Current Waveforms in Spinal Cord Stimulation and Their Impact on the Future of Neuromodulation: A Scoping Review.

BACKGROUND: Neuromodulation is a standard and well-accepted treatment for chronic refractory neuropathic pain. There has been progressive innovation in the field over the last decade, particularly in areas of spinal cord stimulation (SCS) and dorsal root ganglion stimulation. Improved outcomes using proprietary waveforms have become customary in the field, leading to an unprecedented expansion of these products and a plethora of options for the management of pain. Although advances in waveform technology have improved our fundamental understanding of neuromodulation, a scoping review describing new energy platforms and their associated clinical effects and outcomes is needed. The authors submit that understanding electrophysiological neuromodulation may be important for clinical decision-making and programming selection for personalized patient care. OBJECTIVE: This review aims to characterize ways differences in mechanism of action and clinical outcomes of current spinal neuromodulation products may affect contemporary clinical decision-making while outlining a possible path for the future SCS. STUDY DESIGN: The study is a scoping review of the literature about newer generation SCS waveforms. MATERIALS AND METHODS: A literature report was performed on PubMed and chapters to include articles on spine neuromodulation mechanism of action and efficacy. RESULTS: A total of 8469 studies were identified, 75 of which were included for the scoping review after keywords defining recent waveform technology were added. CONCLUSIONS: Clinical data suggest that neuromodulation remains a promising tool in the treatment of chronic pain. The evidence for SCS for treating chronic pain seems compelling; however, more long-term and comparative data are needed for a comparison of waveforms when it comes to the etiology of pain. In addition, an exploration into combination waveform therapy and waveform cycling may be paramount for future clinical studies and the development of new technologies.

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

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

Clinical Longevity of 106,462 Rechargeable and Primary Cell Spinal Cord Stimulators: Real World Study in the Medicare Population.

INTRODUCTION: Spinal cord stimulators (SCS) are available with either primary cell (PC) or rechargeable cell (RC) batteries. Although RC systems are proposed to have a battery longevity upward of nine years, in comparison with four years for PC systems, there are few studies of longevity of SCS in the real world. MATERIALS AND METHODS: This was an observational, nonrandomized, retrospective study of Medicare beneficiaries who received neurostimulator implants in the outpatient hospital. This study used Medicare fee-for-service claims data from 2013 to 2020. The clinical longevity of the implantable pulse generator (IPG), defined as the duration from implant until removal for any reason, was compared between PC and RC devices. Life distribution analysis was used to approximate device lifespan. The secondary analysis separated removals into explant or replacements. The statistics were adjusted for relevant clinical covariates. RESULTS: A total of 25,856 PC and 79,606 RC systems were included in the study. At seven years after implant, 53.8% of PC IPGs and 55.0% of RC IPGs remained in use. The life distribution modeling analysis projected a median lifespan of 8.2 years for PC and 9.0 years for RC devices. The rate of explant was lower for PC devices (19.2%) than for RC devices (22.0%, hazard ratio (HR) = 0.96, p = 0.082), whereas the rate of replacements was higher for PC devices (33.7%) than for RC devices (29.5%, HR = 1.31, p < 0.001). An analysis of the battery type used in device replacements showed an increasing adoption of PC devices over time. CONCLUSIONS: This large, retrospective, real-world analysis of Medicare claims data demonstrated that the clinical longevity of neurostimulator devices is similar for PC and RC batteries. In the past, clinicians may have defaulted to RC devices based on the assumption that they provided extended battery life. Considering this longevity data, clinicians should now consider the choice between PC and RC devices based on other individual factors pertinent to the patient experience and not on purported longevity claims.

Association Between Levels of Functional Disability and Health-Related Quality of Life With Spinal Cord Stimulation for Chronic Pain.

OBJECTIVES: Pain score, functional disability, and health-related quality of life (HRQoL) are core outcome domains for chronic pain clinical trials. Although greater levels of pain reduction have been shown to be linked to larger gains in HRQoL, little is known of the association between HRQoL and disability in the setting of chronic pain. The aims of this study were to 1) investigate the association between functional disability and HRQoL and 2) estimate the utility values associated with levels of functional disability in patients treated with evoked compound action potential (ECAP) spinal cord stimulation (SCS) for chronic pain. MATERIALS AND METHODS: Data on functional disability assessed using the Oswestry Disability Index (ODI) and HRQoL (EQ-5D-5L) were collected from 204 patients with an Evoke ECAP-SCS device and followed up to 12 months. SF-6D utility scores also were retrieved for 134 of these patients. Multivariable linear regression models adjusted for baseline utility values and patient demographics were used to compare differences in utility values across ODI categories. RESULTS: Significant improvements in functional disability and HRQoL were observed at three- and 12-month follow-up after SCS. Patients reporting "minimum disability," "moderate disability," "severe disability," and "crippled" had mean EQ-5D scores of 0.82, 0.73, 0.59, and 0.45, respectively. The mean change in EQ-5D score was 0.007 per unit change in total ODI score. The R2 statistic showed a moderate level association (49%-64% of variance in EQ-5D explained by ODI). CONCLUSION: ECAP-SCS results in significant improvements in functional disability and HRQoL. This study shows that improvement in function of people with chronic pain before and after ECAP-SCS is associated with improvement in HRQoL.

Neuromodulation in Treating Pelvic Pain.

PURPOSE OF REVIEW: Chronic pelvic pain (CPP) is a complex condition that can be multifactorial, disabling, and difficult to treat. It is important to understand the various diagnoses and pathways that can be involved and have an understanding of the available treatment options. RECENT FINDINGS: There is a complex innervation of the pelvic region which makes its treatment very challenging. There are pathophysiological similarities of CPP to disease states like complex regional pain syndrome and sympathetically driven pain. CPP is poorly understood and includes psychological, psychosocial, cultural, and economic influences. Treatment options vary, but neuromodulation does remain a centerpiece and can include sacral stimulation, SCS, DRG stimulation, and PNS.

A Systematic Literature Review of Peripheral Nerve Stimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of peripheral nerve stimulation (PNS) for pain. DESIGN: Grade the evidence for PNS. METHODS: An international interdisciplinary work group conducted a literature search for PNS. Abstracts were reviewed to select studies for grading. Inclusion/exclusion criteria included prospective randomized controlled trials (RCTs) with meaningful clinical outcomes that were not part of a larger or previously reported group. Excluded studies were retrospective, had less than two months of follow-up, or existed only as abstracts. Full studies were graded by two independent reviewers using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: Peripheral nerve stimulation was studied in 14 RCTs for a variety of painful conditions (headache, shoulder, pelvic, back, extremity, and trunk pain). Moderate to strong evidence supported the use of PNS to treat pain. CONCLUSION: Peripheral nerve stimulation has moderate/strong evidence. Additional prospective trials could further refine appropriate populations and pain diagnoses.

A Systematic Literature Review of Dorsal Root Ganglion Neurostimulation for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain. DESIGN: Grade the evidence for DRG stimulation. METHODS: An international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: DRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies. CONCLUSIONS: Moderate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of spinal cord stimulation (SCS) for pain. DESIGN: Grade the evidence for SCS. METHODS: An international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year's duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: SCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT). CONCLUSIONS: High-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.

Burst Spinal Cord Stimulation: A Clinical Review.

OBJECTIVE: Clinical review on outcomes using burst spinal cord stimulation (SCS) in the treatment of chronic, intractable pain. DESIGN: Narrative clinical literature review conducted utilizing a priori search terms including key words for burst spinal cord stimulation. Synthesis and reporting of data from publications including an overview of comparative SCS outcomes. RESULTS: Burst SCS demonstrated greater pain relief over tonic stimulation in multiple studies, which included blinded, sham-controlled, randomized trials. Additionally, burst stimulation impacts multiple dimensions of pain, including somatic pain as well as emotional and psychological elements. Patient preference is weighted toward burst over tonic due to increased pain relief, a lack of paresthesias, and impression of change in condition. CONCLUSION: Burst SCS has been shown to be both statistically and clinically superior to tonic stimulation and may provide additional benefits through different mechanisms of action. Further high-quality controlled studies are warranted to not only elucidate the basic mechanisms of burst SCS but also address how this unique stimulation signature/pattern may more adequately handle the multiple affective dimensions of pain in varying patient populations.

Mechanism of Action in Burst Spinal Cord Stimulation: Review and Recent Advances.

OBJECTIVE: This is a comprehensive, structured review synthesizing and summarizing the current experimental data and knowledge about the mechanisms of action (MOA) underlying spinal cord stimulation with the burst waveform (as defined by De Ridder) in chronic pain treatment. METHODS: Multiple database queries and article back-searches were conducted to identify the relevant literature and experimental findings for results integration and interpretation. Data from recent peer-reviewed conference presentations were also included for completeness and to ensure that the most up-to-date scientific information was incorporated. Both human and animal data were targeted in the search to provide a translational approach in understanding the clinical relevance of the basic science findings. RESULTS/CONCLUSIONS: Burst spinal cord stimulation likely provides pain relief via multiple mechanisms at the level of both the spinal cord and the brain. The specific waveforms and temporal patterns of stimulation both play a role in the responses observed. Differential modulation of neurons in the dorsal horn and dorsal column nuclei are the spinal underpinnings of paresthesia-free analgesia. The burst stimulation pattern also produces different patterns of activation within the brain when compared with tonic stimulation. The latter may have implications for not only the somatic components of chronic pain but also the lateral and affective pathway dimensions as well.

Neuromodulation of the Dorsal Root Ganglion for Chronic Postsurgical Pain.

OBJECTIVE: The objective of this study is to review the available evidence for dorsal root ganglion (DRG) stimulation for the treatment of complex regional pain syndrome type II (CRPS II; peripheral causalgia) associated with chronic neuropathic postsurgical pain (NPP). DESIGN: Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from published articles also were reviewed for relevant citations. RESULTS: The data published to date support the use of DRG stimulation to treat chronic NPP of the groin, knee, and foot. NPP following procedures such as thoracotomy, hernia surgery, and knee replacement surgery were identified as some of the conditions for which DRG stimulation is likely to be effective. CONCLUSION: DRG stimulation is known to be an effective treatment for focal neuropathic pain. Currently, NPP of the foot, groin, and knee all appear to be the conditions with the most clinical experience, backed by a limited but growing body of evidence. However, prospective studies lag behind real-world clinical experience and are needed to confirm these findings.

A Comprehensive Algorithm for Management of Neuropathic Pain.

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

Dorsal Root Ganglion Stimulation for Chronic Pelvic Pain: A Case Series and Technical Report on a Novel Lead Configuration.

INTRODUCTION: Chronic pelvic pain (CPP) is an elusive and complex neuropathic condition that is notoriously recalcitrant to treatment. The term "CPP" encompasses a number of treatment-resistant conditions like pudendal neuralgia, interstitial cystitis, coccygodynia, vulvodynia. CPP has been presented neuromodulators attempting to utilize conventional spinal cord stimulation (SCS), with constant frustration and high explant rates. Contrary to SCS, dorsal root ganglion stimulation (DRGS) delivers targeted target to focal areas, does not rely on paresthesias, and is able to reliably capture body parts like the pelvis making it an ideal modality for the treatment of CPP. We present seven patients with intractable CPP, resistant to conventional treatment methods, all successfully treated with DRGS. METHODS: The case series includes seven patients with severe, CPP who failed to respond to a variety interventional treatments, and in some cases SCS. All seven patients were successfully trialed with DRGS utilizing leads placed over the bilateral L1 and S2 DRG's-to our knowledge, no publications describing either this particular lead configuration, or utilizing DRG stimulation on CPP, exist. RESULTS: Following treatment, all seven patients experienced significant pain relief as well as reduction in opioid consumption and some cases improvement with sexual function and urination. Four of these patients have been implanted and continue to self-report sustained pain relief with high-satisfaction and functional improvement. To date no explants or instances of loss of efficacy have occurred (>1 year since implant). CONCLUSION: Like most neuropathic pain states, CPP is resilient, difficult to manage, and typically unresponsive to the traditional therapeutics and SCS. Our case series demonstrates no only that DRGS is potentially effective, long-term treatment modality for CPP, but that the L1/S2 lead placement is the configuration of choice despite distinct differences in etiologies of pain and location.

DRG FOCUS: A Multicenter Study Evaluating Dorsal Root Ganglion Stimulation and Predictors for Trial Success.

INTRODUCTION: Dorsal root ganglion stimulation (DRGS) is a powerful tool in the treatment of chronic, neuropathic pain. The premise of DRGS is similar to that of conventional spinal cord stimulation (cSCS), however, there is more variability in how it can be utilized. While it is this variability that likely gives it its versatility, DRGS is not as straightforward to implement as cSCS. The purpose of this study was to assess the efficacy of DRGS on a broad number of diagnoses, determine which dorsal root ganglia were associated with better outcomes for particular body parts/diagnoses, and evaluate what factors/parameters were associated with higher rates of trial success. METHODS: This is a physician initiated, multicenter retrospective registry of 217 patients trialed with DRGS. Data were collected via an online questionnaire that assessed specifics regarding the patient's pain, distribution, size, and response to treatment. The data were analyzed to see if there were certain diagnoses and/or parameters that were more or less associated with trial success. RESULTS: DRGS was found to be an effective treatment in all diagnoses evaluated within this study, most of which had statistically significant improvements in pain. The most important predictor of trial success was the amount of painful area covered by paresthesias during the programing phase. The number of leads utilized had a direct and indirect impact on trial success. Pain in the distribution of a specific peripheral nerve responded best and there was no statistical difference based on what body part was being treated. CONCLUSION: DRGS can be an effective treatment for a variety of neuropathic pain syndromes, in addition to CRPS. It is recommended that a minimum of 2 leads should be utilized per area being treated. In addition, this therapy was shown to be equally efficacious in any body part/region so long as the area being treated is focal and not widespread.

Spinal Cord Stimulation for the Treatment of Failed Neck Surgery Syndrome: Outcome of a Prospective Case Series.

OBJECTIVES: Spinal cord stimulation (SCS) is an accepted, cost-effective treatment option for a variety of chronic pain syndromes, including failed back surgery syndrome (FBSS). The application of SCS in the cervical spine, particularly for pain after cervical spine surgery, has been drawn into question in recent years by payers due to a purported lack of clinical evidence. To challenge this claim, we analyzed data from a prospective registry to support the use of SCS in the cervical spine for pain after spine surgery. MATERIALS AND METHODS: Data from the EMPOWER and PAIN registries were analyzed on patients diagnosed with pain after neck surgery (C-FBSS) for the following outcomes: patient reported percent pain relief (PRPR), pain disability index (PDI), quality of life (QoL), and satisfaction at 3-, 6-, and 12-month post-implantation. Statistical analysis was provided for all measures. RESULTS: Fifteen patients with C-FBSS were successfully implanted with SCS leads in the cervical spine. PRPR was 65.2%, 62.4%, and 71.9% at 3-, 6-, and 12-month post-implantation, respectively. PDI scores were significantly reduced from baseline (51.21-23.70 at 12 months, p = 0.001). At one-year post-implantation, the average overall QoL was reported to be improved/greatly improved and patient satisfaction was rated satisfied/greatly satisfied. CONCLUSIONS: For many, the application of SCS in the neck for pain after surgery is based on the obvious similarities to FBSS or anecdotal experience rather than published data. The data contained herein suggest SCS for C-FBSS is an effective therapy that improves QoL and patient satisfaction, as well as decreasing pain and PDI. The use of successful application of neurostimulation as a therapy has largely been predicated on the principles of patient selection, implantation technique, and stimulation parameters. As such, SCS would appear to be an appropriate and valid treatment for C-FBSS that requires further study and investigation to make additional recommendations.

Selective Radiofrequency Stimulation of the Dorsal Root Ganglion (DRG) as a Method for Predicting Targets for Neuromodulation in Patients With Post Amputation Pain: A Case Series.

OBJECTIVE: While spinal cord stimulation (SCS) has established itself as an accepted and validated treatment for neuropathic pain, there are a number of conditions where it has experienced less, long-term success: post amputee pain (PAP) being one of them. Dorsal root ganglion (DRG) stimulation has shown great promise, particularly in conditions where traditional SCS has fallen short. One major difference between DRG stimulation and traditional SCS is the ability to provide focal stimulation over targeted areas. While this may be a contributing factor to its superiority, it can also be a limitation insofar stimulating the wrong DRG(s) can lead to failure. This is particularly relevant in conditions like PAP where neuroplastic maladaptation occurs causing the pain to deviate from expected patterns, thus creating uncertainty and variability in predicting targets for stimulation. We propose selective radiofrequency (RF) stimulation of the DRG as a method for preoperatively predicting targets for neuromodulation in patients with PAP. METHODS: We present four patients with PAP of the lower extremities. RF stimulation was used to selectively stimulate individual DRG's, creating areas of paresthesias to see which most closely correlated/overlapped with the painful area(s). RF stimulation to the DRG's that resulted in the desirable paresthesia coverage in the residual or the missing limb(s) was recorded as "positive." Trial DRG leads were placed based on the positive RF stimulation findings. RESULTS: In each patient, stimulating one or more DRG(s) produced paresthesias patterns that were contradictory to know dermatomal patterns. Upon completion of a one-week trial all four patients reported 60-90% pain relief, with coverage over the painful areas, and opted for permanent implant. CONCLUSIONS: Mapping the DRG via RF stimulation appears to provide improved accuracy for determining lead placement in the setting of PAP where pain patterns are known to deviate from conventional dermatomal mapping.

Dorsal Root Ganglion Stimulation as a Salvage Treatment for Complex Regional Pain Syndrome Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series.

OBJECTIVE: The efficacy of traditional spinal cord stimulation (t-SCS) tends to decay over time in patients with complex regional pain syndrome (CRPS). While it has been shown that dorsal root ganglion (DRG) stimulation is extremely effective in t-SCS-naïve patients with CRPS, its efficacy in patients who had previously failed t-SCS is unknown. Given that DRG-SCS and t-SCS target different spinal pathways, a failure with t-SCS should not automatically preclude a patient from attempting DRG-SCS. MATERIALS AND METHODS: Two patients with lower extremity CRPS, previously implanted with t-SCS systems, experienced relapses in the pain despite exhaustive reprogramming. Both patients were offered DRG stimulation as a means to salvage treatment. RESULTS: Patient 1 reported 90% pain reduction with significant gait improvement during the DRG stimulation trial. The patient subsequently proceeded to implant and have the t-SCS implantable pulse generator explanted. Patient 2 was unable to undergo a trial with DRG-SCS because of health insurance constraints, so she elected to undergo a surgical revision of her existing system whereby a DRG-SCS system was added to the existing t-SCS to create a hybrid system with two implantable pulse generators. The patient reported an immediate improvement in pain because of the introduction of the DRG-SCS. Additionally, she was instructed to document her pain scores with each system on individually, as well as with both on-her pain scores were at the lowest with the DRG-SCS on by itself. At eight-month follow-up, both patients reported sustained pain improvement and retained their functional gains. CONCLUSIONS: Our case series demonstrates that a failure of t-SCS is not necessarily a failure of neurostimulation as a whole. The efficacy of DRG-SCS is independent of prior t-SCS therapy outcomes in these two patients and a history of t-SCS failure serves no predictive value in these two patients for future DRG stimulation success. Therefore, DRG-SCS can be considered as a reasonable next-step to salvage patients with CRPS who had failed other SCS treatments.

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.