Safety of Scrambler Therapy: A Systematic Review of Complications and Adverse Effects.

OBJECTIVE: The objective was to qualitatively synthesize all reported cases of complications, adverse effects, side effects, or harms arising from the use of scrambler therapy (ST). METHODS AND DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The PubMed, Embase, Scopus, Web of Science, United States National Library of Medicine clinical trials registry, and Cochrane Central Register of Controlled Trials databases were searched from database inception to December 10, 2021. Case reports/series, abstracts, retrospective studies, and prospective studies (e.g., open-label trials, randomized controlled trials) pertaining to ST and any description of a complication, adverse effect, side effect, or harm were screened. The search protocol was developed a priori and registered via the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021291838). RESULTS: A total of six RCTs, 19 prospective open-label trials, and 11 case series / case reports met the inclusion criteria, comprising 1,152 total patients. Two patients experienced contact dermatitis, and one patient reported minor ecchymosis that resolved without intervention. This yielded a composite complication rate of 0.26% (3/1,152). There were zero reported serious adverse events. CONCLUSIONS: When used in accordance with the treatment protocols described by the United States Food and Drug Administration and device manual, ST is associated with a reported composite complication rate that is orders of magnitude lower than those of invasive neuromodulation devices. ST neuromodulation is a safe alternative for patients who cannot undergo invasive neuromodulation device implantation because of either risk or preference.

Complex Regional Pain Syndrome: Evidence-Based Advances in Concepts and Treatments.

PURPOSE OF REVIEW: This review presents the most current information about the epidemiology of complex regional pain syndrome (CRPS), classification and diagnostic criteria, childhood CRPS, subtypes, pathophysiology, conventional and less conventional treatments, and preventive strategies. RECENT FINDINGS: CRPS is a painful disorder with multifactorial pathophysiology. The data describe sensitization of the central and peripheral nervous systems, inflammation, possible genetic factors, sympatho-afferent coupling, autoimmunity, and mental health factors as contributors to the syndrome. In addition to conventional subtypes (type I and type II), cluster analyses have uncovered other proposed subtypes. Prevalence of CRPS is approximately 1.2%, female gender is consistently associated with a higher risk of development, and substantial physical, emotional, and financial costs can result from the syndrome. Children with CRPS seem to benefit from multifaceted physical therapy leading to a high percentage of symptom-free patients. The best available evidence along with standard clinical practice supports pharmacological agents, physical and occupational therapy, sympathetic blocks for engaging physical restoration, steroids for acute CRPS, neuromodulation, ketamine, and intrathecal baclofen as therapeutic approaches. There are many emerging treatments that can be considered as a part of individualized, patient-centered care. Vitamin C may be preventive. CRPS can lead to progressively painful sensory and vascular changes, edema, limb weakness, and trophic disturbances, all of which substantially erode healthy living. Despite some progress in research, more comprehensive basic science investigation is needed to clarify the molecular mechanisms of the disease so that targeted treatments can be developed for better outcomes. Incorporating a variety of standard therapies with different modes of action may offer the most effective analgesia. Introducing less conventional approaches may also be helpful when traditional treatments fail to provide sufficient improvement.

Emerging innovation in pain medicines.

The treatment of pain remains a critical, unmet public health challenge. According to the CDC, in 2021, an estimated 20.9% of US adults (51.6 million people) endured chronic pain, and 6.9% (17.1 million people) endured high-impact chronic pain. Additionally, the impact of the social determinants of health on pain treatment are beginning to emerge. Treating pain addresses its control and relief, enhancing patient outcomes and quality of life. However, current treatment options have limitations, creating a significant need for innovative solutions. This raises the role of innovation in identifying new pain medicines. Thus, the clinical development of novel pain medicines is an unmet need to address public health worldwide.

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Peripherally restricted cannabinoid and mu-opioid receptor agonists synergistically attenuate neuropathic mechanical hypersensitivity in mice.

ABSTRACT: Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors ( Cnr1 and Oprm1 ) is coexpressed across different neuron clusters. Myc-CB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain.

Shifts in Students' Attitudes Towards Pain Patients, Pain, and Opioid Management Following a Dedicated Medical School Pain Curriculum.

Objective: To examine the immediate effects of a comprehensive pain course on medical students' pre-existing perceptions and attitudes toward pain patients and opioid management. Methods: First-year medical students at a major academic medical center enrolled in a required pre-clerkship pain course in June 2020 and completed pre- and post-course online surveys with Likert-scale questions about their attitudes toward pain management and opioid-related issues. Additionally, the surveys included a free-text question where the students listed the first five words that came to mind when hearing the word "opioids". These words were categorized as "professional" or "lay" words and further as having "positive", "negative", or "neutral" connotations. Data analyses included descriptive statistics, as well as non-parametric and parametric tests. Results: Fifty-four of the 119 students responded to pretest and posttest surveys and were included in paired analyses. There was a significant difference between the number of professional words used before (M=1.21, SD=0.97) and after the course (M=2.40 SD=1.33); t(52)=-6.39, P<0.001. Students also used more lay-positive words after the course (M=0.81, SD=0.63) than they used pre-course (M=0.23, SD=0.43); t(51)=-5.98, P<0.001. Students' post-course responses to several key Likert-scale questions showed significant shifts toward more positive attitudes about caring for patients with pain. For example, students acknowledged greater comfort in providing opioids for chronic pain (P<0.001) where appropriate, and enhanced interest in handling complex pain cases (P<0.001). Conclusion: Results showed that a comprehensive, multi-disciplinary pain course could greatly enhance first-year medical students' attitudes toward pain management, chronic pain patients, and the complex issues surrounding opioids.

Perioperative Management of Antiplatelet and Anticoagulant Therapy in Patients Undergoing Interventional Techniques: 2024 Updated Guidelines from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: The frequency of performance of interventional techniques in chronic pain patients receiving anticoagulant and antiplatelet therapy continues to increase. Understanding the importance of continuing chronic anticoagulant therapy, the need for interventional techniques, and determining the duration and discontinuation or temporary suspension of anticoagulation is crucial to avoiding devastating complications, primarily when neuraxial procedures are performed. Anticoagulants and antiplatelets target the clotting system, increasing the bleeding risk. However, discontinuation of anticoagulant or antiplatelet drugs exposes patients to thrombosis risk, which can lead to significant morbidity and mortality, especially in those with coronary artery or cerebrovascular disease. These guidelines summarize the current peer reviewed literature and develop consensus-based guidelines based on the best evidence synthesis for patients receiving anticoagulant and antiplatelet therapy during interventional procedures. STUDY DESIGN: Review of the literature and development of guidelines based on best evidence synthesis. OBJECTIVES: To provide a current and concise appraisal of the literature regarding the assessment of bleeding and thrombosis risk during interventional techniques for patients taking anticoagulant and/or antiplatelet medications. METHODS: Development of consensus guidelines based on best evidence synthesis included review of the literature on bleeding risks during interventional pain procedures, practice patterns, and perioperative management of anticoagulant and antiplatelet therapy. A multidisciplinary panel of experts developed methodology, risk stratification based on best evidence synthesis, and management of anticoagulant and antiplatelet therapy. It also included risk of cessation of anticoagulant and antiplatelet therapy based on a multitude of factors. Multiple data sources on bleeding risk, practice patterns, risk of thrombosis, and perioperative management of anticoagulant and antiplatelet therapy were identified. The relevant literature was identified through searches of multiple databases from 1966 through 2023. In the development of consensus statements and guidelines, we used a modified Delphi technique, which has been described to minimize bias related to group interactions. Panelists without a primary conflict of interest voted on approving specific guideline statements. Each panelist could suggest edits to the guideline statement wording and could suggest additional qualifying remarks or comments as to the implementation of the guideline in clinical practice to achieve consensus and for inclusion in the final guidelines, each guideline statement required at least 80% agreement among eligible panel members without primary conflict of interest. RESULTS: A total of 34 authors participated in the development of these guidelines. Of these, 29 participated in the voting process. A total of 20 recommendations were developed. Overall, 100% acceptance was obtained for 16 of 20 items. Total items were reduced to 18 with second and third round voting. The final results were 100% acceptance for 16 items (89%). There was disagreement for 2 statements (statements 6 and 7) and recommendations by 3 authors. These remaining 2 items had an acceptance of 94% and 89%. The disagreement and dissent were by Byron J. Schneider, MD, with recommendation that all transforaminals be classified into low risk, whereas Sanjeeva Gupta, MD, desired all transforaminals to be in intermediate risk. The second disagreement was related to Vivekanand A. Manocha, MD, recommending that cervical and thoracic transforaminal to be high risk procedures.Thus, with appropriate literature review, consensus-based statements were developed for the perioperative management of patients receiving anticoagulants and antiplatelets These included the following: estimation of the thromboembolic risk, estimation of bleeding risk, and determination of the timing of restarting of anticoagulant or antiplatelet therapy.Risk stratification was provided classifying the interventional techniques into three categories of low risk, moderate or intermediate risk, and high risk. Further, on multiple occasions in low risk and moderate or intermediate risk categories, recommendations were provided against cessation of anticoagulant or antiplatelet therapy. LIMITATIONS: The continued paucity of literature with discordant recommendations. CONCLUSION: Based on the review of available literature, published clinical guidelines, and recommendations, a multidisciplinary panel of experts presented guidelines in managing interventional techniques in patients on anticoagulant or antiplatelet therapy in the perioperative period. These guidelines provide a comprehensive assessment of classification of risk, appropriate recommendations, and recommendations based on the best available evidence.

Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments.

Epidural Interventions in the Management of Chronic Spinal Pain: American Society of Interventional Pain Physicians (ASIPP) Comprehensive Evidence-Based Guidelines.

BACKGROUND: Chronic spinal pain is the most prevalent chronic disease with employment of multiple modes of interventional techniques including epidural interventions. Multiple randomized controlled trials (RCTs), observational studies, systematic reviews, and guidelines have been published. The recent review of the utilization patterns and expenditures show that there has been a decline in utilization of epidural injections with decrease in inflation adjusted costs from 2009 to 2018. The American Society of Interventional Pain Physicians (ASIPP) published guidelines for interventional techniques in 2013, and guidelines for facet joint interventions in 2020. Consequently, these guidelines have been prepared to update previously existing guidelines. OBJECTIVE: To provide evidence-based guidance in performing therapeutic epidural procedures, including caudal, interlaminar in lumbar, cervical, and thoracic spinal regions, transforaminal in lumbar spine, and percutaneous adhesiolysis in the lumbar spine. METHODS: The methodology utilized included the development of objective and key questions with utilization of trustworthy standards. The literature pertaining to all aspects of epidural interventions was viewed with best evidence synthesis of available literature and  recommendations were provided. RESULTS: In preparation of the guidelines, extensive literature review was performed. In addition to review of multiple manuscripts in reference to utilization, expenditures, anatomical and pathophysiological considerations, pharmacological and harmful effects of drugs and procedures, for evidence synthesis we have included 47 systematic reviews and 43 RCTs covering all epidural interventions to meet the objectives.The evidence recommendations are as follows: Disc herniation: Based on relevant, high-quality fluoroscopically guided epidural injections, with or without steroids, and results of previous systematic reviews, the evidence is Level I for caudal epidural injections, lumbar interlaminar epidural injections, lumbar transforaminal epidural injections, and cervical interlaminar epidural injections with strong recommendation for long-term effectiveness.The evidence for percutaneous adhesiolysis in managing disc herniation based on one high-quality, placebo-controlled RCT is Level II with moderate to strong recommendation for long-term improvement in patients nonresponsive to conservative management and fluoroscopically guided epidural injections. For thoracic disc herniation, based on one relevant, high-quality RCT of thoracic epidural with fluoroscopic guidance, with or without steroids, the evidence is Level II with moderate to strong recommendation for long-term effectiveness.Spinal stenosis: The evidence based on one high-quality RCT in each category the evidence is Level III to II for fluoroscopically guided caudal epidural injections with moderate to strong recommendation and Level II for fluoroscopically guided lumbar and cervical interlaminar epidural injections with moderate to strong recommendation for long-term effectiveness.The evidence for lumbar transforaminal epidural injections is Level IV to III with moderate recommendation with fluoroscopically guided lumbar transforaminal epidural injections for long-term improvement. The evidence for percutaneous adhesiolysis in lumbar stenosis based on relevant, moderate to high quality RCTs, observational studies, and systematic reviews is Level II with moderate to strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. Axial discogenic pain: The evidence for axial discogenic pain without facet joint pain or sacroiliac joint pain in the lumbar and cervical spine with fluoroscopically guided caudal, lumbar and cervical interlaminar epidural injections, based on one relevant high quality RCT in each category is Level II with moderate to strong recommendation for long-term improvement, with or without steroids. Post-surgery syndrome: The evidence for lumbar and cervical post-surgery syndrome based on one relevant, high-quality RCT with fluoroscopic guidance for caudal and cervical interlaminar epidural injections, with or without steroids, is Level II with moderate to strong recommendation for long-term improvement. For percutaneous adhesiolysis, based on multiple moderate to high-quality RCTs and systematic reviews, the evidence is Level I with strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. LIMITATIONS: The limitations of these guidelines include a continued paucity of high-quality studies for some techniques and various conditions including spinal stenosis, post-surgery syndrome, and discogenic pain. CONCLUSIONS: These epidural intervention guidelines including percutaneous adhesiolysis were prepared with a comprehensive review of the literature with methodologic quality assessment and determination of level of evidence with strength of recommendations.

A Statistically-Oriented Asymmetric Localization (SOAL) Model for Neuronal Outgrowth Patterning by Caenorhabditis elegans UNC-5 (UNC5) and UNC-40 (DCC) Netrin Receptors.

Neurons extend processes that vary in number, length, and direction of "outgrowth". Extracellular cues help determine outgrowth patterns. In Caenorhabditis elegans, neurons respond to the extracellular UNC-6 (netrin) cue via UNC-40 (DCC) and UNC-5 (UNC5) receptors. Previously, we presented evidence that UNC-40 asymmetric localization at the plasma membrane is self-organizing, and that UNC-40 can localize and mediate outgrowth at randomly selected sites. Here, we provide further evidence for a statistically-oriented asymmetric localization (SOAL) model in which UNC-5 receptor activity affects patterns of axon outgrowth by regulating UNC-40 asymmetric localization. According to the SOAL model, the direction of outgrowth activity fluctuates across the membrane over time. Random walk modeling predicts that increasing the degree to which the direction of outgrowth fluctuates will decrease the outward displacement of the membrane. By differentially affecting the degree to which the direction of outgrowth activity fluctuates over time, extracellular cues can produce different rates of outgrowth along the surface and create patterns of "extension". Consistent with the SOAL model, we show that unc-5 mutations alter UNC-40 asymmetric localization, increase the degree to which the direction of outgrowth fluctuates, and reduce the extent of outgrowth in multiple directions relative to the source of UNC-6 These results are inconsistent with current models, which predict that UNC-5 mediates a "repulsive" response to UNC-6 Genetic interactions suggest that UNC-5 acts through the UNC-53 (NAV2) cytoplasmic protein to regulate UNC-40 asymmetric localization in response to both the UNC-6 and EGL-20 (Wnt) extracellular cues.

Comprehensive, evidence-based, consensus guidelines for prescription of opioids for chronic non-cancer pain from the American Society of Interventional Pain Physicians (ASIPP)

Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed

Experimental evidence for UNC-6 (netrin) axon guidance by stochastic fluctuations of intracellular UNC-40 (DCC) outgrowth activity.

How the direction of axon guidance is determined is not understood. In Caenorhabditis elegans the UNC-40 (DCC) receptor mediates a response to the UNC-6 (netrin) guidance cue that directs HSN axon development. UNC-40 becomes asymmetrically localized within the HSN neuron to the site of axon outgrowth. Here we provide experimental evidence that the direction of guidance can be explained by the stochastic fluctuations of UNC-40 asymmetric outgrowth activity. We find that the UNC-5 (UNC5) receptor and the cytoskeletal binding protein UNC-53 (NAV2) regulate the induction of UNC-40 localization by UNC-6. If UNC-40 localization is induced without UNC-6 by using an unc-53 mutation, the direction of UNC-40 localization undergoes random fluctuations. Random walk models describe the path made by a succession of randomly directed movement. This model was experimentally tested using mutations that affect Wnt/PCP signaling. These mutations inhibit UNC-40 localization in the anterior and posterior directions. As the axon forms in Wnt/PCP mutants, the direction of UNC-40 localization randomly fluctuates; it can localize in either the anterior, posterior, or ventral direction. Consistent with a biased random walk, over time the axon will develop ventrally in response to UNC-6, even though at a discrete time UNC-40 localization and outgrowth can be observed anterior or posterior. Also, axon formation is slower in the mutants than in wild-type animals. This is also consistent with a random walk since this model predicts that the mean square displacement (msd) will increase only linearly with time, whereas the msd increases quadratically with time for straight-line motion.