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      Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities


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          Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.


          In 2018, the Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened to discuss strategies to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

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          Pathophysiology of Migraine: A Disorder of Sensory Processing.

          Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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            Willful modulation of brain activity in disorders of consciousness.

            The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patient's capacity to show behavioral signs of awareness is diminished. At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patient's ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions. Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside. These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive. 2010 Massachusetts Medical Society
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              Pain regulation by non-neuronal cells and inflammation

              Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

                Author and article information

                Nat Rev Neurol
                Nat Rev Neurol
                Nature Reviews. Neurology
                Nature Publishing Group UK (London )
                15 June 2020
                15 June 2020
                : 16
                : 7
                : 381-400
                [1 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Surgery and Institute of Medical Science, , University of Toronto, ; Toronto, ON Canada
                [2 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Division of Brain, Imaging and Behaviour, Krembil Brain Institute, Toronto Western Hospital, , University Health Network, ; Toronto, ON Canada
                [3 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Anesthesiology, Perioperative and Pain Medicine, , Stanford University School of Medicine, ; Stanford, CA USA
                [4 ]ISNI 0000 0004 0483 9882, GRID grid.418488.9, Teva Pharmaceuticals, ; Frazer, PA USA
                [5 ]ISNI 000000041936754X, GRID grid.38142.3c, Center for Pain and the Brain, , Harvard Medical School, ; Boston, MA USA
                [6 ]Mycroft Bioanalytics, Salt Lake City, UT USA
                [7 ]Teva Pharmaceutical Industries, Frazer, PA USA
                [8 ]Xyzagen, Pittsboro, NC USA
                [9 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Pain Management Center, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [10 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, The Vivian L. Smith Department of Neurosurgery, , The University of Texas Health Science Center at Houston, McGovern Medical School, ; Houston, TX USA
                [11 ]ISNI 0000 0004 3497 6087, GRID grid.429651.d, Department of Perioperative Medicine, , Clinical Center, NIH, ; Rockville, MD USA
                [12 ]ISNI 0000 0004 3497 6087, GRID grid.429651.d, Division of Translational Research, , National Institute of Neurological Disorders and Stroke, NIH, ; Rockville, MD USA
                [13 ]ISNI 0000 0004 1936 9510, GRID grid.253615.6, The Biostatistics Center, Milken Institute School of Public Health, , The George Washington University, ; Washington, DC USA
                [14 ]ISNI 0000 0004 1936 9094, GRID grid.40263.33, Department of Neuroscience and Department of Neurosurgery, Carney Institute for Brain Science, , Brown University, ; Providence, RI USA
                [15 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Department of Anesthesiology, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [16 ]ISNI 0000 0004 0384 8146, GRID grid.417832.b, Neurocognitive Disorders, , Pain and New Indications, Biogen, ; Cambridge, MA USA
                [17 ]Asarina Pharma, Copenhagen, Denmark
                [18 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Nuffield Department of Clinical Neurosciences, , University of Oxford, ; Oxford, UK
                [19 ]Chronic Pain Research Alliance, Bethesda, MD USA
                [20 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Department of Anesthesiology, Perioperative Care and Pain Medicine, , NYU School of Medicine, ; New York, NY USA
                [21 ]ISNI 0000 0001 2179 2404, GRID grid.254880.3, Department of Psychological and Brain Sciences, , Dartmouth College, ; Hanover, NH USA
                [22 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Anesthesiology and Perioperative Medicine and Psychiatry, , University of Pittsburgh, ; Pittsburgh, PA USA
                © The Authors(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Consensus Statement
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                © Springer Nature Limited 2020

                biomarkers, chronic pain


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