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.

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.

High-Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Combined Neck and Arm Pain: Results From a Prospective Multicenter Study.

BACKGROUND: Intractable neck and upper limb pain has historically been challenging to treat with conventional spinal cord stimulation (SCS) being limited by obtaining effective paresthesia coverage. OBJECTIVE: To assess the safety and effectiveness of the 10-kHz SCS system, a paresthesia-independent therapy, in the treatment of neck and upper limb pain. METHODS: Subjects with chronic, intractable neck and/or upper limb pain of ≥5 cm (on a 0-10 cm visual analog scale [VAS]) were enrolled in 6 US centers following an investigational device exemption from the Food and Drug Administration (FDA) and institutional review board approval. Each subject was implanted with 2 epidural leads spanning C2-C6 vertebral bodies. Subjects with successful trial stimulation were implanted with a Senza® system (Nevro Corp) and included in the evaluation of the primary safety and effectiveness endpoints. RESULTS: In the per protocol population, the primary endpoint (≥50% pain relief at 3 mo) was achieved in 86.7% (n = 39/45) subjects. Compared to baseline, subjects reported a significant reduction (P < .001) in their mean (± standard error of the mean) VAS scores at 12-mo assessment for neck pain (7.6 ± 0.2 cm, n = 42 vs 1.5 ± 0.3 cm, n = 37) and upper limb pain (7.1 ± 0.3 cm, n = 24 vs 1.0 ± 0.2 cm, n = 20). At 12-mo assessment, 89.2% of subjects with neck pain and 95.0% with upper limb pain had ≥50% pain relief from baseline, 95.0% reported to be "satisfied/very satisfied" and 30.0% either eliminated or reduced their opioid intake. CONCLUSION: In conclusion, 10-kHz SCS can treat intractable neck and upper limb pain with stable long-term outcomes.

Paresthesia-Independence: An Assessment of Technical Factors Related to 10 kHz Paresthesia-Free Spinal Cord Stimulation.

BACKGROUND: Spinal cord stimulation (SCS) has been successfully used to treat chronic intractable pain for over 40 years. Successful clinical application of SCS is presumed to be generally dependent on maximizing paresthesia-pain overlap; critical to achieving this is positioning of the stimulation field at the physiologic midline. Recently, the necessity of paresthesia for achieving effective relief in SCS has been challenged by the introduction of 10 kHz paresthesia-free stimulation. In a large, prospective, randomized controlled pivotal trial, HF10 therapy was demonstrated to be statistically and clinically superior to paresthesia-based SCS in the treatment of severe chronic low back and leg pain. HF10 therapy, unlike traditional paresthesia-based SCS, requires no paresthesia to be experienced by the patient, nor does it require paresthesia mapping at any point during lead implant or post-operative programming. OBJECTIVES: To determine if pain relief was related to technical factors of paresthesia, we measured and analyzed the paresthesia responses of patients successfully using HF10 therapy. STUDY DESIGN: Prospective, multicenter, non-randomized, non-controlled interventional study. SETTING: Outpatient pain clinic at 10 centers across the US and Italy. METHODS: Patients with both back and leg pain already implanted with an HF10 therapy device for up to 24 months were included in this multicenter study. Patients provided pain scores prior to and after using HF10 therapy. Each patient's most efficacious HF10 therapy stimulation program was temporarily modified to a low frequency (LF; 60 Hz), wide pulse width (~470 mus), paresthesia-generating program. On a human body diagram, patients drew the locations of their chronic intractable pain and, with the modified program activated, all regions where they experienced LF paresthesia. Paresthesia and pain drawings were then analyzed to estimate the correlation of pain relief outcomes to overlap of pain by paresthesia, and the mediolateral distribution of paresthesia (as a surrogate of physiologic midline lead positioning). RESULTS: A total of 61 patients participated across 11 centers. Twenty-eight men and 33 women with a mean age of 56 ± 12 years of age participated in the study. The average duration of implantable pulse generator (IPG) implant was 19 ± 9 months. The average predominant pain score, as measured on a 0 - 10 visual analog scale (VAS), prior to HF10 therapy was 7.8 ± 1.3 and at time of testing was 2.5 ± 2.1, yielding an average pain relief of 70 ± 24%. For all patients, the mean paresthesia coverage of pain was 21 ± 28%, with 43% of patients having zero paresthesia coverage of pain. Analysis revealed no correlation between percentage of LF paresthesia overlap of predominant pain and HF10 therapy efficacy (P = 0.56). Exact mediolateral positioning of the stimulation electrodes was not found to be a statistically significant predictor of pain relief outcomes. LIMITATIONS: Non-randomized/non-controlled study design; short-term evaluation; certain technical factors not investigated. CONCLUSION: Both paresthesia concordance with pain and precise midline positioning of the stimulation contacts appear to be inconsequential technical factors for successful HF10 therapy application. These results suggest that HF10 therapy is not only paresthesia-free, but may be paresthesia-independent.

Comparison of 10-kHz High-Frequency and Traditional Low-Frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: 24-Month Results From a Multicenter, Randomized, Controlled Pivotal Trial.

BACKGROUND: Pain relief with spinal cord stimulation (SCS) has focused historically on paresthesias overlapping chronically painful areas. A higher level evidence supports the use of SCS in treating leg pain than supports back pain, as it is difficult to achieve adequate paresthesia coverage, and then pain relief, in the low back region. In comparison, 10-kHz high-frequency (HF10 therapy) SCS therapy does not rely on intraoperative paresthesia mapping and remains paresthesia-free during therapy. OBJECTIVE: To compare long-term results of HF10 therapy and traditional low-frequency SCS. METHODS: A pragmatic randomized, controlled, pivotal trial with 24-month follow-up was conducted across 11 comprehensive pain treatment centers. Subjects had Visual Analog Scale scores of ≥5.0/10.0 cm for both back and leg pain, and were assigned randomly (1:1) to receive HF10 therapy or low-frequency SCS. The primary end point was a responder rate, defined as ≥50% back pain reduction from baseline at 3 months with a secondary end point at 12 months (previously reported). In this article, 24-month secondary results are presented. Non-inferiority was first assessed, and if demonstrated the results were tested for superiority. RESULTS: In the study, 198 subjects were randomized (101 HF10 therapy, 97 traditional SCS). One hundred seventy-one subjects (90 HF10 therapy, 81 traditional SCS) successfully completed a short-term trial and were implanted. Subjects averaged 54.9 ± 12.9 years old, 13.6 ± 11.3 years since diagnosis, 86.6% had back surgery, 88.3% were taking opioid analgesics. 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 < .001 for both back and leg pain comparisons, non-inferiority and superiority). At 24 months, more subjects were responders to HF10 therapy than traditional SCS (back pain: 76.5% vs 49.3%; 27.2% difference, 95% CI, 10.1%-41.8%; P < .001 for non-inferiority and superiority; leg pain: 72.9% vs 49.3%; 23.6% difference, 95% CI, 5.9%-38.6%; P < .001 for non-inferiority and P = .003 for superiority). Also at 24 months, back pain decreased to a greater degree with HF10 therapy (66.9% ± 31.8%) than traditional SCS (41.1% ± 36.8%, P < .001 for non-inferiority and superiority). Leg pain also decreased to a greater degree with HF10 therapy (65.1% ± 36.0%) than traditional SCS (46.0% ± 40.4%, P < .001 for non-inferiority and P = .002 for superiority). CONCLUSION: This study demonstrates long-term superiority of HF10 therapy compared with traditional SCS in treating both back and leg pain. The advantages of HF10 therapy are anticipated to impact the management of chronic pain patients substantially. ABBREVIATIONS: IPG, implantable pulse generatorMCID, minimal clinically important differencePI, permanent implantODI, Oswestry Disability IndexSCS, spinal cord stimulationVAS, Visual Analog Scale.

Peripheral Neurostimulation with a Microsize Wireless Stimulator.

Implementation of wireless technology enables tremendous reduction in the size of implantable neurostimulator devices. Without the need for tethering to an implantable pulse generator, a multitude of clinical applications can be envisioned, utilizing safe, rapidly implanted, economical, and culturally sensitive methods. External pulse generators providing power to implanted microsize wireless leads and/or contact pairs can be incorporated into belts, fabric, jewelry, and other suitable and convenient accoutrements. Microsized wireless neurostimulator lead placements can provide neuromodulation therapies without mechanically compromising normal physiological function in numerous anatomical locations not so accessible now. Avoiding implantation of the pulse generator dramatically reduces the expense of these therapies and can potentially lead to wider global access of care for neuromodulation in general.

Pulse width programming in spinal cord stimulation: a clinical study.

BACKGROUND: With advances in spinal cord stimulation (SCS) technology, particularly rechargeable implantable, patients are now being offered a wider range of parameters to treat their pain. In particular, pulse width (PW) programming ranges of rechargeable implantable pulse generators now match that of radiofrequency systems (with programmability up to 1000 microseconds. The intent of the present study was to investigate the effects of varying PW in SCS. OBJECTIVE: To understand the effects of PW programming in spinal cord stimulation (SCS). DESIGN: Single-center, prospective, randomized, single-blind evaluation of the technical and clinical outcomes of PW programming. SETTING: Acute, outpatient follow-up. METHODS: Subjects using fully-implanted SCS for > 3 months to treat chronic intractable low back and/or leg pain. Programming of a wide range (50-1000 microseconds) of programmed PW settings using each patient's otherwise unchanged 'walk-in' program. OUTCOME MEASURES: Paresthesia thresholds (perception, maximum comfortable, discomfort), paresthesia coverage and patient choice of tested programs. RESULTS: We found strength-duration parameters of chronaxie and rheobase to be 295 (242 - 326) microseconds and 2.5 (1.3 - 3.3) mA, respectively. The median PW of all patients' 'walk-out' programs was 400 microseconds, approximately 48% higher than median chronaxie (p = 0.01), suggesting that chronaxie may not relate to patient-preferred stimulation settings. We found that 7/19 patients selected new PW programs, which significantly increased their paresthesia-pain overlap by 56% on average (p = 0.047). We estimated that 10/19 patients appeared to have greater paresthesia coverage, and 8/19 patients appeared to display a 'caudal shift' of paresthesia coverage with increased PW. LIMITATIONS: Small number of patients. CONCLUSIONS: Variable PW programming in SCS appears to have clinical value, demonstrated by some patients improving their paresthesia-pain overlap, as well as the ability to increase and even 'steer' paresthesia coverage.