The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for Spinal Cord Stimulation Long-Term Outcome Optimization and Salvage Therapy.

INTRODUCTION: The International Neuromodulation Society (INS) has recognized a need to establish best practices for optimizing implantable devices and salvage when ideal outcomes are not realized. This group has established the Neurostimulation Appropriateness Consensus Committee (NACC)® to offer guidance on matters needed for both our members and the broader community of those affected by neuromodulation devices. MATERIALS AND METHODS: The executive committee of the INS nominated faculty for this NACC® publication on the basis of expertise, publications, and career work on the issue. In addition, the faculty was chosen in consideration of diversity and inclusion of different career paths and demographic categories. Once chosen, the faculty was asked to grade current evidence and along with expert opinion create consensus recommendations to address the lapses in information on this topic. RESULTS: The NACC® group established informative and authoritative recommendations on the salvage and optimization of care for those with indwelling devices. The recommendations are based on evidence and expert opinion and will be expected to evolve as new data are generated for each topic. CONCLUSIONS: NACC® guidance should be considered for any patient with less-than-optimal outcomes with a stimulation device implanted for treating chronic pain. Consideration should be given to these consensus points to salvage a potentially failed device before explant.

Targeted Nerve Root Stimulation Alleviates Intractable Chronic Limb Pain Associated with Complex Regional Pain Syndrome - A Prospective Multi-Center Feasibility Study.

BACKGROUND: There are limited therapeutic options to treat complex regional pain syndrome (CRPS). Spinal cord stimulation and dorsal root ganglion stimulation are proven therapies for treating chronic low limb pain in CRPS patients. There is limited evidence that stimulation of dorsal nerve roots can also provide relief of lower limb pain in these patients. OBJECTIVES: To demonstrate that electrical stimulation of dorsal nerve roots via epidural lead placement provides relief of chronic lower limb pain in patients suffering from CRPS. STUDY DESIGN: Prospective, open label, single arm, multi-center study. SETTING: The study was performed at the Center for Interventional Pain and Spine (Exton, PA), Millennium Pain Center (Bloomington, IL), and the Carolinas Pain Center (Huntersville, NC). It was approved by the Western Institutional Review Board-Copernicus Group Institutional Review Board and is registered at clinicaltrials.gov (NCT03954080). METHODS: Sixteen patients with intractable chronic severe lower limb pain associated with CRPS were enrolled in the study. A standard trial period to evaluate a patients' response to stimulation of the dorsal nerve roots was conducted over 3 to 10-days. Patients that obtained 50% or greater pain relief during the trial period underwent permanent implantation of a neurostimulation system. The primary outcome was the evaluated pain level after 3 months of device activation, based on NRS pain score relative to baseline. Patients were followed up for 6 months after activation of the permanently implanted system. RESULTS: At the primary endpoint, patients reported a significant (P = 0.0006) reduction in pain of 3.3 points, improvement in quality of life, improved neuropathic pain characteristics, improved satisfaction, and an overall perception of improvement with the therapy. Improvements were sustained throughout the duration of the study up to the final 6-month visit. LIMITATIONS: Due to the COVID-19 pandemic occurring during patient enrollment, only 16 patients were enrolled and trialed, with 12 being permanently implanted. Nine were able to complete the end of study evaluation at 6 months. CONCLUSIONS: The results of this short feasibility study confirm the functionality, effectiveness, and safety of intraspinal stimulation of dorsal nerve roots in patients with intractable chronic lower limb pain due to CRPS using commercially approved systems and conventional parameters.

Drug-Free Noninvasive Thermal Nerve Block: Validation of Sham Devices.

Headache is a leading cause of disability and suffering. One major challenge in developing device treatments is demonstrating their efficacy given devices' often-high placebo rate. This paper reviews the importance of validating sham devices as part of finalizing the design for larger-scale prospective randomized controlled trials in patients with chronic headache as well as the results of a prospective, single-blind trial to validate two potential sham noninvasive thermal nerve block devices. Study participants were trained to self-administer thermal nerve block treatment using sham devices in an office visit. Two different sham systems with different temperature profiles were assessed. Devices were offered for patients to use daily at-home for one week to assess the durability of sham placebo effects before participants were given active treatment in a second office visit followed by another optional week of self-administered active treatment at-home use. Sham treatments reduced pain scores by an average of 31% from 6.0 ± 2.3 to 4.3 ± 3.3, including two participants who fell asleep during the in-office treatment and woke up with no pain, but whose pain recurred after returning home during at-home use of the sham system. In-office active treatments reduced pain scores by 52% from 6.7 ± 2.1 to 3.3 ± 2.9 with sustained pain relief during optional at-home use. Successful blinding for the study was confirmed with an ideal Bang's Blinding Index of 0 and an ideal James' Blinding Index of 1. Both the sham and active treatments were viewed by participants as highly credible, and credibility increased from the beginning to end of sham treatments on average.

Objective wearable measures correlate with self-reported chronic pain levels in people with spinal cord stimulation systems.

Spinal Cord Stimulation (SCS) is a well-established therapy for treating chronic pain. However, perceived treatment response to SCS therapy may vary among people with chronic pain due to diverse needs and backgrounds. Patient Reported Outcomes (PROs) from standard survey questions do not provide the full picture of what has happened to a patient since their last visit, and digital PROs require patients to visit an app or otherwise regularly engage with software. This study aims to assess the feasibility of using digital biomarkers collected from wearables during SCS treatment to predict pain and PRO outcomes. Twenty participants with chronic pain were recruited and implanted with SCS. During the six months of the study, activity and physiological metrics were collected and data from 15 participants was used to develop a machine learning pipeline to objectively predict pain levels and categories of PRO measures. The model reached an accuracy of 0.768 ± 0.012 in predicting the pain intensity of mild, moderate, and severe. Feature importance analysis showed that digital biomarkers from the smartwatch such as heart rate, heart rate variability, step count, and stand time can contribute to modeling different aspects of pain. The results of the study suggest that wearable biomarkers can be used to predict therapy outcomes in people with chronic pain, enabling continuous, real-time monitoring of patients during the use of implanted therapies.

Differential target multiplexed spinal cord stimulator: a review of preclinical/clinical data and hardware advancement.

Spinal cord stimulation (SCS) is an effective neuromodulation technique for treating chronic neuropathic pain. Recent rapid growth in understanding its mechanism has led to the development of glial cell-based differential target multiplexed (DTM) stimulation and its derivative algorithm. Both preclinical research and clinical trials in humans showed superior pain relief using DTM SCS compared with traditional SCS. Another multicenter prospective clinical trial showed significant pain score reduction and energy saving using the DTM derivative algorithm. This review paper summarizes the evidence related to using DTM stimulation for other painful conditions such as nonsurgical low back pain and upper-limb pain. All these advanced programming options can be delivered using an innovative platform, the Medtronic Intellis™ neurostimulator.

Diagnosis, Treatment, and Management of Painful Scar: A Narrative Review.

Painful scars can develop after surgery or trauma, with symptoms ranging from a minor itch to intractable allodynia. The problem of the painful scar may involve both intraneural and extraneural structures, requiring a systematic approach to diagnosis and treatment of this neuropathic pain condition that can impact quality of life and function profoundly. In this review, we outline the algorithm for the diagnosis, management, medical and surgical treatment of painful scars.

Cross-Validation of the Foundation Pain Index with PROMIS-29 in Chronic Pain Patients.

PURPOSE: Discovery and validation of pragmatic biomarkers represent significant advancements in the field of pain management. Evaluating relationships between objective biomarkers and patient-reported outcomes (PROs) is an effective way to gain mechanistic insight into the potential role of biochemistry in chronic pain. The aim of this study was to validate the Foundation Pain Index (FPI) by evaluating associations between deranged biochemical function and PROMIS-29 domains in individuals living with chronic pain. PATIENTS AND METHODS: PROMIS-29 scores and FPI test results were obtained from 298 patients with chronic pain in this retrospective, observational study. Statistical analysis was performed using clinical test data to evaluate relationships between deranged biochemical function and quality of life measures across 8 universal domains. RESULTS: FPI scores significantly associated with multiple PROMIS-29 domains including physical function, impact score, fatigue, pain interference, and depression (P < 0.05). Moreover, specific analytes that comprise the FPI significantly correlated with PROMIS-29 domains, including 5-hydroxyindolacetic acid (pain interference, physical function, and pain impact scores), hydroxymethylglutarate (physical function), homocysteine (pain impact scores), kynurenic acid (pain interference and physical function), and quinolinic acid (physical function) (P < 0.05). CONCLUSION: Cross-validation of the FPI with PROMIS-29 domains further supports the role of deranged biochemical function in the etiology of chronic pain. Objective identification of atypical biochemical function and subsequent correction holds tremendous promise for the non-opioid management of pain. Continued research efforts will aim to determine the impact of biochemical optimization in pre-surgical periods and post-surgical outcomes in patients with chronic pain.

The Cost of Lost Productivity in an Opioid Utilizing Pain Sample.

BACKGROUND AND AIMS: Chronic pain affects more adults in the United States than any other condition. Opioid medications are widely used in the treatment of chronic pain, but there remains considerable risk and cost associated with their use. This study aims to characterize the effects of opioid prescribing for chronic pain and similar pain conditions on lost productivity in the United States. METHODS: This was a retrospective, longitudinal, observational study of chronic pain patients in 2011-2014. We identified patients with a diagnosis of musculoskeletal pain receiving index prescription for opioids in administrative claims and studied disability absence in a linked health and productivity management database. Patients were grouped as de novo and continued use opioid users before index, and by opioid dose in the year after index. Days of disability were compared before and after index with bootstrapping. Effect of opioid dose group on disability was evaluated with negative binomial regression. Lost productivity cost was compared before and after index. RESULTS: The cohort contained 16,273 de novo and 6604 continued use patients. On average, de novo patients used 24.8 days of disability after index, an increase of 18.3 more days compared to before (p < 0.001). Continued use patients used 30.7 days after index, 9 more days than before (p < 0.001). There was a dose-response relationship between dose group and days of disability in de novo patients (p < 0.001). The weighted-average cost per person of lost productivity was $4344 higher in the year after index compared to the year before. CONCLUSION: Opioid prescriptions for pain patients were associated with significant disability use and lost productivity costs. With the evolution of opioid-prescribing practices, CDC recommendations, and the HHS Pain Management Best Practices, there is opportunity to use alternative pain therapies without the risks of opioid-induced side effects to improve work productivity.

Temperature-Mediated Nerve Blocks in the Treatment of Pain.

PURPOSE OF REVIEW: Analgesic hot and cold temperatures have been used for both conservative and ablative therapies for millennia. There are well-known locoregional neurovascular changes associated with the application of heat or ice in the literature and in practice. The oscillation between heat and cold has recently been identified as a synergistic mechanism of action with early translational results in humans. RECENT FINDINGS: Recent mechanistic work in the feline model has demonstrated that a reliable, reversible nerve block can be achieved within a temperature range that is non-destructive (15-45°C). The underlying mechanism is a newly described hysteresis in the responsiveness of peripheral nerves to alternating thermal stimuli resulting in nerve blockade. Recently presented feasibility data reports positive results in subjects with occipital pain and peripheral scar pain in terms of pain and associated symptom improvement. Temperature-mediated changes in pain and sensation have been observed for hot and cold applications at a variety of temperatures. Recent insights into the synergy between preheating followed by cooling resulting in peripheral nerve fiber block has potential in a variety of conditions in which peripheral nerve etiology is noted. Recent findings in chronic headache patients report decreased pain and symptom improvement. Further studies are ongoing to understand the indications for this novel therapy.

Multicenter Retrospective Review of Safety and Efficacy of a Novel Minimally Invasive Lumbar Interspinous Fusion Device.

INTRODUCTION: Several treatment options exist for those with spinal stenosis, as well as degenerative changes. This series evaluates the use of an interspinous fixation (ISF) device as performed by interventional pain physicians. METHODS: This is a retrospective analysis identifying 32 patients with the diagnosis of lumbar degenerative disc disease with secondary diagnosis of lumbar spinal stenosis being treated with ISF with Aurora Spine Zip Interspinous Spacer. Serious adverse events, specifically nerve injury, hematoma, infection, and death, were analyzed quantitatively for reported complications within 90 days from the procedure. In addition, VAS was analyzed for patient reported outcomes. RESULTS: Adverse event rate was 0% with no incidences of reoperation, or device removal. Estimated blood loss was recorded as less than 50 cc for all patients. The preoperative pain assessment demonstrated an average pain score of 8.1 and a postoperative pain score of 2.65 equating to a percentage pain reduction of 67%. CONCLUSION: This case series demonstrates the success and safety of ISF being performed by interventional pain physicians in an outpatient setting. It is a valuable tool in the treatment of moderate to severe lumbar spinal stenosis and degenerative disc disease that has decreased morbidity and significant efficacy.

Cooperation, involuntary defection, and Polymorphic Evolutionary Games.

The subject of involuntary defection in the context of cycles of interaction approach to direct reciprocal cooperation was introduced some time ago (J. Theor. Biol., 242: 873-879). Current work is motivated by the subsequent accumulation of empirical evidence and the advances in the methodology of evolutionary games. In recent decades it become clear that individuals in many animal species vary consistently in their behavioral responses to specific challenges-animal personality. Moreover, these differences have a hereditary component. Finally, investigations into the effects of neuropeptides on behavior suggest that the variations in animal personalities involve polymorphisms based on non-Mendelian heritability within the neuropeptide signaling systems. The last observation suggests that animal personalities can be productively analyzed via Polymorphic Evolutionary Games, which allow us to add genetic model(s) to standard (phenotypic) evolutionary games. Such an analysis of reciprocal cooperation is the subject of the current paper. The results indicate that there is a marked difference between models that assume Mendelian vs. non-Mendelian inheritance of the pertinent traits. Monomorphic and polymorphic-Mendelian models predict pure-strategy (single phenotype) ESS, whereas the non-Mendelian genetic model predicts a mixed strategy ESS exhibiting all three phenotypes.

Long-Term Efficacy of a Novel Spinal Cord Stimulation Clinical Workflow Using Kilohertz Stimulation: Twelve-Month Results From the Vectors Study.

BACKGROUND AND OBJECTIVES: Multiple variables play a role in spinal cord stimulation (SCS) treatment outcomes, including patient anatomy, pain pattern, lead location, stimulation parameters, and so on. A wide range of stimulation parameters are considered safe and on-label, and as a result a growing number of new frequencies and frequency-combinations are being incorporated into standard practice. A standardized approach to therapy delivery may provide more consistent outcomes for more patients. The Vectors study evaluated whether there is significant sustained improvement in pain and functional outcomes when therapy is delivered using a standardized approach. MATERIALS AND METHODS: Vectors, a post-market, single-arm study evaluated the safety and efficacy of SCS with an implantable neurostimulator starting with 1 kHz stimulation, targeting the T9-T10 disc space following paresthesia mapping. Subjects with chronic intractable low back and leg pain (visual analogue scale [VAS] ≥ 50 mm) were enrolled. The primary endpoint was change in overall pain (VAS) at the three-month visit compared to baseline. Subjects were followed through 12 months. Secondary endpoints included changes in low back and leg pain, quality of life (European Quality of Life - Five Dimensions, EQ-5D-5L), disability (Oswestry Disability Index, ODI), individual subject goals, and subject satisfaction. RESULTS: There was a significant reduction in overall pain (VAS; 45.4 mm) through the three-month visit, which was sustained through 12 months. At 12 months, 79% of subjects had ≥50% improvement in at least one pain domain (overall, lowback or leg) with 85% of subjects reporting therapy satisfaction. There was a decrease in disability and an improvement in quality of life with 70% of subjects achieving a personal activity goal by the three-month visit. CONCLUSIONS: Long-term pain relief and improvement in quality of life and function were achieved when following a standardized workflow. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03345472.

Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and explain our current understanding of the clinical use of low-dose naltrexone in the treatment of chronic pain. RECENT FINDINGS: Recent pre-clinical uses and clinical studies further elucidate the use of low-dose naltrexone in the treatment of chronic pain. Low-dose naltrexone (LDN) has shown promise to reduce symptoms related to chronic pain conditions such as fibromyalgia, inflammatory bowel conditions, and multiple sclerosis. The mechanism of LDN appears to be modulation of neuro-inflammation, specifically, the modulation of the glial cells and release of inflammatory chemicals in the central nervous system. These effects appear to unique at low dosage compared to dosage for food and drug administration approved use for alcohol and opioid dependence. We review the evidence that LDN has shown more than promise and should be further investigated in clinical practice.

A Systematic Literature Review of Dorsal Root Ganglion Neurostimulation for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain. DESIGN: Grade the evidence for DRG stimulation. METHODS: An international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded 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: DRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies. CONCLUSIONS: Moderate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

Prospective, Multicenter Feasibility Study to Evaluate Differential Target Multiplexed Spinal Cord Stimulation Programming in Subjects With Chronic Intractable Back Pain With or Without Leg Pain.

OBJECTIVE: This prospective, open-label, multicenter study evaluated the feasibility of spinal cord stimulation (SCS) therapy programming for chronic low back pain that uses multiple electrical pulsed signals (Differential Target Multiplexed). METHODS: Twenty-five SCS candidates with low back pain equal to or greater than lower limb pain were enrolled at 7 sites in the United States. The subjects evaluated standard and Differential Target Multiplexed programs, each for 4 ± 1 days. A commercially available SCS trial system was used for standard SCS therapy programming. During the trialing of the multiplexed programs, implanted temporary leads were connected to an investigational external trial stimulator system. RESULTS: Twenty subjects concluded the study. The mean baseline numeric pain rating scale (NPRS) score for low back pain was 7.4, with a mean age of 62.4 years and mean pain duration of 18.0 years. Significant relief in back pain was observed for both treatments, with significantly better response with multiplexed programming. At the end of the trial period, subjects reported a reduction in their mean NPRS score from baseline to 4.2 after standard programming and to 2.4 after Differential Target Multiplexed programming. The difference between standard and multiplexed programming was significant. The responder rate for low back pain relief was 50% for standard programming and 80% for Differential Target Multiplexed programming. Eighty-five percent of subjects who evaluated both programming approaches preferred Differential Target Multiplexed SCS. CONCLUSION: In this difficult-to-treat patient population, subjects reported significant reduction in chronic back pain when using multiplexed programming. A randomized clinical trial is needed to confirm the results from this feasibility study.

Polymorphic Evolutionary Games and Non-Mendelian Genetics.

Classical evolutionary game theory (EGT) focuses on competition among phenotypes while assuming asexual transmission of these phenotypes to the next generation. However, phenotypic selection and sexual recombination are not necessarily mutually reinforcing in populations with sexual reproduction. In particular, it has been long known that some of the evolutionarily stable strategies derived by EGT methods cannot be achieved by sexually reproducing, real-world, populations. Thus, the recently formulated polymorphic evolutionary game theory (PEGT), which adds underlying genetics and sexual reproduction to evolutionary games, has the potential to revolutionize game theoretical modeling of coevolutionary processes. To illustrate the advantages of PEGT over classical EGT, I analyze two of the best known EGT models: Hawk/Retaliator/Dove and Defector/Tit-for-Tat/Altruist, by PEGT methods. I show that if one admits non-Mendelian genetics-common in heritable behavior, both of these games exhibit the properties of moderated aggression and conditional cooperation as components of population-level polymorphisms.

A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of spinal cord stimulation (SCS) for pain. DESIGN: Grade the evidence for SCS. METHODS: An international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year's duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded 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: SCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT). CONCLUSIONS: High-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.

Limited Access to On-Label Formulations of Buprenorphine for Chronic Pain as Compared with Conventional Opioids.

IMPORTANCE: Buprenorphine is a Schedule III analgesic that is recommended as the firstline long-acting opioid for the treatment of chronic pain due to its ceiling effect on respiratory depression, adverse effect profile, and analgesic efficacy. However, prescription drug coverage policies commonly require that patients try and fail multiple Schedule II conventional opioids before approval of on-label use of buprenorphine for chronic pain. DESIGN: A retrospective review was performed looking at coverage of buprenorphine in the forms of Butrans and Belbuca. Patient denial letters, web searches of insurance and pharmacy benefit managers (PBMs), and an online tool (formularylookup.com) were used to assess the coverage and availability of buprenorphine for chronic pain. RESULTS: Unrestricted access to Butrans was reported for 42% of commercial lives and 11% of Medicare lives in all locations. Unrestricted access to Belbuca was reported for 53% of commercial lives and 23% of Medicare lives in all locations. Oxycodone immediate-release has unrestricted access for 84% of commercial plans and 97% of Medicare plans. Morphine extended-release has unrestricted access for 62% of commercial lives and 65% of Medicare lives. CONCLUSIONS AND RELEVANCE: There are >17,000 prescription opioid-involved deaths each year in the United States. By substituting buprenorphine as the firstline treatment for chronic and even acute pain, there may be fewer prescribed conventional opioids in the United States. Schedule III buprenorphine formulations for chronic pain should be given unrestricted access for appropriate patients before considering a Schedule II opioid as a public health priority.