Network Meta-analysis and Economic Evaluation of Neurostimulation Interventions for Chronic Non-surgical Refractory back Pain.

OBJECTIVES: Different types of spinal cord stimulation (SCS) have now been evaluated for the management of chronic non-surgical refractory back pain (NSRBP). A direct comparison between the different types of SCS or between closed-loop SCS with conventional medical management (CMM) for patients with NSRBP has not been previously conducted, and therefore, their relative effectiveness and cost-effectiveness remain unknown. The aim of this study was to perform a systematic review, network meta-analysis (NMA) and economic evaluation of closed-loop SCS compared with fixed-output SCS and CMM for patients with NSRBP. METHODS: Databases were searched to 8th September 2023. Randomised controlled trials of SCS for NSRBP were included. Results of studies were combined using fixed-effect NMA models. A cost-utility analysis was performed from the perspective of the UK National Health Service with results reported as incremental cost per quality-adjusted life-year (QALY). RESULTS: Closed-loop SCS resulted in statistically and clinically significant reductions in pain intensity (mean difference [MD] 32.72 [95% CrI 15.69-49.78]) and improvements in secondary outcomes compared to fixed-output SCS at 6-months follow-up. Compared to CMM, both closed-loop and fixed-output SCS result in statistically and clinically significant reductions in pain intensity (closed-loop SCS vs. CMM MD 101.58 [95% CrI 83.73-119.48]; fixed-output SCS versus CMM MD 68.86 [95% CrI 63.43-74.31]) and improvements in secondary outcomes. Cost-utility analysis shows that closed-loop SCS dominates fixed-output SCS and CMM, and fixed-output SCS also dominates CMM. DISCUSSION: Current evidence shows that closed-loop and fixed-output SCS provide more benefits and are cost-saving compared to CMM for patients with NSRBP.

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

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

Impact of temperature on the magnitude and duration of relief after lumbar facets medial branch nerves radiofrequency ablation: a randomized double-blinded study.

INTRODUCTION: There are numerous studies appraising the variables that may influence the clinical outcomes after lumbar thermal radiofrequency ablation (RFA). Expanding the lesion size may increase the likelihood of capturing the target nerves in the lesion, thereby increasing the technical success rate of RFA. However, our literature search has failed to identify a consensus on the optimal target temperature. A retrospective study demonstrated that there seems to be significant functional improvement associated with the temperature of 90°C compared with 80°C. The authors prospectively studied the subject in a double-blinded randomized fashion. METHODS: Patients undergoing RFA for lumbar facetogenic pain were randomized in two cohorts (80°C and 90°C). Physicians and patients were blinded to the temperature used. The primary outcome was self-reported pain scores up to 12 months. Secondary outcomes included: self-reported functional improvement, duration of relief as measured by the time before repeat ablation of the same medial branches nerves, opioids' consumption, and patient satisfaction. RESULTS: Both groups reported pain improvement in all follow-up time points. Overall, both groups achieved statistically significant pain reduction (p<0.05). The median time to repeat RFA in the 80°C group was 112 (49-252) days, while it was 217 (198-348) days in the 90°C group (p<0.04). The univariate analysis emphasized that the RFA temperature is a statistically significant factor for pain improvement of more than 50%, OR 2.7 (1.1 to 6.6) p value=0.031. CONCLUSION: RFA has been demonstrated as an effective therapeutic modality for lumbar facetogenic back pain. Yet, the several factors involved in determining a favorable outcome of this procedure require further research and optimization. This prospective double-blinded randomized trial demonstrated that RFA at both temperatures (80°C, 90°C) provided significance at all the time periods examined. However, RFA at 90°C was superior to 80°C in regard to the duration of relief.

Patient and physician radiation exposure during minimally invasive lumbar decompression: A prospective assessment of X-ray exposure risks.

INTRODUCTION: Minimally invasive lumbar decompression (mild®) is becoming a popular procedure for treating lumbar spinal stenosis (LSS) secondary to hypertrophic ligamentum flavum (LF). The mild® procedure is commonly performed under live fluoroscopic guidance and carries a risk of radiation exposure to the patient and healthcare. METHODS: One physician performed mild® on 41 patients at the Cleveland Clinic Department of Pain Management from October 2019 to December 2021, while wearing a radiation exposure monitor (Mirion Technologies). Mean fluoroscopy time, mean exposure per case, and mean exposure per unilateral level decompressed were the primary outcomes measured. The secondary outcome was to provide a comparison of radiation exposure during similar fluoroscopically guided procedures. RESULTS: Mean patient fluoroscopy exposure time was 2.1 min ±0.9 (range: 1.1-5.6) fluoroscopy time per unilateral level decompressed. The mean patient radiation skin exposure from mild® was 1.1 ± 0.9 mGym2, and the mean total dose was 142.3 ± 108.6 mGy per procedure. On average, the physician was exposed to an average deep tissue exposure of 4.1 ± 3.2 mRem, 2.9 ± 2.2 mRem estimated eye exposure, and 14.7 ± 11.0 mRem shallow tissue exposure per unilateral level decompressed. An individual physician would exceed the annual exposure limit of 5 Rem after approximately 610 mild® procedures per year. CONCLUSIONS: This study is an attempt to quantify the radiation exposure to the physician and patient during the mild® procedure. Compared with other fluoroscopically guided pain management procedures, patient and physician radiation exposure during mild® was low.

Does industry funding and study location impact findings from randomized controlled trials of spinal cord stimulation? A systematic review and meta-analysis.

BACKGROUND/IMPORTANCE: Concerns have been raised that effects observed in studies of spinal cord stimulation (SCS) funded by industry have not been replicated in non-industry-funded studies and that findings may differ based on geographical location where the study was conducted. OBJECTIVE: To investigate the impact of industry funding and geographical location on pain intensity, function, health-related quality of life and adverse events reported in randomized controlled trials (RCTs) of SCS. EVIDENCE REVIEW: Systematic review conducted using MEDLINE, CENTRAL, EMBASE and WikiStim databases until September 2022. Parallel-group RCTs evaluating SCS for patients with neuropathic pain were included. Results of studies were combined in random-effects meta-analysis using the generic-inverse variance method. Subgroup meta-analyses were conducted according to funding source and study location. Risk of bias was assessed using Cochrane RoB 2.0 tool. FINDINGS: Twenty-nine reports of 17 RCTs (1823 participants) were included. For the comparison of SCS with usual care, test for subgroup differences indicate no significant differences (p=0.48, moderate certainty evidence) in pain intensity score at 6 months for studies with no funding or funding not disclosed (pooled mean difference (MD) -1.96 (95% CI -3.23 to -0.69; 95% prediction interval (PI) not estimable, I2=0%, τ2=0)), industry funding (pooled MD -2.70 (95% CI -4.29 to -1.11; 95% PI -8.75 to 3.35, I2=97%, τ2=2.96) or non-industry funding (MD -3.09 (95% CI -4.47 to -1.72); 95% PI, I2 and τ2 not applicable). Studies with industry funding for the comparison of high-frequency SCS (HF-SCS) with low-frequency SCS (LF-SCS) showed statistically significant advantages for HF-SCS compared to LF-SCS while studies with no funding showed no differences between HF-SCS and LF-SCS (low certainty evidence). CONCLUSION: All outcomes of SCS versus usual care were not significantly different between studies funded by industry and those independent from industry. Pain intensity score and change in pain intensity from baseline for comparisons of HF-SCS to LF-SCS seem to be impacted by industry funding.

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.

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.

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.

Defining the Patient with Lumbar Discogenic Pain: Real-World Implications for Diagnosis and Effective Clinical Management.

There is an enormous body of literature that has identified the intervertebral disc as a potent pain generator. However, with regard to lumbar degenerative disc disease, the specific diagnostic criteria lack clarity and fail to capture the primary components which include axial midline low back pain with or without non-radicular/non-sciatic referred leg pain in a sclerotomal distribution. In fact, there is no specific ICD-10-CM diagnostic code to classify and define discogenic pain as a unique source of pain distinct from other recognized sources of chronic low back pain including facetogenic, neurocompressive including herniation and/or stenosis, sacroiliac, vertebrogenic, and psychogenic. All of these other sources have well-defined ICD-10-CM codes. Corresponding codes for discogenic pain remain absent from the diagnostic coding vernacular. The International Society for the Advancement of Spine Surgery (ISASS) has proposed a modernization of ICD-10-CM codes to specifically define pain associated with lumbar and lumbosacral degenerative disc disease. The proposed codes would also allow the pain to be characterized by location: lumbar region only, leg only, or both. Successful implementation of these codes would benefit both physicians and payers in distinguishing, tracking, and improving algorithms and treatments for discogenic pain associated with intervertebral disc degeneration.

The Choice of Spinal Cord Stimulation Versus Targeted Drug Delivery in the Management of Chronic Pain: Validation of an Outcomes Predictive Formula.

OBJECTIVE: In 2020, Mekhail et al published a formula that predicted the likelihood of a successful outcome for those who undergo spinal cord stimulation (SCS) for long-term pain management, based on retrospectively collected clinical and demographic data from one major medical center. The aim of this study is to validate such a predictive formula, prospectively, in a cohort of patients from multiple medical practices that are more representative of real-life clinical practice. MATERIALS AND METHODS: For the study, 939 patients who underwent successful SCS or targeted drug delivery (TDD) trials at multiple independent medical centers in the USA were enrolled into the Medtronic product surveillance registry data base before they underwent SCS or TDD device implantation, from 2018 to 2020. The registry data were collected prospectively but not specifically for this study. The data examined included demographic information, pain diagnosis, pain scores (visual analog scale [VAS]), Oswestry Disability Index scores, and quality-of-life scores at baseline and six months after implant. Because our goal is to validate the previously published predictive formula, in addition to the outcomes data previously mentioned, we collected the variables necessary for such a task: sex, age, depression, the presence of neuropathic pain, spine-related pain diagnosis, and persistent spinal pain syndrome "post laminectomy syndrome." Spine-related pain diagnosis included subjects with chronic spine pain who never had back surgery and whose pain was not radicular nor neuropathic. RESULTS: Of 619 patients with SCS, 138 (22%) achieved ≥ 50% reductions of the baseline VAS at six months. The logistic model predicts SCS success with an area under the receiver operating characteristic curve (AUC) of 80% in the current validation data set. Of 320 patients with TDD, 147 (46%) achieved ≥ 50% reduction of the baseline VAS at six months. The logistic model predicts TDD success with an AUC of 78% in the current validation data set. CONCLUSION: The study provides real life validation of the previously published predictive formula(4).

Pain Management Interventions for the Treatment of Chronic Low Back Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: Determine the relative effectiveness and safety profiles of percutaneous and minimally invasive interventions for chronic low back pain. METHODS: A systematic search was performed for randomized controlled trials published in the past 20 years reporting on radiofrequency ablation of the basivertebral, disk annulus and facet nerve structures, steroid injection of the disk, facet joint, and medial branch, biological therapies, and multifidus muscle stimulation. Outcomes evaluated included Visual Analog Scale (VAS) pain scores, Oswestry Disability Index (ODI) scores, quality of life (SF-36 and EQ-5D) scores, and serious adverse event (SAE) rates. Basivertebral nerve (BVN) ablation was chosen as the subject of comparison to all other therapies using a random-effects meta-analysis. RESULTS: Twenty-seven studies were included. BVN ablation was found to provide statistically significant improvements in VAS and ODI scores for 6-, 12- and 24-month follow-up ( P ≤0.05). Biological therapy and multifidus muscle stimulation were the only 2 treatments with both VAS and ODI outcomes not significantly different from BVN ablation at 6-, 12-, and 24-month follow-up. All outcomes found to be statistically significant represented inferior results to those of BVN ablation. Insufficient data precluded meaningful comparisons of SF-36 and EQ-5D scores. The SAE rates for all therapies and all reported time points were not significantly different from BVN ablation except for biological therapy and multifidus muscle stimulation at the 6-month follow-up. CONCLUSIONS: BVN ablation, biological therapy, and multifidus stimulation all provide significant, durable improvements in both pain and disability compared with other interventions, which provided only short-term pain relief. Studies on BVN ablation reported no SAEs, a significantly better result than for studies of biological therapy and multifidus stimulation.

ReActiv8 Stimulation Therapy vs. Optimal Medical Management: A Randomized Controlled Trial for the Treatment of Intractable Mechanical Chronic Low Back Pain (RESTORE Trial Protocol).

INTRODUCTION: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally. The role of restorative neurostimulation in the treatment of patients with refractory mechanical CLBP and multifidus muscle dysfunction has been established in one randomized controlled trial (RCT) and several clinical studies that demonstrated both safety and clinical benefit. This post-market trial provides a direct comparison to optimized medical management to test the hypothesis that the addition of restorative neurostimulation to current care paradigms results in significant improvements in back pain-related disability. METHODS AND ANALYSIS: This trial will include people who have reported significant levels of back pain and back pain-related disability with symptoms that have persisted for longer than 6 months prior to enrollment and resulted in pain on most days in the 12 months prior to enrollment. Eligible patients will be randomized to either optimal medical management or optimal medical management plus ReActiv8® restorative neurostimulation therapy. Patient-reported outcomes will be collected at regular intervals out to the 1-year primary endpoint, at which time the patients in the control arm will be offered implantation with the ReActiv8 system. Assessment of each group will continue for an additional year. ETHICS AND DISSEMINATION: The RESTORE trial follows the principles of the Declaration of Helsinki. The WCG IRB acts as the Central Institutional Review Board (IRB) for most sites and some sites will receive local IRB approval prior to enrollment of patients. Each IRB assessed the protocol and related documentation. The protocol complies with Good Clinical Practice (GCP). All patients provide written informed consent to participate in the trial. PROTOCOL VERSION: Version C, 07 Sep 2022. CLINICALTRIALS: gov registration number. NCT04803214 registered March 17, 2021.

Restorative neurostimulation is a treatment for intractable CLBP associated with dysfunction of the multifidus muscle, which normally provides functional stability to the lumbar spine. To date, ReActiv8^® (Mainstay Medical) is the only neurostimulator specifically developed and approved for this indication. Electrical stimulation of the muscle's nerve overrides the dysfunction and reactivates it. Several prior studies demonstrated that the most of participants experienced clinically substantial and durable symptom relief compared to baseline. This protocol describes a second RCT in which all participants are on individualized optimal medical management and half of them are randomly selected to be implanted with a ReActiv8 system to receive restorative neurostimulation. The purpose of this design is to measure if there is any clinical benefit of restorative neurostimulation over individualized optimal medical management alone over the course of a full year.

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

BACKGROUND: Treatment response to spinal cord stimulation (SCS) is focused on the magnitude of effects on pain intensity. However, chronic pain is a multidimensional condition that may affect individuals in different ways and as such it seems reductionist to evaluate treatment response based solely on a unidimensional measure such as pain intensity. AIM: The aim of this article is to add to a framework started by IMMPACT for assessing the wider health impact of treatment with SCS for people with chronic pain, a "holistic treatment response". DISCUSSION: Several aspects need consideration in the assessment of a holistic treatment response. SCS device data and how it relates to patient outcomes, is essential to improve the understanding of the different types of SCS, improve patient selection, long-term clinical outcomes, and reproducibility of findings. The outcomes to include in the evaluation of a holistic treatment response need to consider clinical relevance for patients and clinicians. Assessment of the holistic response combines two key concepts of patient assessment: (1) patients level of baseline (pre-treatment) unmet need across a range of health domains; (2) demonstration of patient-relevant improvements in these health domains with treatment. The minimal clinical important difference (MCID) is an established approach to reflect changes after a clinical intervention that are meaningful for the patient and can be used to identify treatment response to each individual domain. A holistic treatment response needs to account for MCIDs in all domains of importance for which the patient presents dysfunctional scores pre-treatment. The number of domains included in a holistic treatment response may vary and should be considered on an individual basis. Physiologic confirmation of therapy delivery and utilisation should be included as part of the evaluation of a holistic treatment response and is essential to advance the field of SCS and increase transparency and reproducibility of the findings.

Impact of Long-Term Evoked Compound Action Potential Controlled Closed-Loop Spinal Cord Stimulation on Sleep Quality in Patients With Chronic Pain: An EVOKE Randomized Controlled Trial Study Subanalysis.

OBJECTIVE: Spinal cord stimulation (SCS) is considered an effective interventional nonpharmacologic treatment option for several chronic pain conditions. Here we present the effects of the novel evoked compound action potential (ECAP) controlled closed-loop (ECAP-CL) SCS system on long-term sleep quality outcomes from the EVOKE study. MATERIALS AND METHODS: The EVOKE study is a double-blind, randomized, controlled clinical trial conducted at 13 sites in the United States (N = 134 patients). The clinical trial utilized SCS to manage chronic pain and compared novel ECAP-CL technology to open-loop SCS. Additionally, sleep quality data was collected using the Pittsburgh Sleep Quality Index (PSQI) at baseline and all study visits. RESULTS: The mean PSQI global score for ECAP-CL patients at baseline was 14.0 (n = 62; ± 0.5, SD 3.8), indicating poor sleep quality. Clinically meaningful and statistically significant reductions (p < 0.001) in the global PSQI scores were noted at 12 months (n = 55; 5.7 ± 0.6, SD 4.2). A total of 76.4% of ECAP-CL patients met or exceeded Minimal Clinically Important Difference from baseline in PSQI at 12 months. Additionally, 30.9% of ECAP-CL patients achieved "good sleep quality" scores (PSQI ≤ 5), and 29.1% achieved sleep quality remission. "Normative" sleep scores were observed in 29.6% of ECAP-CL patients at 12 months, and these scores were better than the US general population. Additionally, ECAP-CL patients achieved statistically significant changes from baseline (p < 0.01) across all seven subcomponent scores of PSQI at 12 months. CONCLUSIONS: ECAP-CL SCS elicits consistent neural activation of the target leading to less variability in long-term therapy delivery. In the EVOKE study, this resulted in ECAP-CL patients demonstrating clinically superior and sustained pain relief. Results from this study provide new evidence of long-term improvement in sleep quality and quantity in patients with chronic pain resulting from the use of this novel ECAP-CL SCS technology. CLINICAL TRAIL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02924129.

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

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

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.

Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study).

Background: Chronic pain that follows amputation of a limb is reported as "one of the most severe pains in the human experience," due to the magnitude of tissue injury and the multiple potential of pain generators at the local peripheral, spinal, and cortical levels. The Altius® System was developed to deliver high-frequency nerve block (HFNB) therapy via a cuff electrode applied to the peripheral nerve(s) and an implantable pulse generator. We report a novel clinical trial design for the first study of an active-implantable medical device in subjects with lower-limb post-amputation pain utilizing a multicenter, double-blinded, randomized, active-sham controlled clinical study protocol called QUEST, which is an ongoing investigational device exemption study to support United States Food and Drug Administration approval. Methods: The study enrollment of 180 subjects was completed in September 2021. Subjects were randomized 1:1 to the treatment group or the active-sham control group for the 3-month primary effectiveness and safety endpoints. After month 3, the active-sham control program group crossed over to the treatment program group and all subjects continued to the 12-month study endpoint. Study effectiveness success is determined by a superiority test between responder rates in the treatment and control groups at 3 months. A responder is defined as someone who experiences a 50% or greater reduction in pain scores - after a 30-minute treatment session - for more than 50% of all pain episodes in which the treatment was used. Discussion: The QUEST study design employs an active-sham control group to objectively assess the effectiveness of HFNB therapy. Additionally, the electronic diary repeated measures data collection in QUEST is expected to reduce the intra-subject variation typically observed in pain treatment studies. Finally, the longitudinal measurement of health-related quality of life and use of pain medication may, for example, show effectiveness in reducing opioid use over time.

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.