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.

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.

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.

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.

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.

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.

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.

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.

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.

Animal conflicts in diploid populations with sexual reproduction.

The classical, monomorphic, evolutionary games analyze competition among phenotypes while implicitly assuming monomorphic transmission of phenotypic attributes to successive generations. The recently formulated polymorphic evolutionary game theory (PEGT), which adds the underlying genetics and sexual reproduction to evolutionary games, has the potential to revolutionize game theoretical modeling of co-evolutionary processes. In this paper, I apply PEGT methods to the analysis of animal conflicts - the oldest, and one of the best-developed areas of evolutionary game modeling. Overall, the polymorphic results are consistent with the sequential assessment hypothesis. However, beyond the specific, the results indicate the need for a degree of caution applied to the existing evolutionary stability results - as the polymorphic analysis shows that monomorphic ESS can be destabilized by sexual recombination. Finally, due to the novelty of the analytical approach, I make a particular emphasis on methodology: in particular, demonstrating how to combine generation of pertinent phenotypes with genetic plausibility considerations in the design of PEGT models.

The Evolution of Neuromodulation in the Treatment of Chronic Pain: Forward-Looking Perspectives.

BACKGROUND: The field of neuromodulation is continually evolving, with the past decade showing significant advancement in the therapeutic efficacy of neuromodulation procedures. The continued evolution of neuromodulation technology brings with it the promise of addressing the needs of both patients and physicians, as current technology improves and clinical applications expand. DESIGN: This review highlights the current state of the art of neuromodulation for treating chronic pain, describes key areas of development including stimulation patterns and neural targets, expanding indications and applications, feedback-controlled systems, noninvasive approaches, and biomarkers for neuromodulation and technology miniaturization. RESULTS AND CONCLUSIONS: The field of neuromodulation is undergoing a renaissance of technology development with potential for profoundly improving the care of chronic pain patients. New and emerging targets like the dorsal root ganglion, as well as high-frequency and patterned stimulation methodologies such as burst stimulation, are paving the way for better clinical outcomes. As we look forward to the future, neural sensing, novel target-specific stimulation patterns, and approaches combining neuromodulation therapies are likely to significantly impact how neuromodulation is used. Moreover, select biomarkers may influence and guide the use of neuromodulation and help objectively demonstrate efficacy and outcomes.

Mechanism of Action in Burst Spinal Cord Stimulation: Review and Recent Advances.

OBJECTIVE: This is a comprehensive, structured review synthesizing and summarizing the current experimental data and knowledge about the mechanisms of action (MOA) underlying spinal cord stimulation with the burst waveform (as defined by De Ridder) in chronic pain treatment. METHODS: Multiple database queries and article back-searches were conducted to identify the relevant literature and experimental findings for results integration and interpretation. Data from recent peer-reviewed conference presentations were also included for completeness and to ensure that the most up-to-date scientific information was incorporated. Both human and animal data were targeted in the search to provide a translational approach in understanding the clinical relevance of the basic science findings. RESULTS/CONCLUSIONS: Burst spinal cord stimulation likely provides pain relief via multiple mechanisms at the level of both the spinal cord and the brain. The specific waveforms and temporal patterns of stimulation both play a role in the responses observed. Differential modulation of neurons in the dorsal horn and dorsal column nuclei are the spinal underpinnings of paresthesia-free analgesia. The burst stimulation pattern also produces different patterns of activation within the brain when compared with tonic stimulation. The latter may have implications for not only the somatic components of chronic pain but also the lateral and affective pathway dimensions as well.

Buprenorphine for Chronic Pain: a Systemic Review.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and explain our current understanding of the clinical use of buprenorphine in the treatment of chronic pain. RECENT FINDINGS: There has been few high-quality, unbiased studies performed on the use of buprenorphine in the treatment of chronic pain. Buprenorphine is an effective and safe analgesic that is tolerated at least as well, if not better, than other opioids. Given its safety and mechanistic advantages, the authors believe there is an important role for buprenorphine in the treatment of chronic pain severe enough to warrant the use of an opioid analgesic. Though data is lacking for superiority in chronic pain states, the other advantages of the molecule make it the preferential first-line opioid for around-the-clock pain in our practice.

Cannabis for Pain and Headaches: Primer.

PURPOSE OF REVIEW: Marijuana has been used both medicinally and recreationally since ancient times and interest in its compounds for pain relief has increased in recent years. The identification of our own intrinsic, endocannabinoid system has laid the foundation for further research. RECENT FINDINGS: Synthetic cannabinoids are being developed and synthesized from the marijuana plant such as dronabinol and nabilone. The US Food and Drug Administration approved the use of dronabinol and nabilone for chemotherapy-associated nausea and vomiting and HIV (Human Immunodeficiency Virus) wasting. Nabiximols is a cannabis extract that is approved for the treatment of spasticity and intractable pain in Canada and the UK. Further clinical trials are studying the effect of marijuana extracts for seizure disorders. Phytocannabinoids have been identified as key compounds involved in analgesia and anti-inflammatory effects. Other compounds found in cannabis such as flavonoids and terpenes are also being investigated as to their individual or synergistic effects. This article will review relevant literature regarding medical use of marijuana and cannabinoid pharmaceuticals with an emphasis on pain and headaches.

Polymorphic Evolutionary Games.

In this paper, I present an analytical framework for polymorphic evolutionary games suitable for explicitly modeling evolutionary processes in diploid populations with sexual reproduction. The principal aspect of the proposed approach is adding diploid genetics cum sexual recombination to a traditional evolutionary game, and switching from phenotypes to haplotypes as the new game׳s pure strategies. Here, the relevant pure strategy׳s payoffs derived by summing the payoffs of all the phenotypes capable of producing gametes containing that particular haplotype weighted by the pertinent probabilities. The resulting game is structurally identical to the familiar Evolutionary Games with non-linear pure strategy payoffs (Hofbauer and Sigmund, 1998. Cambridge University Press), and can be analyzed in terms of an established analytical framework for such games. And these results can be translated into the terms of genotypic, and whence, phenotypic evolutionary stability pertinent to the original game.

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.

Pollinators' mating rendezvous and the evolution of floral advertisement.

Successful cross-fertilization in plant species that rely on animal pollinators depends not just on the number of pollinator visits, but also on these visits' duration. Furthermore, in non-deceptive pollination, a visit's duration depends on the magnitude of the reward provided to the pollinator. Accordingly, plants that rely on biotic pollination have to partition their investment in cross-fertilization assurance between attracting pollinator visits - advertisement, and rewarding visitors to assure that the visit is of productive duration. Here we analyze these processes by a combination of optimality methods and game theoretical modeling. Our results indicate that the optimality in such allocation of resources depends on the types of reward offered to the pollinators. More precisely, we show that plants that offer both food reward and mating rendezvous to pollinators will evolve to allocate a higher proportion of their cross-fertilization assurance budget to advertisement than plants that offer only food reward. That is, our results indicate that pollinators' mating habits may play a role in floral evolution.

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.