Unmet Needs in Pain Therapeutics

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Unmet Needs in Pain Therapeutics

Tuesday, April 27, 2010

The New York Academy of Sciences

Chronic pain can be inflammatory, neuropathic or mixed in its etiology, but usually involves neuroplastic changes that result in hypersensitivity in the peripheral and/or central nervous system. Expression and functional changes of receptors and ion channels in neurons,and more recently in glial cells, has been the focus of much chronic pain research in recent years, but major challenges continue to exist in understanding and creating validated models for the human diseases. This symposium is intended to address both early clinical applications and validation of new pain mechanisms useful for the discovery of new treatments for chronic pain syndromes, as well as discuss the progress and barriers to developing effective preclinical models of pain, in particular fibromyalgia. The ultimate goal of developing an effective disease-modifying therapy for chronic pain conditions such as fibromyalgia have yet to be discovered, but with the establishment and validation of preclinical models this could become a reality.

Grant Support

This program is supported by an educational grant from Purdue Pharma L.P.

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Agenda


Tuesday, April 27

8:30 AM

Registration & Continental Breakfast

9:00 AM

Introduction
Chad E. Beyer, University of Colorado School of Medicine, Aurora, CO

9:10 AM

Targeting Neuronal and Glial Signalling in Pain Neuroplasticity
Michael W. Salter, Hospital for Sick Children, University of Toronto, Canada

9:55 AM

Inhibitory Mechanisms for Pain Modalities in the Dorsal Horn of the Spinal Cord
Amy MacDermott, Columbia University, New York, NY

10:40 AM

Refreshments

11:10 AM

Nav1.7 Sodium Channel in Inherited Pain Syndromes
Sulayman D. Dib-Hajj, Yale University School of Medicine, New Haven, CT

11:55 AM

Luncheon

1:00 PM

Fibromyalgia Syndrome: Review of Clinical Presentation, Pathogenesis, Outcome Measures, and Treatment
Daniel J. Clauw, The University of Michigan, Ann Arbor, MI

1:45 PM

Strategies for Developing Effective (& Relevant) Pre-Clinical Models of Pain: Relating Symptoms to Syndromes
Beth A. Winkelstein, University of Pennsylvania, Philadelphia, PA

2:30 PM

Refreshments

3:00 PM

Challenges in Discovering New Treatments and Better Models in Pain
Smriti Iyengar, Eli Lilly & Co., Indianapolis, IN

3:45 PM

Emerging Biomarkers and Translational Models for Pain Therapeutic Development
Mark R. Bowlby, Merck Research Laboratories, West Point, PA

4:30 PM

General Panel Discussion

5:00 PM

Closing Remarks

Speakers

Organizers

Chad E. Beyer

University of Colorado School of Medicine

Mark R. Bowlby

Merck Research Laboratoriess

Ildiko Antal

Bristol-Myers Squibb

Beth A. Winkelstein

University of Pennsylvania

Jennifer Henry

The New York Academy of Sciences

Speakers

Mark R. Bowlby

Merck Research Laboratoriess

Mark Bowlby Ph.D. is currently Director of Exploratory Biomarkers in the Pain and Migraine department at Merck Research Labs in West Point, PA. Dr. Bowlby received his Bachelor's degree from SUNY Stony Brook, followed by a MS and Ph.D. from UC Santa Barbara. His past research has focused on drug discovery for pain-related ion channel targets such as HCN, KCNQ and Nav, and nicotinic acetylcholine receptors and synaptic plasticity for cognition disorders. Dr. Bowlby's current work encompasses identifying and characterizing biomarkers for chronic pain targets, and translating their use from animal studies into clinical trials.

Daniel J. Clauw

The University of Michigan

DR CLAUW is Professor of Anesthesiology, Medicine, and Psychiatry and is Director of the Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor. After receiving his medical degree from the University of Michigan Medical School, Dr Clauw subsequently completed a residency in internal medicine and a fellowship in rheumatology at Georgetown University Medical Center in Washington, DC. Dr Clauw served in various capacities at Georgetown, including Vice Chair of Medicine and Director of Georgetown Center for Chronic Pain and Fatigue Research before returning to the University of Michigan. At the University of Michigan until recently, Dr Clauw served as the Associate Dean for Clinical and Transitional Research and Director of the Institute for Clinical and Health Research. He is a member of several professional societies, including the American Medical Association, the American College of Rheumatology, and the International Association for the Study of Pain. Dr Clauw has authored or coauthored more than 140 articles published in peer-reviewed journals such as Neuropsychopharmacology, Pain, and Psychosomatic Medicine. He is coeditor of Arthritis and Rheumatism and is on the editorial boards for Arthritis Care and Research, Journal of Musculoskeletal Pain, and Current Rheumatology Reviews. With research interests in fibromyalgia and central pain syndromes, stress, mechanisms of pain processing, and functional somatic syndromes, Dr Clauw serves as principal investigator in several clinical studies. His group is best known for work showing how the central nervous system contributes to pain processing in conditions such as fibromyalgia, interstitial cystitis, low back pain, osteoarthritis, and Gulf War illnesses. He has presented his research findings at national and international meetings and is the recipient of a Clinical and Translational Science Award funded by the National Center for Research Resources, a part of the National Institutes of Health.

Sulayman D. Dib-Hajj

Yale University School of Medicine

Sulayman D. Dib-Hajj, PhD, is a Research Scientist in the Department of Neurology and the Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut. After earning an undergraduate and master’s degree from the American University of Beirut, Beirut, Lebanon, Dr. Dib-Hajj earned his doctorate degree in molecular, cellular, and developmental biology from the Ohio State University, Columbus, Ohio. Dr. Dib-Hajj’s research focuses on the role of voltage-gated sodium channels in inherited and acquired pain disorders. Dr. Dib-Hajj is the authored many articles, abstracts, and book chapters. His work has been published in the Proceedings of the National Academy of Sciences (USA), Annual Review of Neuroscience, Journal of Neuroscience, Brain, Annals of Neurology, Trends in Neurosciences, Trends in Molecular Medicine, Nature Protocols, Nature Clinical Practice Neurology, Journal of Biological Chemistry, Pain, Neurology, Molecular Pain, Journal of Physiology, Journal of Neurophysiology, European Journal of Neuroscience. He serves on the editorial boards of The Journal of Neuroscience, The Open Pain Journal, The Open Drug Discovery Journal and Pain Research and Treatment. He lectures internationally and holds a patent on nucleic acid encoding sodium channels in dorsal root ganglia. Dr. Dib-Hajj is a member of the Society for Neurosciences, the International Association for the Study of Pain, the American Society for Biochemistry and Molecular Biology, and the American Association for the Advancement of Science.

Smriti Iyengar

Eli Lilly & Co.

Smriti Iyengar, Ph.D. received her Ph.D. from the University of Baroda, India and her post-doctoral training at the division of Neuroscience and Physiology, Rutgers University. She is currently at Eli Lilly and Company, where she joined in 1991 as a neuropharmacologist within the Neuroscience Research division. Her research interests in glutamate, neuropeptides, monoamines and ion channels have focused on pain and psychiatric disorders. Her broad expertise in Neuroscience Drug Discovery has been targeted towards discovery and clinical development of several novel therapeutic targets and drug candidates. Smriti has published and presented extensively and has been invited to participate in several prestigious academic/external cross functional committees.

Amy MacDermott

Columbia University

Amy MacDermott’s research interests focus on synaptic regulation of the nociceptive pathway within the spinal cord. She mainly uses electrophysiology, immunocytochemistry and imaging to investigate excitability changes in nociceptors as well as synaptic transmission within the spinal cord dorsal horn. She studies synaptic transmission between peripheral sensory neurons and dorsal horn target neurons as well as how local inhibitory and excitatory interneurons work to regulate activity within the superficial dorsal horn. She expects these studies will provide insights into new targets for pain management. Dr. MacDermott received her training in Physiology from Dr. Rodney Parsons at the University of Vermont. She subsequently worked at the NIAAA, NIH, and Columbia University. She is currently a Professor in the Department of Physiology and Cellular Biophysics and the Department of Neuroscience at Columbia University.

Michael W. Salter

Hospital for Sick Children, University of Toronto

Dr. Salter received his MD at the University of Western and his PhD from McGill University. As the Canada Research Chair in Neuroplasticity and Pain, Dr. Salter is determining the molecular and cellular mechanisms of normal and pathological neuroplasticity. He is using his discoveries to design and test new types of treatment for individual suffering from a variety of disorders of the central nervous system (CNS). He is developing molecules that target major cell signalling pathways in neurons and in glial cells involved in pain and stroke.

Beth A. Winkelstein

University of Pennsylvania

Beth Winkelstein is an Associate Professor of Bioengineering and Neurosurgery at the University of Pennsylvania. She received her BSE in Bioengineering from the University of Pennsylvania (1993) and earned a PhD in Biomedical Engineering from Duke in 1999. She joined Penn’s faculty in 2002 after completing a post-doctoral fellowship with Dr. Joyce DeLeo in Anesthesiology/Pharmacology/Toxicology at Dartmouth in the neuroimmunology of low back pain. Dr. Winkelstein’s research focuses on defining mechanisms of painful neck and spine injuries, mechanical and cellular mechanisms of chronic pain, and mechanotransductive pathways of pain. She has pioneered several rat models of neck injury, which are the first painful neck injury models with clinically-relevant pain symptoms. She has also developed a non-invasive model of TMJ pain in the rat. Her group implements rigorous engineering analyses in these in vivo systems to define biomechanical loading and relate those metrics to cellular mechanisms that drive pain. Her group also is developing new imaging approaches in ligament tissue biomechanics studies to understand subfailure micro- and macro-scale tissue responses. Dr. Winkelstein’s research has been recognized by awards from the Stapp Car Crash Conference, the International Society for the Study of the Lumbar Spine, and ASME. She was awarded a Whitaker Young Investigator Award, NIH Career Award, NSF-CAREER, and the 2006 YC Fung Young Investigator Award for the most promising young Bioengineer. She has been funded by the Whitaker Foundation, NSF, NHTSA, CDC, NIH, CSRS, DoD, and industry partners. She serves on the Editorial Board for Spine and the Journal of Biomechanical Engineering and has published over 55 peer-reviewed papers and 8 book chapters. Dr. Winkelstein served as primary research mentor for 17 graduate students and postdoctoral fellows, as well as many undergraduates. She is the faculty advisor for Penn’s chapters of BMES and SWE and is active in the ASME–BED, BMES and World Congress of Biomechanics.

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Grant Support

This program is supported by an educational grant from Purdue Pharma L.P.

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Abstracts

Targeting Neuronal and Glial Signalling in Pain Neuroplasticity

Michael W. Salter, Hospital for Sick Children, University of Toronto

Over the past decade a body of evidence has emerged indicating that pain behaviours resulting from injury to peripheral nerves are critically dependent upon interactions between neurons and glia in the dorsal horn of the spinal cord. Microglia have been found to play a causal role in neuropathic pain behaviours resulting from peripheral nerve injury, and specific neuron-microglia-neuron signalling pathways have been elucidated. Within the dorsal horn, microglia suppress neuronal inhibition by a sequence of steps involving activation of microglial P2X4 receptors causing the release of BDNF. BDNF acts on trkB receptors which leads to a rise in intracellular chloride concentration in dorsal horn nociceptive output neurons, transforming the response properties of these neurons. In addition to suppressed inhibition, evidence indicates that following nerve injury there is activity-dependent facilitation at dorsal horn glutamatergic synapses which enhances nociceptive transmission. This enhancement is mediated by intracellular signalling networks involving serine/threonine and tyrosine kinases within nociceptive transmission neurons. Key for this enhancement is facilitation of NMDA receptor function by the non-receptor tyrosine kinase Src. Src is anchored within the NMDA receptor complex by the protein ND2. Disrupting the ND2-Src interaction in vivo attenuates behavioural pain hypersensitivity without the deleterious consequences of directly blocking NMDARs. Thus, understanding of the pathological signalling not only within neurons but also in glial cells, and, as well, the interactions between neurons and glia within the dorsal horn may lead to novel strategies for the management of chronic pain states, strategies not previously expected from a solely neuron-centric view of pain. Supported by the Canadian Institutes of Health Research, the Krembil Foundation and the Howard Hughes Medical Institute.

Inhibitory Mechanisms for Pain Modalities in the Dorsal Horn of the Spinal Cord

Amy MacDermott, Columbia University

The key site in the central nervous system at which pain signaling is transmitted from the periphery, modulated and then projected to higher brain centers is the spinal cord dorsal horn. The most superficial layer of the dorsal horn receives input from small diameter afferent fibers sensitive to noxious heat, cold, mechanical and chemical stimuli. This small region of the central nervous system is predominantly populated by local interneurons. Approximately 30% of these neurons provide local inhibitory control. Working together with descending inhibitory inputs from the brainstem, the inhibitory interneurons in the dorsal horn control the intensity of pain signaling and in some cases, act to prevent non-pain sensory modalities from spilling over into pain pathways. GABA and glycine are the primary inhibitory neurotransmitters released by the inhibitory interneurons. Synaptic release of GABA and glycine transiently activates postsynaptic receptors, suppressing excitability in postsynaptic neurons. Ambient extrasynaptic GABA and glycine can exert a tonic effect on neuronal excitability. Peripheral nerve or spinal cord injury removes this inhibitory control, allowing excitatory drive to become overly strong, contributing to the sensations of hyperalgesia and allodynia. During this presentation, we will be considering the location specificity of inhibition in the dorsal horn and the implications of this specificity for control of excitability related to chronic pain.

Nav1.7 Sodium Channel in Inherited Pain Syndromes

Sulayman D. Dib-Hajj, Yale University School of Medicine

Neuropathic pain is maladaptive and unmet medical need which is associated with hyperexcitability of dorsal root ganglion (DRG) neurons, and is often unresponsive to pharmacotherapy. Transmission of the signal along the pain axis is dependent on voltage-gated sodium channels and first-line drug treatments for neuropathic pain includes non-selective sodium channel blockers. Voltage-gated sodium channel Nav1.7 is preferentially expressed within DRG and sympathetic ganglion neurons, and its gating properties permit amplification of small, slow depolarizations thus acting as a threshold channel. Nav1.7 has recently been shown to underlie inherited human pain syndromes and contributes to pain caused by injury, inflammation and metabolic disorders, making this channel a desirable target for pain treatment. Two sets of autosomal dominant Nav1.7 gain-of-function mutations linked to distinct pain syndromes have recently been identified. Nav1.7 mutations that hyperpolarize activation, slow deactivation, and increase the ramp response to small depolarizations cause Inherited Erythromelalgia (IEM), a disorder characterized by searing, burning pain in distal extremities in response to mild warmth. The characterization of more than ten IEM mutations suggests a correlation of age-of-onset and severity of symptoms with the extent of hyperpolarizing shift in activation of mutant channels. A new Nav1.7 mutation is characterized by different age-of-onset of pain symptoms within the same family, and depolarized fast-inactivation in a splice-isoform-dependent manner. A different set of Nav1.7 mutations that impair fast-inactivation and produce persistent and resurgent currents are associated with Paroxysmal Extreme Pain Disorder (PEPD) characterized by perirectal, perimandibular and periocular pain, triggered by bowel movement and perineal pressure. IEM and PEPD mutations induce hyperexcitability of DRG neurons that express mutant Nav1.7 channels. It is not known why the different types of gain-of-function mutations produce different pain phenotypes. Finally, loss-of-function mutations of Nav1.7 have been identified in patients with congenital insensitivity to pain. Interestingly, while Nav1.7 is normally present within sympathetic ganglion neurons as well as DRG neurons, Nav1.7-related CIP patients do not display autonomic deficits. Studies on Nav1.7-related heritable pain syndromes, and the dynamic regulation of Nav1.7 expression in human painful neuromas and animal models of inflammation and diabetic neuropathy, provide compelling reasons why Nav1.7-specific blockade may provide a new approach for effective treatment of chronic pain.

Fibromyalgia Syndrome: Review of Clinical Presentation, Pathogenesis, Outcome Measures, and Treatment

Daniel J. Clauw, The University of Michigan

Fibromyalgia (FM) is the second most common rheumatic disorder, affecting approximately 2 – 3% of the population. The 1990 American College of Rheumatology criteria require that individuals have a history of chronic widespread pain, and display diffuse tenderness on examination, based on having 11 or greater (or a possible 18) tender points on examination. Alternate diagnostic criteria have been developed that do not require a tender point exam, and instead require both widespread pain and multiple somatic symptoms (e.g. fatigue, memory difficulties, insomnia). Considerable research in the past decade has taught us a great deal about fibromyalgia. It is now clear that this is now one of many “central pain” conditions where the pain and other sensory symptoms are not due to damage or inflammation in peripheral tissues, but instead in part due to augmented processing of pain and sensory information in the central nervous system (CNS). This phenomenon can be identified using experimental pain testing, functional neuroimaging, and analysis of neurotransmitters in the CNS that are involved in pain and sensory transmission. Similarly augmented pain processing (also termed hyperalgesia or allodynia) is also identifiable in the majority of individuals with a variety of other chronic pain states, such as irritable bowel syndrome, idiopathic low back pain, temporomandibular disorder, interstitial cystitis, chronic prostatitis, vulvodynia, and endometriosis. These central pain states: 1) occur approximately 1.5 – 2X as commonly in females than males, 2) have very strong familial and genetic underpinnings, 3) can be triggered by a variety of different stressors, including infection, as well as physical and emotional trauma, and thus deployment to war appears to be a potent trigger of these conditions, 4) respond the same types of pharmacological and non-pharmacological therapies. In fact, even subsets of individuals with “peripheral” pain states such as osteoarthritis will have hyperalgesia/allodynia, and respond to treatments commonly used in the setting of FM, rather than “peripherally based treatments such as NSAIDs, opioids, or procedures. The most effective therapy for FM and related conditions is to employ a patient-centric, multimodal approach that combines the use of pharmacological therapies aimed at improving symptoms, and nonpharmacological therapies aimed at improving function. The non-pharmacological therapies with the highest level of evidence are education, exercise, and cognitive behavioral therapy. The pharmacological therapies with the highest level of evidence include classes or drugs that raise serotonin and norepinephrine (e.g. tricyclics, dual re-uptake inhibitors) and/or drugs that inhibit the release of excitatory neurotransmitters such as Substance P and glutamtate (e.g. pregabalin, gabapentin). One of the primary lessons learned from the study of FM and related conditions is that “central” pain is extremely common in clinical practice, and practitioners need to better understand this type of pain and modify their peripherally-directed (or dualistic) diagnostic and treatment paradigms that assume that pain is either due to inflammation or damage, or due to psychological causes.

Strategies for Developing Effective (& Relevant) Pre-Clinical Models of Pain: Relating Symptoms to Syndromes

Beth A. Winkelstein, University of Pennsylvania

While there is increased basic science work defining specific regulatory pathways of nociception and pain, the development of useful and meaningful pre-clinical models of pain remains an important aspect of developing and implementing effective pain therapeutics and treatment approaches. We combine engineering techniques with behavioral, cellular and molecular assays to develop novel models of injury in the rodent that are relevant to the modes of injury and their pathomechanisms, as well as being clinically-relevant in terms of the symptoms they produce. We use these models to define relationships between tissue insult and injury, local tissue responses, and the widespread cellular mechanisms of nociception, and pain symptoms. This presentation will present this framework for developing pre-clinical models of pain that are useful and relevant. As such, it will summarize findings from integrated clinical studies, in vitro assays, and mechanical experiments that were coordinated to establish several painful models in the rat. This work will be presented with a view towards potential directions for therapeutic interventions and understanding the mechanisms by which pain is initiated and maintained. In particular, relationships between the local tissue environment and the overall systemic responses will be presented to provide a framework for understanding the complete picture of pain and its pathomechanisms. Findings will be presented in the context of diagnosis and treatment to build a foundation for understanding these and other painful disorders. This work has been funded by the CDC, NIH, NSF, NHTSA, DoD, and the Catharine Sharpe Foundation.

Challenges in Discovering New Treatments and Better Models in Pain

Smriti Iyengar, Eli Lilly & Co.

Evolving concepts in pain and the failure of many drug candidates have led to the questioning of current preclinical models of pain. The present talk will attempt to clarify the mechanistic basis and rationale for the use of selected models, relevance of these models to clinical pain, use of these models for drug development, limitations of these models and some newly proposed models.

Emerging Biomarkers and Translational Models for Pain Therapeutic Development

Mark R. Bowlby, Merck Research Laboratories

Biomarkers are defined as quantifiable changes in the expression or state of a protein that correlates with disease severity and response to treatment. Biomarkers have been used for many years in the cardiovascular and oncology fields for determining both treatments and outcomes, but their use in the pain field has only recently gained widespread use. Driven by drug failures and escalating costs in clinical trails, biomarkers have become an important component in the translation of preclinical results into the clinic. Biomarkers are traditionally applied to patients to obtain an objective determination of disease outcome, but in the pain field patient reported outcomes are currently the standard measure of efficacy. Biomarkers, however, are important in pain drug development to demonstrate target engagement and pharmacodynamic activity for a new therapeutic agent, thus providing an empirical link between target and pharmacokinetic data. The use of pharmacodynamic biomarkers and experimental pain models such as capsaicin induced pain and dermal vasodilation, threshold tracking and fMRI will be discussed.

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