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.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial.

AIMS: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). METHODS: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding. RESULTS: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. CONCLUSIONS: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier, NCT03228420.

Combination therapy with simultaneous delivery of spinal cord stimulation modalities: COMBO randomized controlled trial.

Aim: The Combining Mechanisms for Better Outcomes randomized controlled trial assessed the effectiveness of various spinal cord stimulation (SCS) modalities for chronic pain. Specifically, combination therapy (simultaneous use of customized sub-perception field and paresthesia-based SCS) versus monotherapy (paresthesia-based SCS) was evaluated. Methods: Participants were prospectively enrolled (key inclusion criterion: chronic pain for ≥6 months). Primary end point was the proportion with ≥50% pain reduction without increased opioids at the 3 month follow-up. Patients were followed for 2 years. Results: The primary end point was met (n = 89; p < 0.0001) in 88% of patients in the combination-therapy arm (n = 36/41) and 71% in the monotherapy arm (n = 34/48). Responder rates at 1 and 2 years (with available SCS modalities) were 84% and 85%, respectively. Sustained functional outcomes improvement was observed out to 2 years. Conclusion: SCS-based combination therapy can improve outcomes in patients with chronic pain. Clinical Trial Registration: NCT03689920 (ClinicalTrials.gov), Combining Mechanisms for Better Outcomes (COMBO).

Spinal cord stimulation (SCS) is a device-based therapy for chronic pain that delivers electrical impulses to the spinal cord, disrupting pain signals to the brain. Pain relief can be achieved using different SCS techniques that use or do not use paresthesia (stimulation that produces a tingling sensation). These approaches affect patients in different ways, suggesting that different biological processes are involved in enabling pain relief. Research also suggests that better long-term results occur when patients can choose the therapy that is best for their own needs. This clinical study compared pain relief and other functional activities in those receiving combination therapy (simultaneous use of SCS that does and does not produce tingling sensation) against those receiving monotherapy (only SCS therapy producing tingling sensation) for 3 months. In the study, 88% of those receiving combination therapy and 71% with monotherapy alone reported a 50% (or greater) decrease in overall pain (the 'responder rate') without an increased dose of opioid drugs at 3 months after the start of therapy. This responder rate was found to be 84% at 1 year and 85% at 2 years (with all SCS therapy options available). Analysis of functional activities or disability showed that patients improved from 'severely disabled' at study start to 'moderately disabled' after 2 years, indicating that effective long-term (2 year) improvement can be achieved using SCS-based combination therapy for chronic pain.

High-Frequency 10-kHz Spinal Cord Stimulation Improves Health-Related Quality of Life in Patients With Refractory Painful Diabetic Neuropathy: 12-Month Results From a Randomized Controlled Trial.

Objective: To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy. Patients and Methods: A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months. Results: The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% (95% CI, 70.1-78.5), and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95% CI, 0.104-0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were "satisfied" or "very satisfied" with the 10-kHz SCS treatment. Conclusion: The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy. Trial registration: clincaltrials.gov Identifier: NCT03228420.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial.

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system. Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. Design, Setting, and Participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS. Main Outcomes and Measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published). Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. Conclusions and Relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

Ten kHz spinal cord stimulation for the treatment of chronic peripheral polyneuropathy: 12-Month results from prospective open-label pilot study.

BACKGROUND: The goal of this study was to demonstrate that the paresthesia-independent 10 kHz spinal cord stimulation (SCS) can provide long-term pain relief in patients with peripheral polyneuropathy (PPN). Clinically diagnosed subjects with PPN refractory to conventional medical management were enrolled in this prospective, multicenter study between November 2015 and August 2016, after institutional review board approval and patient informed consent were obtained. METHODS: Subjects underwent trial stimulation utilizing 2 epidural leads, and if successful, were implanted with a permanent 10 kHz SCS system and followed up for 12 months post-implant. Outcome measures included adverse events, pain, neurological assessments, disability, function, quality of life, pain interference, sleep, satisfaction, and global impression of change. Data are presented as descriptive statistics. Permanent implant population results are reported as mean ± standard error. RESULTS: Twenty-one of the 26 trialed subjects had a successful trial and 18 received a permanent implant. All subjects had the leads placed anatomically without the need for paresthesia. Subjects experienced significant and sustained pain relief (at least 65% at all timepoints) whereas physicians noted improvements in neurological function. Significant improvements in disability, function, sleep, sensory, and affective dimensions of pain were reported at all timepoints. All adverse events were resolved without sequelae. CONCLUSION: Findings from this study suggest that 10 kHz SCS may provide sustained pain relief and disability improvements in patients suffering from PPN.

Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial.

Importance: Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments. Objective: To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). Design, Setting, and Participants: The prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A1c (HbA1c) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated. Interventions: Implanted medical device delivering 10-kHz SCS. Main Outcomes and Measures: The prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. Results: Of 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001). Conclusions and Relevance: Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can safely and effectively treat patients with refractory PDN. Trial Registration: ClincalTrials.gov Identifier: NCT03228420.

10-kHz spinal cord stimulation treatment for painful diabetic neuropathy: results from post-hoc analysis of the SENZA-PPN study.

Aim: Previous studies of 10 kHz spinal cord stimulation demonstrated its safety and efficacy for treatment of neuropathic pain of the trunk and/or limbs. This study analyzed data from a subset of subjects with painful diabetic neuropathy enrolled in a prospective, multicenter study of peripheral polyneuropathy with various etiologies. Materials & methods: Of the eight subjects that had permanent devices, seven attended the 12-month follow-up assessment. Results & conclusion: At 12 months, 6/7 subjects were treatment responders (≥50% pain relief) and had pain remission (visual analog scale ≤ 3.0 cm). Worsening of neurologic deficits was not reported in any subject. Instead, 5/7 subjects showed improvements in sensory testing and/or reflexes. These results support further investigation of 10 kHz spinal cord stimulation as a safe and effective treatment for intractable painful diabetic neuropathy.

10-kHz Spinal Cord Stimulation for Chronic Postsurgical Pain: Results From a 12-Month Prospective, Multicenter Study.

BACKGROUND: Chronic postsurgical pain (CPSP) can be caused by peripheral nerve injury (PNI) resulting from surgical procedures and has a significant neuropathic component. This prospective, single-arm study was conducted to document the effectiveness of 10-kHz spinal cord stimulation (10-kHz SCS) as a treatment for patients with CPSP. METHODS: Subjects with CPSP who were refractory to conventional medical interventions and reported pain scores of ≥5 cm on a 10-cm VAS underwent trial stimulations lasting up to 14 days. Epidural leads were implanted at locations appropriate for the primary area of pain, and trials resulting in ≥40% pain relief were considered successful. Subjects with successful trials underwent implantation with a permanent 10-kHz SCS system and were followed for 12 months after implantation. RESULTS: Of the 34 subjects who underwent trial stimulation, 1 was withdrawn early and 29 (87.9%) had a successful trial and received a permanent implant. After 12 months of treatment, the mean VAS score decreased by 6.5 cm, the response rate was 88.0% (22/25), and 18 subjects (62.1%) were remitters with VAS scores sustained at ≤3.0 cm. Scores for all components of the short-form McGill Pain Questionnaire 2 were significantly reduced, including affective descriptors of pain. Pain catastrophizing and vigilance, patient function, physical and mental well-being, and sleep quality all improved over the course of the study. No neurologic deficits reported in the study. CONCLUSIONS: 10-kHz SCS is effective and tolerated in patients with CPSP, and further study of its clinical application in this population is warranted.

Outcomes of a Multicenter, Prospective, Crossover, Randomized Controlled Trial Evaluating Subperception Spinal Cord Stimulation at ≤1.2 kHz in Previously Implanted Subjects.

OBJECTIVE: The WHISPER randomized controlled trial (RCT) evaluates safety and clinical effectiveness of subperception spinal cord stimulation (SCS) at ≤1.2 kHz in subjects previously implanted with an SCS system for treatment of chronic, neuropathic pain. METHODS: WHISPER is a prospective, multicenter RCT with a crossover design sponsored by Boston Scientific, Marlborough, MA (ClinicalTrials.gov: NCT02314000). Eligible subjects were randomized (N = 140) to receive subperception or supraperception for three months and then crossed over to receive the alternative. Upon completion of crossover period, subjects who preferred subperception were followed up to one year. Overall pain, quality-of-life, and other outcomes were collected in the study. The primary endpoint was the overall pain responder rate (≥50% improvement from baseline) with no increase in medications. Secondary endpoints consisted of pain scores, physical disability, quality of life, and treatment preference. RESULTS: The study met its primary endpoint and demonstrated noninferiority between supraperception and subperception in a prespecified cohort of 70 randomized subjects (Interim Analysis). Thirty-nine percent of subjects with subperception settings and 29% with supraperception settings had a greater than or equal to 50% reduction in their overall pain scores with no increase in average daily medication at three-months post-activation as compared with baseline. Further assessment of all participating study subjects (N = 140) revealed similar results. Subjects were previously implanted 3.8 ± 2 years and had a disability score (Oswestry Disability Index) of 70.2 ± 11.4 at study start. Of the randomized subjects that completed the End of Period 2 Visit, 93 (66%) preferred subperception SCS and their mean overall pain reduced from 7.3 ± 1.1 (N = 89) at baseline to 4.0 ± 2.1 (N = 80) at 12-months post-activation. Post hoc analysis also demonstrated that multiple options provide superior outcomes, as supported by a 74% increase in the responder rate when subjects could choose their most effective option (47%) compared with supraperception alone (27%). DISCUSSION: Subperception SCS at ≤1.2 kHz is safe and effective in subjects with extreme physical disability and previously implanted for chronic pain. Further, by providing study participants with different waveform options, increased pain relief was achieved.

Therapy Habituation at 12 Months: Spinal Cord Stimulation Versus Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome Type I and II.

The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE substudy was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months postpermanent implant) for all subjects that completed trial stimulation (DRG:N = 73, SCS:N = 72). For both groups, mean PPR was significantly greater at end-of-trial (DRG = 82.2%, SCS =0 77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range = 69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. PERSPECTIVE: This article reports on an ACCURATE substudy, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed.

Paresthesia-Free Dorsal Root Ganglion Stimulation: An ACCURATE Study Sub-Analysis.

INTRODUCTION: ACCURATE, a randomized controlled trial comparing dorsal root ganglion (DRG) stimulation to spinal cord stimulation, showed that DRG stimulation is a safe and effective therapy in individuals with lower extremity chronic pain due to complex regional pain syndrome (CRPS) type I or II. Investigators noted that DRG stimulation programming could be adjusted to minimize, or eliminate, the feeling of paresthesia while maintaining adequate pain relief. The present study explores treatment outcomes for DRG subjects who were paresthesia-free vs. those who experienced the sensation of paresthesia, as well as the factors that predicted paresthesia-free analgesia. METHODS: A retrospective analysis of therapy outcomes was conducted for 61 subjects in the ACCURATE study who received a permanent DRG neurostimulator. Outcomes of subjects who were paresthesia-free were compared to those who experienced paresthesia-present therapy at 1, 3, 6, 9, and 12-month follow-ups. Predictor variables for the presence or absence of paresthesias with DRG stimulation were also explored. RESULTS: The percentage of subjects with paresthesia-free pain relief increased from 16.4% at 1-month to 38.3% at 12-months. Paresthesia-free subjects generally had similar or better outcomes for pain severity, pain interference, quality of life, and mood state as subjects with paresthesia-present stimulation. Factors that increased the odds of a subject feeling paresthesia were higher stimulation amplitudes and frequencies, number of implanted leads, and younger age. CONCLUSIONS: Some DRG subjects achieved effective paresthesia-free analgesia in the ACCURATE trial. This supports the observation that paresthesia is not synonymous with pain relief or required for optimal analgesia with DRG stimulation.

Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial.

BACKGROUND: Spinal cord stimulation has been an established treatment for chronic back and leg pain for more than 50 years; however, outcomes are variable and unpredictable, and objective evidence of the mechanism of action is needed. A novel spinal cord stimulation system provides the first in vivo, real-time, continuous objective measure of spinal cord activation in response to therapy via recorded evoked compound action potentials (ECAPs) in patients during daily use. These ECAPs are also used to optimise programming and deliver closed-loop spinal cord stimulation by adjusting the stimulation current to maintain activation within patients' therapeutic window. We aimed to examine pain relief and the extent of spinal cord activation with ECAP-controlled closed-loop versus fixed-output, open-loop spinal cord stimulation for the treatment of chronic back and leg pain. METHODS: This multicentre, double-blind, parallel-arm, randomised controlled trial was done at 13 specialist clinics, academic centres, and hospitals in the USA. Patients with chronic, intractable pain of the back and legs (Visual Analog Scale [VAS] pain score ≥60 mm; Oswestry Disability Index [ODI] score 41-80) who were refractory to conservative therapy, on stable pain medications, had no previous experience with spinal cord stimulation, and were appropriate candidates for a spinal cord stimulation trial were screened. Eligible patients were randomly assigned (1:1) to receive ECAP-controlled closed-loop spinal cord stimulation (investigational group) or fixed-output, open-loop spinal cord stimulation (control group). The randomisation sequence was computer generated with permuted blocks of size 4 and 6 and stratified by site. Patients, investigators, and site staff were masked to the treatment assignment. The primary outcome was the proportion of patients with a reduction of 50% or more in overall back and leg pain with no increase in pain medications. Non-inferiority (δ=10%) followed by superiority were tested in the intention-to-treat population at 3 months (primary analysis) and 12 months (additional prespecified analysis) after the permanent implant. This study is registered with ClinicalTrials.gov, NCT02924129, and is ongoing. FINDINGS: Between Feb 21, 2017, and Feb 20, 2018, 134 patients were enrolled and randomly assigned (67 to each treatment group). The intention-to-treat analysis comprised 125 patients at 3 months (62 in the closed-loop group and 63 in the open-loop group) and 118 patients at 12 months (59 in the closed-loop group and 59 in the open-loop group). The primary outcome was achieved in a greater proportion of patients in the closed-loop group than in the open-loop group at 3 months (51 [82·3%] of 62 patients vs 38 [60·3%] of 63 patients; difference 21·9%, 95% CI 6·6-37·3; p=0·0052) and at 12 months (49 [83·1%] of 59 patients vs 36 [61·0%] of 59 patients; difference 22·0%, 6·3-37·7; p=0·0060). We observed no differences in safety profiles between the two groups. The most frequently reported study-related adverse events in both groups were lead migration (nine [7%] patients), implantable pulse generator pocket pain (five [4%]), and muscle spasm or cramp (three [2%]). INTERPRETATION: ECAP-controlled closed-loop stimulation provided significantly greater and more clinically meaningful pain relief up to 12 months than open-loop spinal cord stimulation. Greater spinal cord activation seen in the closed-loop group suggests a mechanistic explanation for the superior results, which aligns with the putative mechanism of action for spinal cord stimulation and warrants further investigation. FUNDING: Saluda Medical.

Comparison of Paresthesia Coverage of Patient's Pain: Dorsal Root Ganglion vs. Spinal Cord Stimulation. An ACCURATE Study Sub-Analysis.

OBJECTIVES: This was a sub-analysis of the ACCURATE clinical trial that evaluated the accuracy and necessity of targeting paresthesia coverage of painful areas with dorsal root ganglion (DRG) stimulation vs. tonic spinal cord stimulation (SCS). MATERIALS AND METHODS: On diagrams of the torso and lower limbs, subjects marked where they felt pain at baseline and paresthesias at three months postimplant. Seventy-five subjects (41 DRG and 34 SCS) with diagrams of sufficient quality were scanned, digitized, and included in this analysis. Subject completed diagrams were digitized and superimposed with a grid of 1398 squares. Quantification of the percentage of bodily areas affected by pain and stimulation induced paresthesias was performed. RESULTS: The percent of painful areas covered by paresthesia was significantly lower for DRG subjects than for SCS subjects (13% vs. 28% of the painful regions, p < 0.05), possibly because significantly more DRG subjects felt no paresthesia during stimulation when compared to SCS subjects (13/41 DRG vs. 3/34 SCS) (p < 0.05). The amount of paresthesia produced outside the painful areas (unrequired paresthesia) was significantly lower in DRG subjects than that of SCS subjects. On average, the percent of unrequired paresthesia was only 20% of the subjects' total painful body surface area in the DRG group compared to 210% in the SCS group (p < 0.01). CONCLUSIONS: The results of this ACCURATE study sub-analysis show that DRG stimulation produces paresthesias, on average, that are less frequent, less intense, with a smaller footprint on the body and less dependent on positional changes.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.