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

PP2A phosphatase suppresses function of the mesenchymal invasion regulator NEDD9

The mesenchymal mode of cancer cell invasion characterized by active adhesion turnover and a polarized actin cytoskeleton, is critically regulated by the adaptor protein NEDD9/HEF1/Cas-L. While it is known that NEDD9 is subject to extensive phosphorylation modification, the molecules that determine NEDD9 phosphorylation to stimulate adhesion turnover and mesenchymal cell morphologies are currently unknown. Earlier studies have suggested that the serine/threonine phosphatase PP2A regulates interconversion between a low molecular mass NEDD9 phosphoform and higher molecular mass phosphoforms. However, previous studies have used chemical inhibitors to block PP2A activity. In the present study we therefore aimed to specifically inhibit PP2A activity via siRNA and dominant negative approaches to investigate the effect of PP2A on interconversion between 115. kDa and 105. kDa NEDD9 and determine the functional consequence of PP2A activity for NEDD9 function. Strikingly, we find that while the phosphatase inhibitor Calyculin A indeed abrogates detachment-induced dephosphorylation of the 115. kDa NEDD9 phosphoform, PP2A depletion does not inhibit 115. kDa to 105. kDa interconversion. Our data suggest instead that PP2A targets discrete NEDD9 phosphorylation modifications separate to the events that mediate interconversion between the two forms. Functionally, PP2A depletion increases NEDD9 mediated cell spreading and mutation of S369 in the serine-rich region of NEDD9 to aspartate mimics this effect. Importantly, mutation of S369 to alanine abrogates the ability of dominant negative PP2A to increase NEDD9-mediated cell spreading. Collectively, our data reveal that the tumour suppressor PP2A may act via S369 to regulated NEDD9-mediated cell spreading. © 2011

Pulse Dosing of 10 kHz Paresthesia-Independent Spinal Cord Stimulation Provides Same Efficacy with Substantial Reduction of Device Recharge Time.

OBJECTIVE: This study was designed to assess whether using pulse dosing (PD: regularly-cycled intermittent stimulation) of high-frequency 10 kHz spinal cord stimulation (10kHzSCS) can reduce device recharge time while maintaining efficacy in patients with chronic intractable back pain with/without leg pain. DESIGN: Prospective, multi-center, observational study. METHODS: Patients successfully using 10kHzSCS at 100%ON (no PD) for \u3e3-months were consecutively enrolled. After a 1-week Baseline period of documenting their pain twice-daily using a 0-10 numerical rating scale (NRS) using 100%ON of their favorite program, all subjects were reprogrammed to 14%PD for 10-14 days. If subjects preferred 14%PD to 100%ON, they were programmed to 3%PD; otherwise, they were programmed to 50%PD. Subjects used this next program for another 10-14 days. Subjects then entered a 3-month observational period where they were requested but not limited to use their most preferred %PD program. Towards the end of 3-months, subjects completed a 7-day NRS diary and indicated a final %PD program preference. Study endpoints included %PD preference, mean diary NRS by %PD, and daily minutes and patterns of charging. RESULTS: Of 31 subjects completing the study, 81% preferred less than 100%ON. Preferences: 39% subjects preferred 3%PD, 32% preferred 14%PD, 10% preferred 50%PD, and 19% preferred 100%ON. Average daily charge durations: 3%PD = 8.3 ± 3.1 min, 14%PD = 13.9 ± 4.9 min, 50% PD = 26.2 ± 7.4 min, 100%ON = 43.8 ± 10.9 min. Regression modeling suggested pain relief was weighted more than twice as influential as charging in preference for reduced %PD. CONCLUSIONS: This prospective study suggests that 10kHzSCS therapy with PD may be successfully employed in a large majority of 10kHzSCS responders, maintaining efficacy while reducing device charging time by nearly two-thirds

Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A

Background: ß-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described <i>in vitro</i>. Objective: We sought to elucidate the molecular mechanisms by which ß-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B-exacerbated allergic airways disease (AAD). Methods: Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]). Results: Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor κB subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A <i>in vitro</i> isolated from human airway epithelial cells. Conclusions: Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits

Best Practices from the American Society of Pain and Neuroscience (ASPN) for Clinical Research During a Pandemic or Emergency

The COVID-19 pandemic caught many areas of medicine in a state of unpreparedness for conducting research and completing ongoing projects during a global crisis, including the field of pain medicine. Waves of infection led to a disjointed ability to provide care and conduct clinical research. The American Society of Pain and Neuroscience (ASPN) Research Group has created guidance for pragmatic and ethical considerations for research during future emergency or disaster situations. This analysis uses governmental guidance, scientific best practices, and expert opinion to address procedure-based or device-based clinical trials during such times. Current literature offers limited recommendations on this important issue, and the findings of this group fill a void for protocols to improve patient safety and efficacy, especially as we anticipate the impact of future disasters and spreading global infectious diseases. We recommend local adaptations to best practices and innovations to enable continued research while respecting the stressors to the research subjects, investigator teams, health-care systems, and to local infrastructure

Best Practices from the American Society of Pain and Neuroscience (ASPN) for Clinical Research During a Pandemic or Emergency

The COVID-19 pandemic caught many areas of medicine in a state of unpreparedness for conducting research and completing ongoing projects during a global crisis, including the field of pain medicine. Waves of infection led to a disjointed ability to provide care and conduct clinical research. The American Society of Pain and Neuroscience (ASPN) Research Group has created guidance for pragmatic and ethical considerations for research during future emergency or disaster situations. This analysis uses governmental guidance, scientific best practices, and expert opinion to address procedure-based or device-based clinical trials during such times. Current literature offers limited recommendations on this important issue, and the findings of this group fill a void for protocols to improve patient safety and efficacy, especially as we anticipate the impact of future disasters and spreading global infectious diseases. We recommend local adaptations to best practices and innovations to enable continued research while respecting the stressors to the research subjects, investigator teams, health-care systems, and to local infrastructure

The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity

Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)– and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma

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

A Novel Pulsed Stimulation Pattern in Spinal Cord Stimulation: Clinical Results and Postulated Mechanisms of Action in the Treatment of Chronic Low Back and Leg Pain

OBJECTIVES: The aim of this article is to discuss the possible mechanisms of action (MOAs) and results of a pilot study of a novel, anatomically placed, and paresthesia-independent, neurostimulation waveform for the management of chronic intractable pain. MATERIALS AND METHODS: A novel, multilayered pulsed stimulation pattern (PSP) that comprises three temporal layers, a Pulse Pattern layer, Train layer, and Dosage layer, was developed for the treatment of chronic intractable pain. During preliminary development, the utility was evaluated of anatomical PSP (aPSP) in human subjects with chronic intractable pain of the leg(s) and/or low back, compared with that of traditional spinal cord stimulation (T-SCS) and physiological PSP. The scientific theory and testing presented in this article provide the preliminary justification for the potential MOAs by which PSP may operate. RESULTS: During the pilot study, aPSP (n = 31) yielded a greater decrease in both back and leg pain than did T-SCS (back: -60% vs -46%; legs: -63% vs -43%). In addition, aPSP yielded higher responder rates for both back and leg pain than did T-SCS (61% vs 48% and 78% vs 50%, respectively). DISCUSSION: The novel, multilayered approach of PSP may provide multimechanistic therapeutic relief through preferential fiber activation in the dorsal column, optimization of the neural onset response, and use of both the medial and lateral pathway through the thalamic nuclei. The results of the pilot study presented here suggest a robust responder rate, with several subjects (five subjects with back pain and three subjects with leg pain) achieving complete relief from PSP during the acute follow-up period. These clinical findings suggest PSP may provide a multimechanistic, anatomical, and clinically effective management for intractable chronic pain. Because of the limited sample size of clinical data, further testing and long-term clinical assessments are warranted to confirm these preliminary findings