eBriefing

Unmet Needs in Pain Therapeutics: Neuropathic Pain and Fibromyalgia

Unmet Needs in Pain Therapeutics
Reported by
Megan Stephan

Posted June 29, 2010

Overview

Chronic pain conditions occur when pain sensing and processing pathways are damaged or otherwise functioning incorrectly, leading to the perception of pain without an associated tissue injury or underlying disease process. An estimated 25 million Americans suffer from chronic pain syndromes such as neuropathic pain or fibromyalgia. Current treatments for these pain conditions are usually nonspecific, since it is often difficult to identify an underlying cause, and thus frequently ineffective.

Many investigators, both basic and clinical, are studying the underlying mechanisms of chronic pain and seeking new therapies. Seven of these investigators discussed their work on April 27, 2010, at a symposium jointly organized by the New York Academy of Sciences and the New York Chapter of the American Chemical Society. Topics at the symposium ranged from basic neurobiological research, to clinical studies of specific pain syndromes, to the need for better animal models and biomarkers in chronic pain research if drug development is to become more successful.

Use the tabs above to find a meeting report and multimedia from this event.


Presentations are available from:

Michael W. Salter (Hospital for Sick Children, University of Toronto)
Amy MacDermott (Columbia University)
Sulayman D. Dib-Hajj (Yale University School of Medicine; Veterans Administration Connecticut Healthcare System)
Daniel J. Clauw (The University of Michigan)
Beth A. Winkelstein (University of Pennsylvania)
Mark R. Bowlby (Merck Research Laboratories)


Sponsors

Academy Friends

Bristol-Myers Squibb R&D
NeurogesX, Inc.

Grant Support

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

Web Sites

An Alternate View of Chronic Pain
This Howard Hughes Medical Institute story discusses the work of Michael Salter.

American Academy of Pain Medicine
The American Academy of Pain Medicine is a medical specialty society involved in education, training, advocacy, and research in pain medicine.

American Chronic Pain Association
The American Chronic Pain Association offers peer support and education in pain management skills to people with pain, family and friends, and health care professionals.

American Pain Society
The American Pain Society is a multidisciplinary community that brings together scientists, clinicians, and other professionals to increase knowledge and transform public policy and clinical practice to reduce pain-related suffering.

Erythromelalgia Association
The goals of the Erythromelalgia Association are to identify, educate, and support those suffering EM's painful symptoms; to help fund research leading to a cure for this rare disorder; to raise public awareness; and to educate healthcare practitioners to recognize and diagnose EM.

Fibromyalgia misconceptions: Interview with a Mayo Clinic expert
This interview covers some aspects of the current controversy in fibromyalgia.

International Association for the Study of Pain
The International Association for the Study of Pain is an organization that brings together scientists, clinicians, health care providers, and policy makers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide.

National Fibromyalgia Association
The goal of the National Fibromyalgia Association is to develop and execute programs dedicated to improving the quality of life for people with fibromyalgia.


News Articles

Knox R. Newly found gene mutation banishes pain. All Things Considered, NPR. December 13, 2006.

Wade N. 2006. Researchers find gene tied to perception of pain. The New York Times (December 13).


Journal Articles

Michael Salter

Beggs S, Salter MW. 2008. Taking two cuts at pain. Nat. Med. 14: 243-244.

Kalia LV, Kalia SK, Salter MW. 2008. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol. 7: 742-755.

Liu XJ, Gingrich JR, Vargas-Caballero M, et al. 2008. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat. Med. 14: 1325-1332.

Okada-Ogawa A, Suzuki I, Sessle BJ, et al. 2009. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J. Neurosci. 29: 11161-11171. Full Text

Sun HS, Doucette TA, Liu Y, et al. 2008. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39: 2544-2553. Full Text

Trang T, Beggs S, Wan X, et al. 2009. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J. Neurosci. 29: 3518-3528. Full Text

Amy MacDermott

Daniele CA, MacDermott AB. 2009. Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J. Neurosci. 29: 686-695. Full Text

Engelman HS, Anderson RL, Daniele C, et al. 2006. Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate release of inhibitory amino acids in rat spinal cord dorsal horn. Neuroscience 139: 539-553.

Labrakakis C, MacDermott AB. 2003. Neurokinin receptor 1-expressing spinal cord neurons in lamina I and III/IV of postnatal rats receive inputs from capsaicin sensitive fibers. Neurosci. Lett. 352: 121-124.

Tong CK, Kaftan EJ, Macdermott AB. 2008. Functional identification of NR2 subunits contributing to NMDA receptors on substance P receptor-expressing dorsal horn neurons. Mol. Pain. 4: 44. Full Text

Tong CK, MacDermott AB. 2006. Both Ca2+-permeable and -impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. J. Physiol. 575: 133-144. Full Text

Torsney C, MacDermott AB. 2006. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J. Neurosci. 26: 1833-1843. Full Text

Sulayman Dib-Hajj

Ahn HS, Dib-Hajj SD, Cox JJ, et al. 2010. A new Na(v)1.7 sodium channel mutation I234T in a child with severe pain. Eur. J. Pain Apr 10. [Epub ahead of print]

Choi JS, Cheng X, Foster E, et al. 2010. Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia. Brain 133: 1823-1835.

Dib-Hajj SD, Cummins TR, Black JA, et al. 2010. Sodium channels in normal and pathological pain. Annu. Rev. Neurosci. 33: 325-347. Apr 1. [Epub ahead of print]

Estacion M, Harty TP, Choi JS, et al. 2009. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Ann. Neurol. 66: 862-866.

Fischer TZ, Gilmore ES, Estacion M, et al. 2009. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann. Neurol. 65: 733-741.

Stamboulian S, Choi JS, Ahn HS, et al. 2010. ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J. Neurosci. 30: 1637-1647.

Daniel Clauw

Clauw DJ, Witter J. 2009. Pain and rheumatology: thinking outside the joint. Arthritis Rheum. 60: 321-324. Full Text

Clauw DJ. 2009. Fibromyalgia is a controversial disease. Am. J. Med. 122: S1-S2.

Clauw DJ. 2009. Fibromyalgia: an overview. Am. J. Med. 122: S3-S13.

Schmidt-Wilcke T, Clauw DJ. 2010. Pharmacotherapy in fibromyalgia (FM) — Implications for the underlying pathophysiology. Pharmacol. Ther. Apr 11. [Epub ahead of print]

Williams DA, Clauw DJ. 2009. Understanding fibromyalgia: lessons from the broader pain research community. J. Pain 10: 777-791.

Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2010. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. (Hoboken) 62: 600-610.

Beth Winkelstein

Dong L, Winkelstein BA. 2010. Simulated whiplash modulates expression of the glutamatergic system in the spinal cord suggesting spinal plasticity is associated with painful dynamic cervical facet loading. J. Neurotrauma 27: 163-174.

Hubbard RD, Quinn KP, Martinez JJ, et al. 2008. The role of graded nerve root compression on axonal damage, neuropeptide changes, and pain-related behaviors. Stapp Car Crash J. 52: 33-58.

Lee KE, Davis MB, Winkelstein BA. 2008. Capsular ligament involvement in the development of mechanical hyperalgesia after facet joint loading: behavioral and inflammatory outcomes in a rodent model of pain. J. Neurotrauma 25: 1383-1393.

Siegmund GP, Davis MB, Quinn KP, et al. 2008. Head-turned postures increase the risk of cervical facet capsule injury during whiplash. Spine (Phila Pa 1976) 33: 1643-1649.

Siegmund GP, Winkelstein BA, Ivancic PC, et al. 2009. The anatomy and biomechanics of acute and chronic whiplash injury. Traffic Inj. Prev. 10: 101-112.

Winkelstein BA,Santos DG. 2008. An intact facet capsular ligament modulates behavioral sensitivity and spinal glial activation produced by cervical facet joint tension. Spine (Phila Pa 1976) 33: 856-862.

Smriti Iyengar

Skljarevski V, Desaiah D, Liu-Seifert H, et al. 2010. Efficacy and safety of duloxetine in patients with chronic low back pain. Spine (Phila Pa 1976)

Skljarevski V, Ossanna M, Liu-Seifert H, et al. 2009. A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain. Eur. J. Neurol. 16: 1041-1048.

Robinson MJ, Edwards SE, Iyengar S, et al. 2009. Depression and pain. Front Biosci. 14: 5031-5051. Full Text

Chappell AS, Ossanna MJ, Liu-Seifert H, et al. 2009. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain 146: 253-260.

Tauscher J, Kielbasa W, Iyengar S, et al. 2010. Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder. Eur. Neuropsychopharmacol. 20: 80-87.

Turk DC, Dworkin RH, McDermott MP, et al. 2008. Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. Pain 139: 485-493.

Wernicke JF, Wang F, Pritchett YL, et al. 2007. An open-label 52-week clinical extension comparing duloxetine with routine care in patients with diabetic peripheral neuropathic pain. Pain Med. 8: 503-513.

Mark Bowlby

Friis S, Mathes C, Sunesen M, et al. 2009. Characterization of compounds on nicotinic acetylcholine receptor alpha7 channels using higher throughput electrophysiology. J. Neurosci. Methods 177: 142-148.

Jow F, Shen R, Chanda P, et al. 2007. Validation of a medium-throughput electrophysiological assay for KCNQ2/3 channel enhancers using IonWorks HT. J. Biomol. Screen. 12: 1059-1067.

Lee YT, Vasilyev DV, Shan QJ, et al. 2008. Novel pharmacological activity of loperamide and CP-339,818 on human HCN channels characterized with an automated electrophysiology assay. Eur. J. Pharmacol. 581: 97-104.

Mayer SC, Butera JA, Diller DJ, et al. 2010. Ion channel screening plates: design, construction, and maintenance. Assay Drug Dev. Technol.

Vasilyev DV, Merrill TL, Bowlby MR. 2005. Development of a novel automated ion channel recording method using "inside-out" whole-cell membranes. J. Biomol. Screen. 10: 806-813.

Vasilyev DV, Shan QJ, Lee YT, et al. 2009. A novel high-throughput screening assay for HCN channel blocker using membrane potential-sensitive dye and FLIPR. J. Biomol. Screen. 14: 1119-1128.

Speakers

Mark R. Bowlby, PhD

Merck Research Laboratories
e-mail | publications

Mark Bowlby is currently director of exploratory biomarkers in the Pain and Migraine department at Merck Research Labs in West Point, PA. Bowlby received his Bachelor's degree from SUNY Stony Brook, followed by a MS and PhD 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. 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, MD

The University of Michigan
e-mail | web site | publications

Daniel 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, Clauw subsequently completed a residency in internal medicine and a fellowship in rheumatology at Georgetown University Medical Center in Washington, DC.

Clauw served in various capacities at Georgetown, including vice chair of medicine and director of the Georgetown Center for Chronic Pain and Fatigue Research before returning to the University of Michigan. At the University of Michigan until recently, 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.

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, 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

Sulayman D. Dib-Hajj, PhD

Yale University School of Medicine
e-mail | web site | publications

Sulayman D. Dib-Hajj 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, Dib-Hajj earned his doctorate degree in molecular, cellular, and developmental biology from the Ohio State University, Columbus, Ohio.

Dib-Hajj's research focuses on the role of voltage-gated sodium channels in inherited and acquired pain disorders. A multi-disciplinary approach has been utilized to investigate the role of sodium channels in electrogenesis within nociceptive neurons under normal and pathological conditions. These studies have yielded information about contribution of peripheral sodium channels to pathophysiology of pain. Dib-Hajj has co-authored more than 100 articles, abstracts, and book chapters. 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.

Smriti Iyengar, PhD

Eli Lilly & Co.
e-mail | publications

Smriti Iyengar received her PhD 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 B. MacDermott

Amy B. MacDermott, PhD

Columbia University
e-mail | web site | publications

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. 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

Michael W. Salter, MD, PhD

Hospital for Sick Children, University of Toronto
e-mail | web site | publications

Michael Salter received his MD at the University of Western Ontario and his PhD from McGill University. As the Canada Research Chair in Neuroplasticity and Pain, 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

Beth A. Winkelstein, PhD

University of Pennsylvania
e-mail | web site | publications

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 Joyce DeLeo in Anesthesiology/Pharmacology/Toxicology at Dartmouth in the neuroimmunology of low back pain.

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.

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. 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.


Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.

Sponsors

Academy Friends

Bristol-Myers Squibb R&D
NeurogesX, Inc.

Grant Support

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