Effectiveness of combined dorsal root ganglion and spinal cord stimulation: a retrospective, single-centre case series for chronic focal neuropathic pain.

OBJECTIVE: This case series retrospectively reviewed the outcomes in patients implanted with combined, synchronous dorsal root ganglion stimulation (DRGS) and spinal cord stimulation (SCS) connected to a single implantable pulse generator (IPG) in a tertiary referral neuromodulation centre in the United Kingdom. METHODS: Twenty-six patients underwent a trial of DRGS+SCS for treating focal neuropathic pain between January 2016 and December 2019, with a follow-up in February 2022. A Transgrade approach was employed for DRGS. Patients were provided with 3 possible stimulation programs: DRGS-only, SCS-only, or DRGS+SCS. Patients were assessed for pain intensity, patients' global impression of change (PGIC), preferred lead(s) and complications. RESULTS: Twenty patients were successful and went on for full implantation. The most common diagnosis was Complex Regional Pain Syndrome. After an average of 3.1 years follow-up, 1 patient was lost to follow-up, and 2 were non-responders. Of the remaining 17 patients, 16 (94%) continued to report a PGIC of 7. The average pain intensity at Baseline was 8.5 on an NRS scale of 0-10. At the last follow-up, the average NRS reduction overall was 78.9% with no statistical difference between those preferring DRGS+SCS (n = 9), SCS-only (n = 3) and DRGS-only (n = 5). The combination of DRGS+SCS was preferred by 53% at the last follow-up. There were no serious neurological complications. CONCLUSIONS: This retrospective case series demonstrates the potential effectiveness of combined DRGS+SCS with sustained analgesia observed at an average follow-up of over 3 years. Implanting combined DRGS+SCS may provide programming flexibility and therapeutic alternatives.

Comparison of Paresthesia Mapping With Anatomic Placement in Burst Spinal Cord Stimulation: Long-Term Results of the Prospective, Multicenter, Randomized, Double-Blind, Crossover CRISP Study.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective therapy for chronic intractable pain. Conventional SCS involves electrode placement based on intraoperative paresthesia mapping; however, newer paradigms like burst may allow for anatomic placement of leads. Here, for the first time, we report the one-year safety and efficacy of burst SCS delivered using a lead placed with conventional, paresthesia mapping, or anatomic placement approach in subjects with chronic low back pain (CLBP). MATERIALS AND METHODS: Subjects with CLBP were implanted with two leads. The first lead was placed to cross the T8/T9 disc and active contacts for this lead were chosen through paresthesia mapping. The second lead was placed at the T9/T10 spinal anatomic landmark. Subjects initially underwent a four-week, double-blinded, crossover trial with a two-week testing period with burst SCS delivered through each lead in a random order. At the end of trial period, subjects expressed their preference for one of the two leads. Subsequently, subjects received burst SCS with the preferred lead and were followed up at 3, 6, and 12 months. Pain intensity (visual analog scale), quality-of-life (EuroQol-5D instrument), and disability (Oswestry Disability Index) were evaluated at baseline and follow-up. RESULTS: Forty-three subjects successfully completed the trial. Twenty-one preferred the paresthesia mapping lead and 21 preferred the anatomic placement lead. Anatomic placement lead was activated in one subject who had no preference. The pain scores (for back and leg) significantly improved from baseline for both lead placement groups at all follow-up time points, with no significant between-group differences. CONCLUSIONS: This study demonstrated that equivalent clinical benefits could be achieved with burst SCS using either paresthesia mapping or anatomic landmark-based approaches for lead placement. Nonparesthesia-based approaches, such as anatomic landmark-based lead placement investigated here, have the potential to simplify implantation of SCS and improve current surgical practice.

Cascade Programming for 10 kHz Spinal Cord Stimulation: A Single Center Case Series of 114 Patients With Neuropathic Back and Leg Pain.

OBJECTIVE: Ten kilohertz spinal cord stimulation (SCS) is usually initiated in a single-bipolar configuration over the radiological reference point T9/T10 intervertebral disc space for neuropathic back and leg pain. Cascade is a duty-cycled, multi-bipolar contact configuration across an entire eight-contact lead. Potential advantages by using a broader area of SCS coverage include mitigation against minor lead migration and a reduction in the need for reprogramming. We report here the results of a retrospective case series of 114 patients using Cascade. MATERIALS AND METHODS: Retrospective data were collected over two years. We selected patients with neuropathic back with or without/leg pain who had a trial of SCS. Pain assessments using Numerical Rating Scales (NRS) and Patient Global Impression of Change (PGIC) scores were collected at baseline, six months, and last follow-up beyond 12 months (mean 15.1 months). Patients were programmed with 10 kHz SCS using Cascade during the trial, which was continued unless reporting inadequate pain relief. Morbidity and deviations from Cascade programming were also obtained. RESULTS: At six months, 87 of 97 (90.6%) patients with active devices were using Cascade and 58 of 72 (81%) patients at the last follow-up >12 months. There was a significant reduction in back NRS (8.3 vs. 3.9 [p < 0.0001], N = 97) and leg pain (7.53 vs. 3.83 [p < 0.0001], N = 77) at 6 months and last follow-up >12 months back (8.3 vs. 3.95 [p < 0.0001] N = 72), leg (7.53 vs. 3.534 [p < 0.0001], N = 58). The PGIC score was 6 of 7 or all of 7 in 72% of patients (70/97) at six months and in 68% (49/72) of patients at the last follow-up beyond 12 months. CONCLUSION: Cascade is an effective programming methodology that may have benefits over a single-bipole configuration for 10 kHz SCS, particularly during a trial of stimulation. Results from this study suggest it is a durable program for patients with neuropathic back and leg pain.

Quantitative sensory phenotyping in chronic neuropathic pain patients treated with unilateral L4-dorsal root ganglion stimulation.

BACKGROUND: In a previous study, we reported that selective dorsal root ganglion stimulation (DRGSTIM) at DRG level L4 promoted a favorable outcome for complex regional pain syndrome (CRPS) patients along with DRGSTIM-related changes of inflammatory biomarkers in blood and saliva. The impact on somatosensation is largely unknown. Herein, we assessed the quantitative sensory profile to quantify L4-DRGSTIM effects in CRPS patients. METHODS: Twelve refractory CRPS patients (4 female; 8 male; mean age 69 ± 9 years) received standardized quantitative sensory testing (QST) protocol at baseline and after 3 months of unilateral L4-DRGSTIM assessing nociceptive and non-nociceptive thermal and mechanical sensitivity of the knee affected by CRPS and the contralateral non-painful knee area. RESULTS: At baseline, CRPS subjects showed significantly increased thresholds for warmth, tactile and vibration detection (WDT, MDT and VDT) and exaggerated pain summation (WUR). After 3 months of unilateral L4-DRGSTIM all pain parameters exhibited trends towards normalization of sensitivity accumulating to a significant overall normalization for pain sensitivity (effect size: 0.91, p < 0.01), while with the one exception of WDT all non-nociceptive QST parameters remained unchanged. Overall change of non-nociceptive detection was negligible (effect size: 0.25, p > 0.40). Notably, reduction of pain summation (WUR) correlated significantly with pain reduction after 3 months of L4-DRGSTIM. CONCLUSIONS: Selective L4-DRGSTIM lowered ongoing pain in CRPS patients and evoked significant normalization in the pain domain of the somatosensory profile. Thermoreception and mechanoreception remained unchanged. However, larger randomized, sham-controlled trials are highly warranted to shed more light on effects and mechanisms of dorsal root ganglion stimulation on quantitative sensory characteristics. The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

Comparison of Neural Activity in Chronic Pain Patients During Tonic and Burst Spinal Cord Stimulation Using Fluorodeoxyglucose Positron Emission Tomography.

OBJECTIVE: Burst spinal cord stimulation (SCS) is a novel stimulation paradigm that seems to provide better pain relief compared to the classic tonic SCS with minimal paresthesia sensation. Based on source localized electroencephalography and clinical data, it has been proposed that burst stimulation as defined by Dirk De Ridder exerts this greater effect by not only modulating the lateral and the descending pain-inhibitory pathways (similar to tonic SCS) but also modulating the medial pain pathway, which encodes the affective, motivational aspects of pain. MATERIAL AND METHODS: The current study evaluates the supraspinal differences between burst and tonic stimulation with another functional imaging technique, namely fluorodeoxyglucose positron emission tomography (FGD-PET) scanning, in seven patients, who underwent both burst and tonic SCS, to confirm this notion of medial pain pathway modulation. RESULTS: The results of the current FGD-PET study show that burst stimulation, in contrast to tonic stimulation, indeed modulates the dorsal anterior cingulate cortex (i.e., medial pain pathway) more than tonic stimulation. DISCUSSION: Our data suggest an inherent difference in the central neural mechanisms during burst and tonic stimulation, which could potentially alter the patient's perception of pain. CONFLICT OF INTEREST: Dr. Yearwood, Dr. De Ridder, Dr. Falowski, and Dr. Vanneste are the consultants of Abbott. Dr. Venkatesan is an employee of Abbott. Hye Bin Yoo and Dr. Wing Ting To have no conflicts of interest to report.

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.

Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling.

BACKGROUND: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. METHODS: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. RESULTS: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. CONCLUSIONS: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain.

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.

Long-term quality of life improvement for chronic intractable back and leg pain patients using spinal cord stimulation: 12-month results from the SENZA-RCT.

PURPOSE: Chronic axial low-back pain is a debilitating disorder that impacts all aspects of an afflicted individual's life. Effective, durable treatments have historically been elusive. Interventional therapies, such as spinal cord stimulation (SCS), have shown limited efficacy at best. Recently, a novel treatment, 10 kHz SCS, has demonstrated superior pain relief compared with traditional SCS in a randomized controlled trial (RCT). In this manuscript, we report on the long-term improvements in quality of life (QoL) outcomes for subjects enrolled in this study. METHODS: A prospective, multicenter, randomized controlled trial (SENZA-RCT) was conducted. Patients with both chronic back and leg pain were enrolled and randomized (1:1) into 10 kHz SCS or traditional SCS treatment groups. A total of 171 subjects received a permanent SCS device implant. QoL and functionality measures were collected up to 12 months. The device remote control utilization, which is an indication of patient interaction with the device for adjustments, was collected at 24-month post-implantation. RESULTS: At 12 months, a higher proportion of 10 kHz SCS subjects had marked improvement of their disability (Oswestry Disability Index) to a "moderate" or "minimal" impact on their daily function versus the control group. The subjects also reported better improvement in the Global Assessment of Functioning, Clinician Global Impression of Change, Pittsburgh Sleep Quality Index, and short-form McGill Pain Questionnaire, compared to traditional SCS subjects. The 10 kHz SCS subjects also reported far higher rates of both driving and sleeping with their device turned on, as well as reduced reliance on their programmers to adjust therapy settings. CONCLUSIONS: In addition to superior pain relief, 10 kHz SCS provides long-term improvements in quality of life and functionality for subjects with chronic low-back and leg pain. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01609972).

An Integrated Quantitative Index for Measuring Chronic Multisite Pain: The Multiple Areas of Pain (MAP) Study.

OBJECTIVE: Despite the high prevalence of chronic multisite pain, there is little consensus on methods to characterize it. Commonly used assessments report only one dimension of pain, that is, intensity, thus ignoring the spatial aspect of pain. We developed a novel pain quantification index, the Integrated Pain Quantification Index (IPQI), on a scale of 0 to 1 that integrates multiple distinct pain measures into a single value, thus representing multidimensional pain information with a single value. DESIGN: Single-visit, noninterventional, epidemiological study. SETTING: Fourteen outpatient multidisciplinary pain management programs. PATIENTS: Patients with chronic pain of the trunk and/or limbs for at least six months with average overall pain intensity of at least 5 on the numeric rating scale. METHODS: Development of IPQI was performed in a large population (N = 810) of chronic pain patients from the Multiple Areas of Pain (MAP) study. RESULTS: Prevalence of two or more noncontiguous painful areas was at 88.3% (95% confidence interval [CI] = 0.86-0.90), with a mean of 6.3 areas (SD = 5.57 areas). Prevalence of more than 10% body area in pain was at 52.8% (95% CI = 0.49-0.56), with a mean at 16.1% (17.16%). On average, IPQI values were near the middle of the scale, with mean and median IPQI at 0.52 (SD = 0.13) and 0.55, respectively. The IPQI was generalizable and clinically relevant across all domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. CONCLUSIONS: IPQI provided a single pain score for representing complex, multidimensional pain information on one scale and has implications for comparing pain populations across longitudinal clinical trials.

Changes of Metabolic Disorders Associated Peripheral Cytokine/Adipokine Traffic in Non-Obese Chronic Back Patients Responsive to Burst Spinal Cord Stimulation.

OBJECTIVES: In our previous study, anti-inflammatory IL-10 serum levels were significantly elevated after burst spinal cord stimulation (SCS) in back pain patients and correlated with pain intensity. This current study extended cytokine analysis including metabolic-associated adipokine/cytokine serum assessment in chronic back pain patients with co-existing metabolic disorders such as diabetes, hypertension, and cardiovascular diseases. METHODS: At baseline and after three months of burst SCS treatment, leptin (LP), adiponectin (AN), and ghrelin (GH) were recorded in non-/pre-obese chronic back pain patients with co-existing metabolic disorders and compared to age-/gender-matched healthy controls (HC). RESULTS: Mean BMI was 22 ± 0.81 kg/m2 in 12 (five male/seven female) participants with diabetes in 6/12 (50%), hypertension in 9 (75%), and CVD in five patients (42%). Pre- and post-SCS LP levels were significantly higher compared to healthy controls: pre-SCS, 30567 (12,996-58,821) vs. HC, 7952 (4932-12,583) pg/mL, p = 0.029; post-SCS, 18,890 (7140-44,719) vs. HC, 7952 (4932-12,583) pg/mL, p = 0.035. Pre- and post-SCS changes of GH (p = 0.18) and AN (p = 0.8) did not differ significantly. GH serum levels correlated with AN (Spearman r = 0.5; p = 0.012; 95 CI 0.11 to -0.76) and AN levels were significantly correlated with higher age (Pearson correlation r = 0.8; p = 0.002; 95 CI 0.41-0.94) at baseline. CONCLUSIONS: This study determined serum changes of metabolic-associated cytokines/adipokines in non-obese chronic back pain patients responsive to burst SCS suggesting that neuroinflammation assessment may consider pain-associated mood, cognition, sleep, and metabolic state.

Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform.

OBJECTIVE: The purpose of the multicenter, randomized, unblinded, crossover Success Using Neuromodulation with BURST (SUNBURST) study was to determine the safety and efficacy of a device delivering both traditional tonic stimulation and burst stimulation to patients with chronic pain of the trunk and/or limbs. METHODS: Following a successful tonic trial, 100 subjects were randomized to receive one stimulation mode for the first 12 weeks, and then the other stimulation mode for the next 12 weeks. The primary endpoint assessed the noninferiority of the within-subject difference between tonic and burst for the mean daily overall VAS score. An intention-to-treat analysis was conducted using data at the 12- and 24-week visits. Subjects then used the stimulation mode of their choice and were followed for one year. Descriptive statistics were used analyze additional endpoints and to characterize the safety profile of the device. RESULTS: The SUNBURST study demonstrated that burst stimulation is noninferior to tonic stimulation (p < 0.001). Superiority of burst was also achieved (p < 0.017). Significantly more subjects (70.8%) preferred burst stimulation over tonic stimulation (p < 0.001). Preference was sustained through one year: 68.2% of subjects preferred burst stimulation, 23.9% of subjects preferred tonic, and 8.0% of subjects had no preference. No unanticipated adverse events were reported and the safety profile was similar to other spinal cord stimulation studies. CONCLUSIONS: The SUNBURST study demonstrated that burst spinal cord stimulation is safe and effective. Burst stimulation was not only noninferior but also superior to tonic stimulation for the treatment of chronic pain. A multimodal stimulation device has advantages.

Spinal Cord Stimulation (SCS) with Anatomically Guided (3D) Neural Targeting Shows Superior Chronic Axial Low Back Pain Relief Compared to Traditional SCS-LUMINA Study.

BACKGROUND: The aim of this study was to determine whether spinal cord stimulation (SCS) using 3D neural targeting provided sustained overall and low back pain relief in a broad routine clinical practice population. STUDY DESIGN AND METHODS: This was a multicenter, open-label observational study with an observational arm and retrospective analysis of a matched cohort. After IPG implantation, programming was done using a patient-specific, model-based algorithm to adjust for lead position (3D neural targeting) or previous generation software (traditional). Demographics, medical histories, SCS parameters, pain locations, pain intensities, disabilities, and safety data were collected for all patients. RESULTS: A total of 213 patients using 3D neural targeting were included, with a trial-to-implant ratio of 86%. Patients used seven different lead configurations, with 62% receiving 24 to 32 contacts, and a broad range of stimulation parameters utilizing a mean of 14.3 (±6.1) contacts. At 24 months postimplant, pain intensity decreased significantly from baseline (ΔNRS = 4.2, N = 169, P < 0.0001) and even more in in the severe pain subgroup (ΔNRS = 5.3, N = 91, P < 0.0001). Axial low back pain also decreased significantly from baseline to 24 months (ΔNRS = 4.1, N = 70, P < 0.0001, on the overall cohort and ΔNRS = 5.6, N = 38, on the severe subgroup). Matched cohort comparison with 213 patients treated with traditional SCS at the same centers showed overall pain responder rates of 51% (traditional SCS) and 74% (neural targeting SCS) and axial low back pain responder rates of 41% and 71% in the traditional SCS and neural targeting SCS cohorts, respectively. Lastly, complications occurred in a total of 33 of the 213 patients, with a 1.6% lead replacement rate and a 1.6% explant rate. CONCLUSIONS: Our results suggest that 3D neural targeting SCS and its associated hardware flexibility provide effective treatment for both chronic leg and chronic axial low back pain that is significantly superior to traditional SCS.

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain.

OBJECTIVES: Burst spinal cord stimulation (SCS) has been reported to reduce back pain and improve functional capacity in Failed Back Surgery Syndrome (FBSS). However, its mechanism of action is not completely understood. Systemic circulating cytokines have been associated with the development of chronic back pain. METHODS: This prospective, feasibility study enrolled 12 refractory FBSS patients with predominant back pain (70% of overall pain) suitable for Burst SCS. Back and leg pain intensity (back pain [VASB ]/leg pain [VASL ]), functional capacity (sleep quality [PSQI]), depressive symptoms (BDI), body weight, stimulation parameters, and plasma levels of pro-inflammatory (Il-1b; TNF; HMGB1)/anti-inflammatory (Il-10) cytokines were collected at baseline and after three months of Burst SCS and compared to healthy controls. RESULTS: Pain intensity (pre VASB : 8.25 ± 0.75 vs. post 1.42 ± 1.24) and functional capacity (PSQI: pre 7.92 ± 3.92 vs. post 3.42 ± 1.24; BDI: pre 20.83 ± 3.56 vs. post 10.92 ± 0.75) significantly improved compared to baseline. Pro-inflammatory HMGB1 remained unchanged (preburst: 3.35 ± 3.25 vs. postburst: 3.78 ± 3.83 ng/mL; p = 0.27; W = -30) versus the HC group (2.53 ± 2.6 ng/mL; p = 0.47; U = 59), while anti-inflammatory IL-10 levels were significantly elevated after burst SCS as compared to baseline (preburst 12.54 ± 22.95 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48) and HC group (HC: 7.03 ± 11.6 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48; p = 0.04). Baseline preburst IL-10 values and preburst VASB significantly correlated (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while correlation was not significant between postburst IL-10 values and postburst VASB (Spearman correlation r = -0.49; p = 0.18; 95 CI -0.83 to -0.15). Postburst IL-10 values correlated significantly with postburst PSQI scores (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while no correlation was found between preburst and postburst changes related to the BDI. CONCLUSIONS: Burst SCS increased systemic circulating anti-inflammatory IL-10, improved FBSS back pain and back pain associated co-morbidities like disrupted sleep architecture and depressive symptoms in FBSS patients. Thus, suggesting a possible relationship between burst SCS and burst-evoked modulation of peripheral anti-inflammatory cytokine IL-10 in chronic back pain.

Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial.

BACKGROUND: Current treatments for chronic pain have limited effectiveness and commonly known side effects. Given the prevalence and burden of intractable pain, additional therapeutic approaches are desired. Spinal cord stimulation (SCS) delivered at 10 kHz (as in HF10 therapy) may provide pain relief without the paresthesias typical of traditional low-frequency SCS. The objective of this randomized, parallel-arm, noninferiority study was to compare long-term safety and efficacy of SCS therapies in patients with back and leg pain. METHODS: A total of 198 subjects with both back and leg pain were randomized in a 1:1 ratio to a treatment group across 10 comprehensive pain treatment centers. Of these, 171 passed a temporary trial and were implanted with an SCS system. Responders (the primary outcome) were defined as having 50% or greater back pain reduction with no stimulation-related neurological deficit. RESULTS: At 3 months, 84.5% of implanted HF10 therapy subjects were responders for back pain and 83.1% for leg pain, and 43.8% of traditional SCS subjects were responders for back pain and 55.5% for leg pain (P < 0.001 for both back and leg pain comparisons). The relative ratio for responders was 1.9 (95% CI, 1.4 to 2.5) for back pain and 1.5 (95% CI, 1.2 to 1.9) for leg pain. The superiority of HF10 therapy over traditional SCS for leg and back pain was sustained through 12 months (P < 0.001). HF10 therapy subjects did not experience paresthesias. CONCLUSION: HF10 therapy promises to substantially impact the management of back and leg pain with broad applicability to patients, physicians, and payers.

Intrathecal administration of Infumorph® vs compounded morphine for treatment of intractable pain using the Prometra® programmable pump.

OBJECTIVES: The intrathecal administration of morphine sulfate has become an established alternative to oral opiate therapy for the treatment of chronic pain. Currently, Infumorph(®) is the only morphine sulfate approved by the US Food and Drug Administration for continuous intraspinal administration with an infusion pump. However, in order to achieve and maintain adequate pain relief, patients may require concentrations outside of those commercially available products resulting in the use of compounded morphine. METHODS: Accuracy, safety, and efficacy data related to Infumorph and compounded morphine use were collected during clinical trials of a new implantable pump. This report compares those results in a total of 154 subjects implanted with the Prometra programmable pump. RESULTS: The mean drug delivery accuracy using only Infumorph in 31 subjects was 100.1% and was comparable with the accuracy reported for the 71 subjects who received only compounded morphine sulfate (97.4%). The percentage of subjects free from device-related serious adverse events (DRSAEs) was similar in both groups. Compounded morphine showed statistically significant improvements in pain and disability, where Infumorph only showed a statistical improvement in pain. Dosing was higher in the compounded group. Results are also presented for a crossover group that received both types of morphine. CONCLUSIONS: ThePrometra system accurately delivers both Infumorph and compounded morphine with no significant differences in DRSAE rates. These results indicate that compounded morphine delivery effectively treats the chronic pain patient population. Higher doses appear to provide better pain relief; however, optimal pain relief will need to be balanced against the risk of granuloma formation.

Novel spinal cord stimulation parameters in patients with predominant back pain.

OBJECTIVES: To examine the feasibility of novel high-frequency spinal cord stimulation therapy in a cohort of patients with chronic predominant back pain during a four day, percutaneous trial. DESIGN: Prospective, multicenter open label pilot trial. SETTING AND PATIENTS: Twenty-four patients with back pain greater than leg pain who were candidates for spinal cord stimulation were trialed at five U.S. centers. INTERVENTIONS: Patients completed a percutaneous trial with a commercially available spinal cord stimulator. The implanted leads were then connected to the novel external stimulation device and patients were trialed for an additional four days. OUTCOME MEASURES: Pain intensity ratings, subjective descriptions, and patients' preference. RESULTS: There was significant improvement from baseline in overall pain scores (8.68 to 2.03, [p < 0.001]) and back pain scores (8.12 to 1.88, [p < 0.001]) with the investigational stimulation. The investigational stimulation was preferred to the commercially available systems in 21 of 24 patients (88%). CONCLUSIONS: Patients with predominant back pain reported a substantial reduction in overall pain and back pain when trialed with high-frequency spinal cord stimulation therapy.

A Call to Action Toward Optimizing the Electrical Dose Received by Neural Targets in Spinal Cord Stimulation Therapy for Neuropathic Pain.

Spinal cord stimulation has seen unprecedented growth in new technology in the 50 years since the first subdural implant. As we continue to grow our understanding of spinal cord stimulation and relevant mechanisms of action, novel questions arise as to electrical dosing optimization. Programming adjustment - dose titration - is often a process of trial and error that can be time-consuming and frustrating for both patient and clinician. In this report, we review the current preclinical and clinical knowledge base in order to provide insights that may be helpful in developing more rational approaches to spinal cord stimulation dosing. We also provide key conclusions that may help in directing future research into electrical dosing, given the advent of newer waveforms outside traditional programming parameters.

Explant rates of electrical neuromodulation devices in 1177 patients in a single center over an 11-year period.

INTRODUCTION: The publication of explant rates has established risk factors and a definitive objective outcome of failure for spinal cord stimulation (SCS) treating neuropathic pain. We present a UK study analyzing explants of electrical neuromodulation devices for different conditions over 11 years in a single center specializing in neuromodulation. METHODS: A retrospective analysis was performed using a departmental database between 2008 and 2019. Explants were analyzed according to condition, mode of stimulation and other demographics using logistic regression and Kaplan-Meier graphs with log-rank (Mantel-Cox) test. RESULTS: Out of a total of 1177 patients, the explant rate was 17.8% at 5 years and 25.2% at 10 years. Loss of efficacy was the most frequent reason for explant 119/181 (65%). Multivariant regression analysis indicated patients with back pain without prior surgery had a reduced risk of explant (p=0.03). Patients with SCS systems that had 10 kHz, options of multiple waveforms, and rechargeable batteries also had a decreased risk of explant (p<0.001). None of these findings were confirmed when comparing Kaplan-Meier graphs, however. Contrary to other studies, we found gender and age were not independent variables for explant. CONCLUSION: These data contribute to a growing list of explant data in the scientific literature and give indications of what factors contribute to long-term utilization of electrical neuromodulation devices.