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.

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.

Neuromodulation in Treating Pelvic Pain.

PURPOSE OF REVIEW: Chronic pelvic pain (CPP) is a complex condition that can be multifactorial, disabling, and difficult to treat. It is important to understand the various diagnoses and pathways that can be involved and have an understanding of the available treatment options. RECENT FINDINGS: There is a complex innervation of the pelvic region which makes its treatment very challenging. There are pathophysiological similarities of CPP to disease states like complex regional pain syndrome and sympathetically driven pain. CPP is poorly understood and includes psychological, psychosocial, cultural, and economic influences. Treatment options vary, but neuromodulation does remain a centerpiece and can include sacral stimulation, SCS, DRG stimulation, and PNS.

A Systematic Literature Review of Peripheral Nerve Stimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of peripheral nerve stimulation (PNS) for pain. DESIGN: Grade the evidence for PNS. METHODS: An international interdisciplinary work group conducted a literature search for PNS. Abstracts were reviewed to select studies for grading. Inclusion/exclusion criteria included prospective randomized controlled trials (RCTs) with meaningful clinical outcomes that were not part of a larger or previously reported group. Excluded studies were retrospective, had less than two months of follow-up, or existed only as abstracts. Full studies were graded by two independent reviewers using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: Peripheral nerve stimulation was studied in 14 RCTs for a variety of painful conditions (headache, shoulder, pelvic, back, extremity, and trunk pain). Moderate to strong evidence supported the use of PNS to treat pain. CONCLUSION: Peripheral nerve stimulation has moderate/strong evidence. Additional prospective trials could further refine appropriate populations and pain diagnoses.

Neurostimulation for the Treatment of Chronic Head and Facial Pain: A Literature Review.

BACKGROUND: Head and facial pain is a common and often difficult to treat disorder. Routine treatments sometimes fail to provide acceptable relief, leaving the patient searching for something else, including narcotics and surgery. Recently, neuromodulation has been expanding to provide another option. Secondary to its potentially temporary nature and relatively manageable risk profile, several reviews have suggested trialing neuromodulation prior to starting narcotics or invasive permanent surgeries. There is evidence that neuromodulation can make a difference in those patients with intractable severe craniofacial pain. OBJECTIVES: To provide a basic overview of the anatomy, epidemiology, pathophysiology and common treatments of several common head and facial disorders. Furthermore, to demonstrate the suggested mechanisms of neuromodulation and the evidence currently existing for the use of neuromodulation. METHODS: A comprehensive review was performed regarding the available literature through targeting articles reporting on the use of neuromodulation to treat pain of the head and face. RESULTS: We compiled and discuss the current evidence available in treating head and facial pain. The strongest evidence currently for neuromodulation is for occipital nerve stimulation for migraine, transcutaneous vagal nerve stimulation for migraine and cluster headache, sphenopalatine ganglion microstimulation for cluster headache, and transcutaneous supraorbital and supratrochlear nerve stimulation for migraine. In addition, there is moderate evidence for occipital nerve stimulation in treating occipital neuralgia. LIMITATIONS: Neuromodulation has been trialed and is promising in several craniofacial pain disorders; however, there remains a need for large-scale, randomized, placebo-controlled clinical trials to further evaluate the efficacy and safety of most treatments. Much of the current data relies on case reports without randomization or placebo controls. CONCLUSIONS: With advancing techniques and technology, neuromodulation can be promising in treating intractable pain of the head and face. Although more randomized controlled trials are warranted, the current literature supports the use of neuromodulation in intractable craniofacial pain. KEY WORDS: Neuromodulation, headache, facial pain, craniofacial pain, migraine, cluster headache, trigeminal neuralgia, occipital neuralgia, peripheral nerve stimulator, high cervical spinal cord stimulator, peripheral nerve field stimulator.

Neuromodulation of the Dorsal Root Ganglion for Chronic Postsurgical Pain.

OBJECTIVE: The objective of this study is to review the available evidence for dorsal root ganglion (DRG) stimulation for the treatment of complex regional pain syndrome type II (CRPS II; peripheral causalgia) associated with chronic neuropathic postsurgical pain (NPP). DESIGN: Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from published articles also were reviewed for relevant citations. RESULTS: The data published to date support the use of DRG stimulation to treat chronic NPP of the groin, knee, and foot. NPP following procedures such as thoracotomy, hernia surgery, and knee replacement surgery were identified as some of the conditions for which DRG stimulation is likely to be effective. CONCLUSION: DRG stimulation is known to be an effective treatment for focal neuropathic pain. Currently, NPP of the foot, groin, and knee all appear to be the conditions with the most clinical experience, backed by a limited but growing body of evidence. However, prospective studies lag behind real-world clinical experience and are needed to confirm these findings.

DRG FOCUS: A Multicenter Study Evaluating Dorsal Root Ganglion Stimulation and Predictors for Trial Success.

INTRODUCTION: Dorsal root ganglion stimulation (DRGS) is a powerful tool in the treatment of chronic, neuropathic pain. The premise of DRGS is similar to that of conventional spinal cord stimulation (cSCS), however, there is more variability in how it can be utilized. While it is this variability that likely gives it its versatility, DRGS is not as straightforward to implement as cSCS. The purpose of this study was to assess the efficacy of DRGS on a broad number of diagnoses, determine which dorsal root ganglia were associated with better outcomes for particular body parts/diagnoses, and evaluate what factors/parameters were associated with higher rates of trial success. METHODS: This is a physician initiated, multicenter retrospective registry of 217 patients trialed with DRGS. Data were collected via an online questionnaire that assessed specifics regarding the patient's pain, distribution, size, and response to treatment. The data were analyzed to see if there were certain diagnoses and/or parameters that were more or less associated with trial success. RESULTS: DRGS was found to be an effective treatment in all diagnoses evaluated within this study, most of which had statistically significant improvements in pain. The most important predictor of trial success was the amount of painful area covered by paresthesias during the programing phase. The number of leads utilized had a direct and indirect impact on trial success. Pain in the distribution of a specific peripheral nerve responded best and there was no statistical difference based on what body part was being treated. CONCLUSION: DRGS can be an effective treatment for a variety of neuropathic pain syndromes, in addition to CRPS. It is recommended that a minimum of 2 leads should be utilized per area being treated. In addition, this therapy was shown to be equally efficacious in any body part/region so long as the area being treated is focal and not widespread.

Dorsal Root Ganglion Stimulation for Chronic Pelvic Pain: A Case Series and Technical Report on a Novel Lead Configuration.

INTRODUCTION: Chronic pelvic pain (CPP) is an elusive and complex neuropathic condition that is notoriously recalcitrant to treatment. The term "CPP" encompasses a number of treatment-resistant conditions like pudendal neuralgia, interstitial cystitis, coccygodynia, vulvodynia. CPP has been presented neuromodulators attempting to utilize conventional spinal cord stimulation (SCS), with constant frustration and high explant rates. Contrary to SCS, dorsal root ganglion stimulation (DRGS) delivers targeted target to focal areas, does not rely on paresthesias, and is able to reliably capture body parts like the pelvis making it an ideal modality for the treatment of CPP. We present seven patients with intractable CPP, resistant to conventional treatment methods, all successfully treated with DRGS. METHODS: The case series includes seven patients with severe, CPP who failed to respond to a variety interventional treatments, and in some cases SCS. All seven patients were successfully trialed with DRGS utilizing leads placed over the bilateral L1 and S2 DRG's-to our knowledge, no publications describing either this particular lead configuration, or utilizing DRG stimulation on CPP, exist. RESULTS: Following treatment, all seven patients experienced significant pain relief as well as reduction in opioid consumption and some cases improvement with sexual function and urination. Four of these patients have been implanted and continue to self-report sustained pain relief with high-satisfaction and functional improvement. To date no explants or instances of loss of efficacy have occurred (>1 year since implant). CONCLUSION: Like most neuropathic pain states, CPP is resilient, difficult to manage, and typically unresponsive to the traditional therapeutics and SCS. Our case series demonstrates no only that DRGS is potentially effective, long-term treatment modality for CPP, but that the L1/S2 lead placement is the configuration of choice despite distinct differences in etiologies of pain and location.

Dorsal Root Ganglion Stimulation as a Salvage Treatment for Complex Regional Pain Syndrome Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series.

OBJECTIVE: The efficacy of traditional spinal cord stimulation (t-SCS) tends to decay over time in patients with complex regional pain syndrome (CRPS). While it has been shown that dorsal root ganglion (DRG) stimulation is extremely effective in t-SCS-naïve patients with CRPS, its efficacy in patients who had previously failed t-SCS is unknown. Given that DRG-SCS and t-SCS target different spinal pathways, a failure with t-SCS should not automatically preclude a patient from attempting DRG-SCS. MATERIALS AND METHODS: Two patients with lower extremity CRPS, previously implanted with t-SCS systems, experienced relapses in the pain despite exhaustive reprogramming. Both patients were offered DRG stimulation as a means to salvage treatment. RESULTS: Patient 1 reported 90% pain reduction with significant gait improvement during the DRG stimulation trial. The patient subsequently proceeded to implant and have the t-SCS implantable pulse generator explanted. Patient 2 was unable to undergo a trial with DRG-SCS because of health insurance constraints, so she elected to undergo a surgical revision of her existing system whereby a DRG-SCS system was added to the existing t-SCS to create a hybrid system with two implantable pulse generators. The patient reported an immediate improvement in pain because of the introduction of the DRG-SCS. Additionally, she was instructed to document her pain scores with each system on individually, as well as with both on-her pain scores were at the lowest with the DRG-SCS on by itself. At eight-month follow-up, both patients reported sustained pain improvement and retained their functional gains. CONCLUSIONS: Our case series demonstrates that a failure of t-SCS is not necessarily a failure of neurostimulation as a whole. The efficacy of DRG-SCS is independent of prior t-SCS therapy outcomes in these two patients and a history of t-SCS failure serves no predictive value in these two patients for future DRG stimulation success. Therefore, DRG-SCS can be considered as a reasonable next-step to salvage patients with CRPS who had failed other SCS treatments.