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.

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.

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.

Clinical Longevity of 106,462 Rechargeable and Primary Cell Spinal Cord Stimulators: Real World Study in the Medicare Population.

INTRODUCTION: Spinal cord stimulators (SCS) are available with either primary cell (PC) or rechargeable cell (RC) batteries. Although RC systems are proposed to have a battery longevity upward of nine years, in comparison with four years for PC systems, there are few studies of longevity of SCS in the real world. MATERIALS AND METHODS: This was an observational, nonrandomized, retrospective study of Medicare beneficiaries who received neurostimulator implants in the outpatient hospital. This study used Medicare fee-for-service claims data from 2013 to 2020. The clinical longevity of the implantable pulse generator (IPG), defined as the duration from implant until removal for any reason, was compared between PC and RC devices. Life distribution analysis was used to approximate device lifespan. The secondary analysis separated removals into explant or replacements. The statistics were adjusted for relevant clinical covariates. RESULTS: A total of 25,856 PC and 79,606 RC systems were included in the study. At seven years after implant, 53.8% of PC IPGs and 55.0% of RC IPGs remained in use. The life distribution modeling analysis projected a median lifespan of 8.2 years for PC and 9.0 years for RC devices. The rate of explant was lower for PC devices (19.2%) than for RC devices (22.0%, hazard ratio (HR) = 0.96, p = 0.082), whereas the rate of replacements was higher for PC devices (33.7%) than for RC devices (29.5%, HR = 1.31, p < 0.001). An analysis of the battery type used in device replacements showed an increasing adoption of PC devices over time. CONCLUSIONS: This large, retrospective, real-world analysis of Medicare claims data demonstrated that the clinical longevity of neurostimulator devices is similar for PC and RC batteries. In the past, clinicians may have defaulted to RC devices based on the assumption that they provided extended battery life. Considering this longevity data, clinicians should now consider the choice between PC and RC devices based on other individual factors pertinent to the patient experience and not on purported longevity claims.

Early US Experience With Stimulation of the Dorsal Root Ganglia for the Treatment of Peripheral Neuropathy in the Lower Extremities: A Multicenter Retrospective Case Series.

BACKGROUND: Peripheral neuropathy is a chronic pain disorder involving physical, chemical, or metabolic damage to peripheral nerves. Its pain can be intense and disabling. Dorsal root ganglion (DRG) stimulation is an effective treatment for neuropathic pain, including cases with the limited regional distributions that often characterize peripheral neuropathy. METHODS: A retrospective analysis was completed. Patients were included on the basis of having chronic intractable peripheral neuropathy of the legs and/or feet and responding successfully to a trial of DRG stimulation with leads at L4-S1. Visual analog scale pain scores and pain medication usage were collected at the baseline visit and after six weeks of treatment. Eight consecutive patients across two study centers were included (7 male, 1 female; mean age: 64.8 ± 10.2 years). Six cases of neuropathy were bilateral and two were unilateral. One patient presented with chronic radiculopathy, two patients had neuropathy associated with diabetes, and five patients had neuropathy not associated with a diabetes history. RESULTS: The pain was rated 7.38 ± 0.74 at baseline and decreased to 1.50 ± 1.31 at the 6-week follow-up, a reduction of 79.5 ± 18.8%. For individual patients, pain relief ranged from 42.86% to 100.00%; two patients experienced complete elimination of pain while seven of the eight patients experienced greater than 50% pain relief. In addition, three patients significantly decreased their pain medication use and four were able to discontinue their medications entirely. CONCLUSION: This small multicenter retrospective case series provides preliminary evidence that the painful symptoms of general peripheral neuropathy in the lower extremities, as well as associated pain medication usage, can be effectively managed by DRG stimulation at the L4-S1 spinal level. Importantly, this treatment appears efficacious for peripheral neuropathy.

The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes. METHODS: The NACC performed a comprehensive literature search of articles about DRG published from 1995 through June, 2017. A total of 2538 article abstracts were then reviewed, and selected articles graded for strength of evidence based on scoring criteria established by the US Preventive Services Task Force. Graded evidence was considered along with clinical experience to create the best practices consensus and recommendations. RESULTS: The NACC achieved consensus based on peer-reviewed literature and experience to create consensus points to improve patient selection, guide surgical methods, improve post-operative care, and make recommendations for management of patients treated with DRG stimulation. CONCLUSION: The NACC recommendations are intended to improve patient care in the use of this evolving therapy for chronic pain. Clinicians who choose to follow these recommendations may improve outcomes.

Evaluation of Abbott's BurstDR stimulation device for the treatment of chronic pain.

INTRODUCTION: Burst stimulation, as described by DeRidder, is a novel waveform made up of closely spaced, high-frequency electrical impulses delivered in packets, which are followed by a quiescent period or interburst interval. Electrically generated burst waveforms were initially designed to treat neural pathology in the auditory cortex and were later applied to the spinal cord through spinal cord stimulation (SCS) devices to treat chronic pain states. When Burst stimulation is applied to the spinal cord, the impulses travel to the thalamus and then diverge, targeting both the somatosensory cortex and the limbic system where they treat both the sensory, affective and attentional components of neuropathic pain. Areas covered: Literature examining clinical and basic research findings with the application of Burst stimulation to pathologically active central neural tissue was found using bibliographic databases including PubMed, Medline, Cochrane, Embase and Google Scholar. Expert commentary: Burst stimulation offers a salvage strategy for failed tonic spinal cord stimulation (tSCS), thus improving both quality of life and cost-effectiveness of SCS by reducing explant rates. The goal of this therapy is to use more than one waveform in the same device so that lost efficacy from tSCS can be salvaged.

The Neurostimulation Appropriateness Consensus Committee (NACC): Recommendations on Bleeding and Coagulation Management in Neurostimulation Devices.

INTRODUCTION: The Neurostimulation Appropriateness Consensus Committee (NACC) was formed by the International Neuromodulation Society (INS) in 2012 to evaluate the evidence to reduce the risk of complications and improve the efficacy of neurostimulation. The first series of papers, published in 2014, focused on the general principles of appropriate practice in the surgical implantation of neurostimulation devices. The NACC was reconvened in 2014 to address specific patient care issues, including bleeding and coagulation. METHODS: The INS strives to improve patient care in an evidence-based fashion. The NACC members were appointed or recruited by the INS leadership for diverse expertise, including international clinical expertise in many areas of neurostimulation, evidence evaluation, and publication. The group developed best practices based on peer-reviewed evidence and, in the absence of specific evidence, on expert opinion. Recommendations were based on international evidence in accordance with guideline creation. CONCLUSIONS: The NACC has recommended specific measures to reduce the risk of bleeding and neurological injury secondary to impairment of coagulation in the setting of implantable neurostimulation devices in the spine, brain, and periphery.

The Neurostimulation Appropriateness Consensus Committee (NACC) Recommendations for Infection Prevention and Management.

INTRODUCTION: The use of neurostimulation for pain has been an established therapy for many decades and is a major tool in the arsenal to treat neuropathic pain syndromes. Level I evidence has recently been presented to substantiate the therapy, but this is balanced against the risk of complications of an interventional technique. METHODS: The Neurostimulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society convened an international panel of well published and diverse physicians to examine the best practices for infection mitigation and management in patients undergoing neurostimulation. The NACC recommendations are based on evidence scoring and peer-reviewed literature. Where evidence is lacking the panel added expert opinion to establish recommendations. RESULTS: The NACC has made recommendations to improve care by reducing infection and managing this complication when it occurs. These evidence-based recommendations should be considered best practices in the clinical implantation of neurostimulation devices. CONCLUSION: Adhering to established standards can improve patient care and reduce the morbidity and mortality of infectious complications in patients receiving neurostimulation.

The Neurostimulation Appropriateness Consensus Committee (NACC) Safety Guidelines for the Reduction of Severe Neurological Injury.

INTRODUCTION: Neurostimulation involves the implantation of devices to stimulate the brain, spinal cord, or peripheral or cranial nerves for the purpose of modulating the neural activity of the targeted structures to achieve specific therapeutic effects. Surgical placement of neurostimulation devices is associated with risks of neurologic injury, as well as possible sequelae from the local or systemic effects of the intervention. The goal of the Neurostimulation Appropriateness Consensus Committee (NACC) is to improve the safety of neurostimulation. METHODS: The International Neuromodulation Society (INS) is dedicated to improving neurostimulation efficacy and patient safety. Over the past two decades the INS has established a process to use best evidence to improve care. This article updates work published by the NACC in 2014. NACC authors were chosen based on nomination to the INS executive board and were selected based on publications, academic acumen, international impact, and diversity. In areas in which evidence was lacking, the NACC used expert opinion to reach consensus. RESULTS: The INS has developed recommendations that when properly utilized should improve patient safety and reduce the risk of injury and associated complications with implantable devices. CONCLUSIONS: On behalf of INS, the NACC has published recommendations intended to reduce the risk of neurological injuries and complications while implanting stimulators.

Clinical Uses of Intrathecal Therapy and Its Placement in the Pain Care Algorithm.

Intrathecal drug delivery is an effective treatment option for patients with severe chronic pain who have not obtained adequate analgesia from more conservative therapies (eg, physical therapy, systemic opioids, nonsteroidal anti-inflammatory drugs, antidepressants, and anticonvulsants). This review focuses on, but is not limited to, the 2 agents currently approved by the U.S. Food and Drug Administration for intrathecal analgesia: preservative-free morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker). We describe the appropriate use of intrathecal therapy in the management of severe chronic pain, based on current best practices. Topics addressed here include patient selection, trialing, dosing and titration, adverse event profiles, long-term management, intrathecal therapy for cancer-related pain, and the placement of intrathecal therapy in the pain care algorithm. In appropriately selected patients with chronic pain, intrathecal therapy can provide substantial pain relief with improved functioning and quality of life. Successful long-term management requires ongoing patient monitoring for changes in efficacy and the occurrence of adverse events, with subsequent changes in intrathecal dosing and titration, the addition of adjuvant intrathecal agents, and the use of concomitant oral medications to address side effects, as needed. Based on an infrequent but clinically concerning risk of overdose, granuloma, and other opioid-induced complications, nonopioid therapy with ziconotide may be preferred as a first-line intrathecal therapy in patients without a history of psychosis or allergy.

The Proper Use of Neurostimulation for Hand Pain.

Upper extremity neuropathic pain states greatly impact patient functionality and quality of life, despite appropriate surgical intervention. This article focuses on the advanced therapies that may improve pain care, including advanced treatment strategies that are available. The article also surveys therapies on the immediate horizon, such as spinal cord stimulation, peripheral nerve stimulation, and dorsal root ganglion spinal cord stimulation. As these therapies evolve, so too will their placement within the pain care algorithm grounded by a foundation of evidence to improve patient safety and management of patients with difficult neuropathic pain.

Peripheral Nerve Stimulation for Pain in Extremities: An Update.

Pain in extremities may occur in a variety of central and peripheral neuropathic and nociceptive syndromes, some of which may respond to central neuromodulation procedures. Peripheral neuromodulation techniques, either as a stand-alone therapy or as an adjuvant to spinal cord stimulation, may be particularly effective when the pain is localized to a part of a single extremity or when the source of the pain is related to the malfunction of a known peripheral nerve. Further, peripheral neuromodulation is used to treat disorders in which central simulation fails to provide discrete therapeutic paresthesia. Despite the fact that there are only a few neuromodulatory devices designed specifically for the periphery, clinical experiences are growing, and here we provide a clinical update on use of peripheral nerve stimulation (PNS) in management of chronic pain in extremities. Historical PNS strategies and innovative methods are reviewed and highlighted in this chapter. With the upcoming technological advances and new stimulation paradigms, along with clear updated guidelines statements, the utilization of PNS will likely continue to increase and improve the management of chronic pain syndromes in the extremities. The potential success of the novel devices specifically designed to target the peripheral nervous system is expected to positively impact and promote the use of PNS in treatment of chronic pain.

A systematic review: current and future directions of dorsal root ganglion therapeutics to treat chronic pain.

OBJECTIVE: The purpose of the study was to systematically review the historical therapeutics for chronic pain care directed at the dorsal root ganglion (DRG) and to identify future trends and upcoming treatment strategies. METHODS: A literature search on bibliographic resources, including EMBASE, PubMed Cochrane Database of Systemic Reviews from literature published from 1966 to December 1, 2012 to identify studies and treatments directed at the DRG to treat chronic pain, and was limited to the English language. Case series, case reports, and preclinical work were excluded. Information on emerging technologies and pharmacologics were captured separately, as they did not meet the inclusion criteria. RESULTS: The literature review yielded three current clinical treatment strategies: ganglionectomy, conventional radiofrequency treatment of the dorsal root ganglion, and pulsed radiofrequency treatment of the DRG. Seven studies were identified utilizing ganglionectomy, 14 for conventional radiofrequency, and 16 for pulsed radiofrequency. Electrical stimulation and novel therapeutic delivery strategies have been proposed and are in development. CONCLUSIONS: Despite a robust understanding of the DRG and its importance in acute nociception, as well as the development and maintenance of chronic pain, relatively poor evidence exists regarding current therapeutic strategies. Novel therapies like electrical and pharmacologic strategies are on the horizon, and more prospective study is required to better qualify the role of the DRG in chronic pain care.

Accidental subdural spinal cord stimulator lead placement and stimulation.

OBJECTIVES: Neuromodulation with spinal cord stimulation has become an increasingly employed intervention for treatment of a variety of neuropathic pain states. As prevalence increases, so does the incidence of complications. Currently, there is sparse literature describing spinal cord stimulation lead placement and stimulation characteristics in the subdural space. In this case report we describe subdural lead placement and the associated stimulation parameters, and provide evidence-based support to initiate a dialog to further reduce procedural morbidity and mortality. MATERIALS AND METHODS: This study is a case report following lead placement during permanent percutaneous spinal cord stimulator placement and stimulation testing. The lead placement and stimulation characteristics were suggestive of extra-epidural lead placement. RESULTS: Using the same cathode/anode configuration (1:anode, 3:cathode, 5:anode), frequency of 40 Hz and pulse width of 650 microseconds, sequential stimulation was performed. Summarizing, the testing demonstrated similar impedance for the left and right leads (within 30 ohms) of approximately 300 ohms, and a large discrepancy in current of 3.2 mA for the left and 0.9 mA for the right. The patient reported "painful intense" stimulation with right lead stimulation. CONCLUSIONS: Evidence suggesting subdural lead placement include the lack of cerebrospinal-fluid despite lavage, the absence of post-dural puncture headache, the recent evidence of intentional and reproducible subdural anesthesia, and the conductive properties of the dural spinal elements. It can be argued that subdural lead placement may occur unrecognized more frequently than originally anticipated.