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.

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.

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.

Long-Term Safety and Efficacy of Minimally Invasive Lumbar Decompression Procedure for the Treatment of Lumbar Spinal Stenosis With Neurogenic Claudication: 2-Year Results of MiDAS ENCORE.

BACKGROUND AND OBJECTIVES: This study evaluated the long-term durability of the minimally invasive lumbar decompression (MILD) procedure in terms of functional improvement and pain reduction for patients with lumbar spinal stenosis and neurogenic claudication due to hypertrophic ligamentum flavum. This is a report of 2-year follow-up for MILD study patients. METHODS: This prospective, multicenter, randomized controlled clinical study compared outcomes for 143 patients treated with MILD versus 131 treated with epidural steroid injections. Follow-up occurred at 6 months and at 1 year for the randomized phase and at 2 years for MILD subjects only. Oswestry Disability Index, Numeric Pain Rating Scale, and Zurich Claudication Questionnaire were used to evaluate function and pain. Safety was evaluated by assessing incidence of device-/procedure-related adverse events. RESULTS: All outcome measures demonstrated clinically meaningful and statistically significant improvement from baseline through 6-month, 1-year, and 2-year follow-ups. At 2 years, Oswestry Disability Index improved by 22.7 points, Numeric Pain Rating Scale improved by 3.6 points, and Zurich Claudication Questionnaire symptom severity and physical function domains improved by 1.0 and 0.8 points, respectively. There were no serious device-/procedure-related adverse events, and 1.3% experienced a device-/procedure-related adverse event. CONCLUSIONS: MILD showed excellent long-term durability, and there was no evidence of spinal instability through 2-year follow-up. Reoperation and spinal fracture rates are lower, and safety is higher for MILD versus other lumbar spine interventions, including interspinous spacers, surgical decompression, and spinal fusion. Given the minimally invasive nature of this procedure, its robust success rate, and durability of outcomes, MILD is an excellent choice for first-line therapy for select patients with central spinal stenosis suffering from neurogenic claudication symptoms with hypertrophic ligamentum flavum. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT02093520.

Study of percutaneous lumbar decompression and treatment algorithm for patients suffering from neurogenic claudication.

BACKGROUND: Symptomatic lumbar spinal stenosis (LSS) patients often suffer from multiple etiologies, and patient symptoms must be differentiated and identified as either neurogenic claudication, radicular pain, or both. The most common symptom associated with LSS is neurogenic claudication, which has been reported to occur in 91% to 100% of the LSS patient population. Neurogenic claudication symptoms are described as pain radiating to the lower extremities that begins and worsens as the patient ambulates. Neurogenic claudication symptoms worsen over time and can eventually result in significant life-altering functional limitations. Symptomatic LSS patients may also suffer from radicular pain, which is a persistent pain transmitted through neural pathways, and is associated with inflammation of the exiting nerve root. OBJECTIVE: To assess patient safety, pain reduction, and functional status of patients treated with percutaneous lumbar decompression. STUDY DESIGN: Single-center, prospective clinical study of 46 consecutive patients with neurogenic claudication symptoms related to lumbar spinal stenosis. SETTING: US interventional pain management practice. METHODS: From March 2010 to January 2011, 46 LSS patients suffering from neurogenic claudication underwent mild percutaneous lumbar decompression. Of these, 12-week, 6-month and one-year follow-up was available for 35 patients. OUTCOME ASSESSMENT: Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and Zurich Claudication Questionnaire (ZCQ). Outcomes were assessed at baseline, 12-week, 6-month and one-year follow-ups. RESULTS: One-year follow-up patients in this study experienced statistically and clinically significant improvement in physical function, as well as reduction of pain intensity. The initial improvement in these patients, which was significant, was sustained through one year, with no significant differences among the interim follow-up visit periods. These results demonstrate early improvement following treatment with a high degree of durability over time. There were no serious device or procedure-related complications reported in this study. LIMITATIONS: Single-center study with no control group. CONCLUSIONS: In this study, the mild procedure was shown to be safe. In addition, patients experienced significant improvement in mobility and reduction of pain one year after the procedure. One-year outcomes were not significantly different from interim results, indicating that the significant improvement following treatment, occurring as early as 12 weeks, was maintained through one year. This high degree of consistency over time indicates the durability of percutaneous lumbar decompression in the treatment of neurogenic claudication in symptomatic LSS.

The use of continuous intrathecal infusion of octreotide in patients with chronic pain of noncancer origin: an evaluation of efficacy in a prospective double-blind fashion.

Objective. We evaluated the efficacy of octreotide when administered in a continuous fashion by intrathecal infusion. Materials and Methods. We used a prospective, randomized, controlled, double-blinded method of analysis to evaluate the efficacy of intrathecal octreotide in a population of patients with noncancer pain diagnoses. The patients in this study had an unacceptable response to intrathecal opioids. In the analysis, the patients served as their own controls with a two-armed approach using a phase of treatment with preservative-free saline and a phase of treatment with preservative-free octreotide to assess pain relief. Assessment tools used included visual analog scales and brief pain inventories. Results. Of the 20 patients randomized in the study, 18 completed all data-collection points. One patient withdrew a week after the first refill because of uncontrollable pain, and the other patient withdrew early due to a lack of transportation. Statistical analysis showed no improvement in efficacy in the octreotide arm at the 6-week end-point when compared to saline. No significant differences were seen in any of the other end-points between the saline and intrathecal drug group. Conclusions. Intrathecal octreotide did not show significant improvement in pain relief when compared to saline in chronic noncancer pain. It did show significant relief when compared to baseline, suggesting a positive effect of placebo in the control phase. While the overall data showed no clinical efficacy, a small group of patients did well and continued on the therapy in an open label fashion after the study concluded. These patients had pain consistent with a neuropathic pain diagnosis. The patients had noncancer pain, which was not responsive to intrathecal morphine. The lack of side-effects suggests that the dose selected for the study should be increased for future analysis of this agent, and patients with neuropathic pain should be more closely examined.

The Use of Continuous Intrathecal Infusion of Octreotide in Patients with Chronic Pain of Noncancer Origin: An Evaluation of Side-effects and Toxicity in a Prospective Double-blind Fashion.

Introduction. Intrathecal octreotide has been considered an alternative to opioids in chronic infusion for pain. Octreotide is an analog of the growth hormone sandostatin. Previous work has shown the drug to be efficacious in cancer patients who had failed intrathecal opioids. In this study, we examined the safety of intrathecal octreotide in noncancer pain using continuous intrathecal infusion. Methods. We examined 20 patients in a double-blind, prospective, randomized fashion comparing safety and adverse effects using saline or octreotide. Data collected include neurologic examination, adverse effect reporting, and cognitive testing. The study was reviewed and approved by the Saint Francis Hospital Institutional Review Board, which also conducted and approved the authorization to use and disclose protected health information for research purposes which describes the privacy law, Health Insurance Portability and Accountability Act (HIPAA). The Saint Francis Hospital IRB and FDA approved the ongoing use of intrathecal octreotide for research. Conclusions. Intrathecal octreotide, at doses as high as 20 µg/hr, appeared to be as safe as saline when given as a continuous intrathecal infusion. Further work is needed on dose-range analysis and efficacy.

Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine.

BACKGROUND CONTEXT: Bupivacaine is a local anesthetic agent of the amide class. This drug has been used in many clinical situations including intrathecal infusion. The literature regarding intrathecal bupivacaine is limited to small case studies, and anecdotal reports. This article examines a large patient group receiving bupivacaine with opioids over an extended period of time and analyzes efficacy and safety. The patients had pain related to failed back surgery syndrome or metastatic cancer to the spine. PURPOSE: The purpose of this study was to determine the efficacy and safety of intrathecal bupivacaine combined with opioids for treatment of pain of spinal origin when opioids alone were inadequate. The secondary purpose of this study was to determine if the combination of bupivacaine and opioids created a neurological safety risk. STUDY DESIGN/SETTING: The study design was retrospective, and involved consecutive medical records review by a disinterested third party. PATIENT SAMPLE: One hundred nine consecutive patients were studied for a total of 6,780 patient weeks of bupivacaine/opioid infusion. These data were compared with a comparable time in the opioid alone treatment arm. The population included 84 noncancer patients and 25 cancer patients. OUTCOME MEASURES: The primary outcome measure was pain relief obtained by a group of patients with a combination of bupivacaine and opioids as compared with opioid alone when delivered by intrathecal infusion. The visual analog scale was used to measure pain levels. Secondary objectives included measuring the amount of oral and transdermal medication required (opioid and nonopioid), emergency visits, routine office visits and patient satisfaction. These secondary objectives give a measure of health-care utilization. We also reviewed neurological complications during the combined arm of treatment. METHODS: The study was done retrospectively with 109 consecutive patients. Patient chart reviews were used to determine the visual analog scales, amount of oral opioids, oral nonopioid adjuvant and patient satisfaction ratings. Patient satisfaction and pain rating was measured by a visual analog scale. Other factors recorded were emergency room visits, doctor's visits (other than the primary pain physician) and pain center visits. We also reviewed records for neurological deficits in the opioid arm and the combined arm. The t test was used to analyze statistical significance. RESULTS: The findings suggested that in the combination arm the pain relief was significantly better (p=.008), the number of oral opioids used were significantly less (p=.008), the number of oral nonopioid adjuvants were reduced, the number of doctor's visits were less in the combined arm (p=.008), the number of pain clinic visits were less (p=.03), the number of emergency visits were significantly less (p=.01) and patient satisfaction was better (p=.003). The total dose of morphine was reduced by 23% in the combined arm (p=.005). During the course of treatment with intrathecal bupivacaine, there were no irreversible complications. CONCLUSION: Bupivacaine, when used in combination with opioids, is a helpful and safe method of treatment in a select population of patients who have not responded to intrathecal opioids alone.