment efficacy of 10 kHz SCS across a wide range of patients with NSRBP.

Neurophysiological outcomes that sustained clinically significant improvements over 3 years of physiologic ECAP-controlled closed-loop spinal cord stimulation for the treatment of chronic pain.

INTRODUCTION: A novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements. METHODS: 41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain. RESULTS: The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively). CONCLUSION: The results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.

Spinal Cord Stimulation for Intractable Visceral Pain Originating from the Pelvic and Abdominal Region: A Narrative Review on a Possible New Indication for Patients with Therapy-Resistant Pain.

Aim: Visceral pain, characterized by pain that is diffuse and challenging to localize, occurs frequently and is difficult to treat. In cases where the pain becomes intractable despite optimal medical management, it can affect patients' Quality of Life (QoL). Spinal Cord Stimulation (SCS) has emerged as a potential solution for intractable visceral pain. Purpose: In this narrative review, we collected all evidence regarding the efficacy of SCS for visceral pain across various underlying conditions. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science in which articles published from October 1st, 1963 up to March 7th, 2023 were identified. Results: Seventy articles were included in this review of which most were retrospective cohort studies, case series and case reports. The studies, often with a small number of participants, reported on SCS for chronic pancreatitis, anorectal pain and bowel disorders, gynaecological diagnoses, visceral pelvic pain, urological disorders and finally general visceral pain. They found positive effects on pain and/or symptom relief, opioid consumption, anxiety and depression and QoL. Complications occurred frequently but were often minor and reversible. Conclusion: Better screening and selection criteria need to be established to optimally evaluate eligible patients who might benefit from SCS. A positive outcome of a sympathetic nerve block appears to be a potential indicator of SCS effectiveness. Additionally, women receiving SCS for endometriosis had a better outcome compared to other indications. Finally, SCS could also relief functional symptoms such as voiding problems and gastroparesis. Complications could often be resolved with revision surgery. Since SCS is expensive and not always covered by standard health insurance, the incorporation of cost-analyses is recommended. In order to establish a comprehensive treatment plan, including selection criteria for SCS, rigorous prospective, possibly randomized and controlled studies that are diagnosis-oriented, with substantial follow-up and adequate sample sizes, are needed.

Cooled radiofrequency ablation versus standard medical management for chronic sacroiliac joint pain: a multicenter, randomized comparative effectiveness study.

INTRODUCTION: Low back pain is the leading cause of disability worldwide, with sacroiliac joint pain comprising up to 30% of cases of axial lower back pain. Conservative therapies provide only modest relief. Although placebo-controlled trials show efficacy for sacral lateral branch cooled radiofrequency ablation, there are no comparative effectiveness studies. METHODS: In this randomized, multicenter comparative effectiveness study, 210 patients with clinically suspected sacroiliac joint pain who obtained short-term benefit from diagnostic sacroiliac joint injections and prognostic lateral branch blocks were randomly assigned to receive cooled radiofrequency ablation of the L5 dorsal ramus and S1-S3 lateral branches or standard medical management consisting of pharmacotherapy, injections and integrative therapies. The primary outcome measure was mean reduction in low back pain score on a 0-10 Numeric Rating Scale at 3 months. Secondary outcomes included measures of quality of life and function. RESULTS: 3 months post-treatment, the mean Numeric Rating Scale pain score for the cooled radiofrequency ablation group was 3.8±2.4 (mean reduction 2.5±2.5) compared with 5.9±1.7 (mean reduction 0.4±1.7) in the standard medical management group (p<0.0001). 52.3% of subjects in the cooled radiofrequency ablation group experienced >2 points or 30% pain relief and were deemed responders versus 4.3% of standard medical management patients (p<0.0001). Comparable improvements favoring cooled radiofrequency ablation were noted in Oswestry Disability Index score (mean 29.7±15.2 vs 41.5+13.6; p<0.0001) and quality of life (mean EuroQoL-5 score 0.68±0.22 vs 0.47±0.29; p<0.0001). CONCLUSIONS: In patients with sacroiliac joint pain, cooled radiofrequency ablation provided statistically superior improvements across the spectrum of patient outcomes compared with standard medical management. TRIAL REGISTRATION NUMBER: NCT03601949.

Durable multimodal and holistic response for physiologic closed-loop spinal cord stimulation supported by objective evidence from the EVOKE double-blind randomized controlled trial.

INTRODUCTION: Chronic pain patients may experience impairments in multiple health-related domains. The design and interpretation of clinical trials of chronic pain interventions, however, remains primarily focused on treatment effects on pain intensity. This study investigates a novel, multidimensional holistic treatment response to evoked compound action potential-controlled closed-loop versus open-loop spinal cord stimulation as well as the degree of neural activation that produced that treatment response. METHODS: Outcome data for pain intensity, physical function, health-related quality of life, sleep quality and emotional function were derived from individual patient level data from the EVOKE multicenter, participant, investigator, and outcome assessor-blinded, parallel-arm randomized controlled trial with 24 month follow-up. Evaluation of holistic treatment response considered whether the baseline score was worse than normative values and whether minimal clinical important differences were reached in each of the domains that were impaired at baseline. A cumulative responder score was calculated to reflect the total minimal clinical important differences accumulated across all domains. Objective neurophysiological data, including spinal cord activation were measured. RESULTS: Patients were randomized to closed-loop (n=67) or open-loop (n=67). A greater proportion of patients with closed-loop spinal cord stimulation (49.3% vs 26.9%) were holistic responders at 24-month follow-up, with at least one minimal clinical important difference in all impaired domains (absolute risk difference: 22.4%, 95% CI 6.4% to 38.4%, p=0.012). The cumulative responder score was significantly greater for closed-loop patients at all time points and resulted in the achievement of more than three additional minimal clinical important differences at 24-month follow-up (mean difference 3.4, 95% CI 1.3 to 5.5, p=0.002). Neural activation was three times more accurate in closed-loop spinal cord stimulation (p<0.001 at all time points). CONCLUSION: The results of this study suggest that closed-loop spinal cord stimulation can provide sustained clinically meaningful improvements in multiple domains and provide holistic improvement in the long-term for patients with chronic refractory pain. TRIAL REGISTRATION NUMBER: NCT02924129.

Durable responses at 24 months with high-frequency spinal cord stimulation for nonsurgical refractory back pain.

OBJECTIVE: The objective of this study was to evaluate the 24-month durability of pain relief, function, quality of life, and safety outcomes for patients with nonsurgical refractory back pain (NSRBP) treated with high-frequency spinal cord stimulation (SCS) within a large, national, multicenter randomized controlled trial (RCT). METHODS: Following the completion of an RCT comparing high-frequency SCS plus CMM with CMM alone for the treatment of NSRBP, patients gave additional consent for a follow-up extension to 24 months. Presented is the cohort analysis of all patients treated with high-frequency SCS following the optional crossover at 6 months. The outcomes assessed to 24 months included responder rate of ≥ 50% pain relief measured according to the visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]), quality of life (EQ-5D 5-level [EQ-5D-5L]), opioid reduction. RESULTS: Of the 125 patients who received a permanent implant, 121 completed the 12-month follow-up, 101 gave additional consent for extended follow-up, and 98 completed the 24-month follow-up. At 24 months after implantation, the mean back pain VAS score was reduced by 73% and the responder rate was 82%. ODI and EQ-5D-5L both improved by at least double the minimal clinically important difference for each measure. No unexpected adverse events were observed, and the rates of serious adverse events (3.4%) and device explantations (4.8%) were low. CONCLUSIONS: The addition of high-frequency SCS to CMM in patients with NSRBP offers profound improvements at 24 months in pain, function, quality of life, and reduced opioid use. This study provides much-needed evidence to inform current clinical practice for managing patients with NSRBP.

Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation: A Proposal for Standardization in Fellowship and Training Programs.

The need to be competent in neuromodulation is and should be a prerequisite prior to completing a fellowship in interventional pain medicine. Unfortunately, many programs lack acceptable candidates for these advanced therapies, and fellows may not receive adequate exposure to neuromodulation procedures. The American Society of Pain and Neuroscience (ASPN) desires to create a consensus of experts to set a minimum standard of competence for neurostimulation procedures, including spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). The executive board of ASPN accepted nominations for colleagues with excellence in the subject matter of neuromodulation and physician education. This diverse group used peer-reviewed literature and, based on grading of evidence and expert opinion, developed critical consensus guides for training that all accredited fellowship programs should adopt. For each consensus point, transparency and recusal were used to eliminate bias, and an author was nominated for evidence grading oversight and bias control. Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation sets a standard for neuromodulation training in pain fellowship training programs. The consensus panel has determined several recommendations to improve care in the United States for patients undergoing neuromodulation. As neuromodulation training in the United States has evolved dramatically, these therapies have become ubiquitous in pain medicine. Unfortunately, fellowship programs and the Accreditation Council for Graduate Medical Education (ACGME) pain program requirements have not progressed training to match the demands of modern advancements. PEAK sets a new standard for fellowship training and presents thirteen practice areas vital for physician competence in neuromodulation.

Multiphase Spinal Cord Stimulation in Participants With Chronic Back or Leg Pain: Results of the BENEFIT-02 Randomized Clinical Trial.

OBJECTIVE: This study aimed to assess the safety and effectiveness of a new charge-distributed multiphase stimulation paradigm during an extended spinal cord stimulation (SCS) trial. MATERIALS AND METHODS: This prospective, multicenter, randomized, single-blind, feasibility study included participants with chronic low back and/or leg pain and baseline numerical rating scale (NRS) for overall pain intensity ≥6. After a successful commercial SCS trial, participants were randomized to multiphase SCS therapy A (approximately 600-1500 Hz) or B (approximately 300-600 Hz), delivered via an investigational external pulse generator and existing leads during an 11-to-12-day testing period. Primary end points were mean NRS change from baseline to final in-office visit for each multiphase therapy and between therapies. Secondary end points included mean NRS change from end of commercial trial to final study visit and incidence of device-related adverse events (AEs). Additional measures included patient-reported outcomes collected at home through electronic watches and written diaries. Power usage was compared between multiphase and commercial therapies. RESULTS: A total of 122 participants initiated a commercial trial; 77 were randomized to a multiphase arm, and 65 completed the study. Reductions in mean NRS scores from baseline to final study visit were significant for multiphase therapy A and B (-4.3 and -4.7, respectively; both p < 0.0001). There was no statistically significant difference in mean NRS reduction or percent pain relief between multiphase therapies. In an additional analysis, 63.9% of participants reported greater pain relief with multiphase than with commercial SCS therapy in the at-home setting. On average, multiphase required less power than did commercial devices. One non-serious device-related AE was reported, and no infections occurred during the extended trial. CONCLUSIONS: Multiphase SCS effectively reduced pain in participants with chronic low back and/or leg pain during a trial, with no unanticipated device-related AEs reported. Future studies should evaluate long-term effectiveness of multiphase stimulation. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03594266.