Testimony

Wednesday, December 8, 2005

Introduction
The National Institutes of Health (NIH) is pleased to submit a statement for the record with respect to pain-related research at the NIH, including trans-NIH activities of the NIH Pain Consortium. The NIH, an agency of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. NIH comprises 27 Institutes and Centers (ICs) and investigates the causes, treatments, and cures for both common and rare diseases.

More than 50 million Americans experience chronic pain and more than half of dying patients experience moderate to severe pain during the last days of their life. Pain is a frequent cause for clinical visits, with approximately 45% of the population seeking medical help for pain at some point in their lives. Pain occurs across the lifespan, and it has been estimated that four out of every ten people with moderate or severe pain do not get adequate relief.

Unlike the short-term, acute pain that people feel when they cut or burn themselves, chronic pain is a disorder that persists for months or years and cannot be fully relieved by standard pain medications. Chronic pain is widely believed to represent a disease itself, causing long-term detrimental changes in the nervous system. It does manifest however, with many other physiologic and psychosocial disorders, including depression and anxiety, increasing the disability and impairment of these conditions. Pain interferes with sleep, activities of daily living, and productivity. It not only lowers the quality of life but also is a risk factor for suicide in patients who suffer from depression. Chronic pain conditions are an enormous burden on health care resources.

Compounding the problem of unrelieved chronic pain is the issue of under-treatment. While advances have been made in the management of pain, these advances have not translated into standard-of-care practices in the clinical setting. A significant proportion of patients report that they are not routinely asked about their pain, are reluctant or afraid to report pain, are unaware of available pain management treatments, do not adhere to pain treatments when provided, and at times are not offered any treatment even when they do report problematic symptoms. Under-treatment is related to fears surrounding the use of opioids, which include concerns about addiction, respiratory depression and other side effects, tolerance, diversion, and fear of regulatory action. These concerns are often exaggerated or unfounded. Pain management has been well studied, resulting in the publication and wide dissemination of clinical practice guidelines through multiple channels and organizations. Despite the long publication history of such guidelines, patients continue to suffer from inadequate relief of their pain.

The NIH investment in pain research has grown considerably over the last several years, increasing from $82 million in 1997 to $223 million in 2004. Perhaps equally significant has been the NIH commitment to a more coordinated, inter- and multi-disciplinary approach to pain research.

The NIH Pain Consortium
The NIH Pain Research Consortium was established in 1996 to fulfill the need for coordination across the many ICs that have programs and activities addressing pain. Revitalized in 2003 by NIH Director Dr. Elias Zerhouni, the Consortium is co-chaired by the Directors of the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Nursing Research (NINR). Currently, 20 NIH ICs and Offices are members of the Consortium, providing an exceptional opportunity to coordinate and integrate resources and activities across multiple scientific areas and the spectrum of basic, translational, and patient-oriented clinical research. The current membership of the Consortium is listed in Appendix 1. Since its revitalization, the Consortium has met twice each year during 2003-2005 and has initiated a number of activities to support its goals. Working subcommittees have been established to plan activities and events directed at accomplishing the goals of the consortium.

Included in the goals of the Pain Consortium are the development of a comprehensive and forward-thinking pain research agenda for the NIH and the coordination of research support across the many NIH ICs that have programs and activities addressing pain. One of the first actions undertaken by the Consortium was the development of a comprehensive inventory of trans-NIH pain research support, relevant resources, and ongoing activities. These data helped to identify research gaps and opportunities in the NIH pain portfolio, particularly those that would benefit from multi-disciplinary NIH participation. The survey helped to identify potential future efforts in pain research; possibilities include increasing understanding of the mechanisms and pathophysiology of pain and pain conditions; enhancing the translation of basic research to pain management in humans; facilitating the development and implementation of promising new therapies for pain management; accurately assessing the epidemiology of various pain associated syndromes; and developing better strategies for introducing research findings into clinical practice. The Consortium developed strategies to address each of these priorities over the short and long terms, as described in the following paragraphs.

Members of the Pain Consortium have coordinated the release of several recent initiatives designed to close gaps in the research portfolio, advance pain research through advances in technologies and knowledge, and improve pain management. These initiatives include program announcements (PAs) and requests for applications (RFAs) in which participating ICs have combined resources and set aside funds to support pain research. Appendix 2 includes recent and current extramural funding opportunities that are either collaborations among Consortium members or released by individual members of the Consortium. They encompass diverse disease topics and research approaches.

The Consortium created a website (http://painconsortium.nih.gov), to serve as a resource for NIH staff, extramural researchers, health care providers, patients and the general public. The website features an alphabetical index of NIH pain-related health information materials, information about clinical trials, conference proceedings and expert panel reports, funding opportunities, news releases and resources such as an interactive textbook on pain and symptom research. The website also provides direct links to PubMed for free searches of the biomedical literature, to MedlinePlus for help locating authoritative health information, and to webcasts of recent pain-related events at NIH.

The Pain Consortium also is working to increase the visibility of important pain research sponsored by NIH. On November, 2, 2005, the Consortium, with NCI leading the effort, conducted a science writers� seminar that introduced reporters to some of the latest research on management of chronic pain, including a technique that has been dubbed a "molecular scalpel" described further below. Leaders in the field of pain management presented their research, and a cancer patient discussed her experience living with severe chronic pain. A syndicated press release highlighting the presentations provided a broad public forum for the information. The seminar was recorded and is available over the NIH videocast website at: http://videocast.nih.gov/PastEvents.asp?c=998.

The Consortium will sponsor a scientific symposium to highlight significant advances in pain research on April 16-17, 2006. It will feature NIH-supported researchers who have contributed to our knowledge of the pathophysiology, epidemiology, and treatment of pain. This symposium is envisioned as the first in a series intended to enhance collaboration among pain researchers and increase awareness of pain research findings to the scientific and health care communities as well as the public. The tentative agenda and list of participants is included as Appendix 3.

The NIH Roadmap and Blueprint for Neuroscience
The NIH Roadmap is a series of far-reaching initiatives designed to transform the Nation's medical research capabilities and speed the movement of research discoveries from the bench to the bedside. It provides a framework of the priorities NIH must address to optimize its entire research portfolio, and it lays out a vision for a more efficient and productive system of medical research. All NIH ICs participate in the Roadmap.

While the Roadmap is not meant to address specific issues, it is providing unprecedented opportunities for pain researchers that could not be possible through the efforts of a single NIH Institute or Center. For example, several Roadmap projects are developing a 21st century toolkit that will enable scientists to better understand the workings of biological systems. The activities within this theme are forging new links between chemistry and biology and newly funded programs will yield new ways to generate and study small molecules, including exquisitely sensitive imaging probes. Such resources will help unravel the functions of genes, cells, pathways and whole organisms, advancing scientists' ability to understand disease such as chronic pain at its earliest stages. Another Roadmap Initiative has established primary research sites and a statistical coordinating center for Patient-Reported Outcomes Measurement Information System (PROMIS) networks. This far-reaching effort aims to develop ways to measure patient-reported symptoms such as pain and fatigue and aspects of health-related quality of life across a wide variety of chronic diseases and conditions. The need to better quantify and validate clinically important symptoms and outcomes is particularly important to the area of chronic pain. Roadmap initiatives are also supporting the development of new informatics approaches to link the measurement of pain to its clinical management and the establishment of a new training program in biobehavioral pain research.

Another unique NIH intra-agency research partnership is the NIH Blueprint for Neuroscience established by the NIH Director in the Fall of 2004 to accelerate neuroscience research. This partnership reinforces ongoing NIH efforts to increase collaborative research and information sharing among 16 NIH ICs that conduct or support research on the brain and nervous system. Information about the Neuroscience Blueprint, including the participating ICs, can be found online at http://neuroscienceblueprint.nih.gov. While each NIH Institute or Center will independently carry out the basic and disease-specific research unique to its mission, the Blueprint targets those neuroscience challenges that are best met collectively, using the full spectrum of NIH expertise. A major emphasis will be integration of neuroscience across all levels of analysis from molecules, through cells, to the functional systems responsible for perception, thinking, emotion, and behavior. The Blueprint will accelerate the translation of basic neuroscience discoveries into better ways to treat and prevent disorders of the nervous system, which include chronic pain. The Blueprint will also spur the development of new analytical methods and conceptual models for the study of disease. Additionally, it will enable increased coordination of public education and outreach campaigns across multiple ICs. Given the multifaceted aspects of pain and the cross-disciplinary approaches needed to understand and treat pain, the Blueprint offers an ideal opportunity to promote pain research.

NIH Research Training Programs
The NIH also supports training programs at both the pre- and post-doctoral level with the goal of giving young scientists and physician-scientists a broad experience in the pharmacological, pathological, and molecular biological methods of pain research. An ambitious new initiative of the NIH Blueprint for Neuroscience Research involves ICs working together to support research education grants that will support the development and initiation or significant expansion of courses on the neurobiology of disease for graduate students receiving basic neuroscience training. It is expected that each course will span a breath of diseases and disorders affecting the nervous system, emphasizing links and common themes across diseases/disorders and addressing both the pathology of these diseases/disorders and their basic science underpinnings. Appendix 4 summarizes current NIH training opportunities pertinent to the area of pain research and neurobiology.

Selected Findings from NIH Pain Research
The NIH pain portfolio extends across a wide array of pain disorders, conditions and types of chronic pain as well as multiple scientific approaches. These range from research on pain pathways, mechanisms of pain processing, pain molecules and neural networks, pain perception and modulation, gender differences and genetics of pain, bio-behavioral and population-based studies of pain as well as the regulation and management of pain, including research on potential new analgesics. Whereas each NIH Institute or Center may emphasize a particular set of chronic pain conditions or disorders that relate to its scientific mission, they collectively contribute to scientific knowledge that cuts across Institutes, programs, and disease areas. Highlighted below are several examples of ongoing NIH-funded research that hold promise for scientific breakthroughs. These findings may bring hope to the millions of Americans who suffer from chronic pain conditions today as well as improved health and quality of life for generations to come.

PAIN MANAGEMENT
Whereas current analgesic drugs help many ease discomfort, millions of others have pain management needs that remain completely or partially unmet. Nearly all available analgesics were developed based on overly simplified, linear models of pain transmission. Recent advances show that pain transmission is a far more dynamic process that often involves multiple routes, or pathways. Each pathway integrates a convergence of molecular signals, and then relays them, in several steps, along their own specific routes to the brain. The research challenge is to define the molecular details of these multiple routes of pain transmission with the aim of increasing the repertoire of pain management strategies. NIH-funded research is helping to identify new factors that alter peripheral neural pathways under conditions of long-term pain. Other research programs are helping to understand changes in neural transmission and signaling in the part of the brain where pain perception is processed. New imaging techniques that allow patients to �view� brain activity related to pain in real time show promise for pain management.

For example, NIH-funded researchers are investigating the function of specific brain structures in mediating pain responses. Other researchers are examining the role of pain as a stressor and its effect on certain inflammatory responses. Still other investigators are researching the possible effects of Brain-Derived Neurotrophic Factor (BDNF) on pain levels in animals. Yet others focus on chronic pain in rehabilitation medicine; over the past five years their work has focused on measurement and treatment of pain in individuals with chronic inherited conditions, including Duchenne muscular dystrophy and cerebral palsy. NIH also supports studies on treatment of low back pain and on the use of virtual reality to reduce pain in children with medical problems such as severe burns who must undergo periodic painful procedures.

A number of behavioral and cognitive-behavioral techniques for managing pain also are under study. Some of the techniques under investigation are spouse-assisted coping training, tailoring treatment approaches to patient coping styles, interventions such as guided relaxation, tai chi, and exercise for pain management, behavioral treatment for the disordered sleep that frequently accompanies chronic pain conditions, and studies of adaptation to pain and stress that might inform future treatment approaches. Other grants have included evaluations of the efficacy of hypnosis and biofeedback.

PAIN PERCEPTION AND TRANSMISSION
Progress is being made to define the biological pathways and networks of pain. This knowledge is important to provide future pain management options. A multidisciplinary group of NIH grantees have discovered several biological factors that influence pain perception using novel, real-time imaging techniques that track the mu-opioid system, a specific type of protein receptor in the brain that researchers have long suspected triggers a dampening of the pain. In a seminal study published last year, the team confirmed the role of the mu-opioid system in enhancing a person's tolerance of pain. This marked the first study ever that combined prolonged pain with simultaneous brain scan monitoring of the mu-opioid system and self-reported pain ratings of human volunteers. The scientists noted that their results establish that people vary both in their capacity to produce mu-opioid receptors and in their ability to release the anti-pain chemicals themselves. This variability appears to determine the emotional and sensory aspects of a painful experience and might explain why some people react to pain differently than others. It may also help to explain why some people are more prone to chronic pain conditions or do not benefit from certain anti-pain medications. Other NIH-funded scientists are investigating whether some chronic pain conditions (fibromyalgia, for example) may arise from an impairment of central sensory processing that results in a higher likelihood of experiencing sensations as painful.

NEURAL STIMULATION
Various models of neural stimulation have been used with success to treat severe cases of chronic pain. These methods work by either electrically activating pain control areas in the brain, or by disrupting the patterns of pain signals that are generated by the brain itself in conditions of neuropathic pain. Though often effective, these types of procedures are invasive.

A novel way to stimulate areas of the brain involved in pain control has been recently developed by NIH researchers, which is completely non-invasive. This technique involves using an fMRI scanner to scan a pain patient�s brain activity. The patient is then shown the activity of a pain control area of their own brain in real time. The patients are then asked to use this feedback to try to increase the activity in this pain control area of the brain. It has been found not only that pain patients can control this area of the brain when given feedback, but that this also results in a significant decrease in their pain levels. The patients come out of this treatment feeling significantly less pain and saying things like how wonderful it is that for the first time in their life they feel they have control over their own pain.

TRANSLATING PAIN TARGETS INTO TREATMENTS
Sizeable gaps exist in our understanding of some of the most basic cellular interactions involved in the pain process. A prime example is the role of glial cells. For decades, scientists assumed that glial cells primarily played a supportive role in the central nervous system and had no direct influence on the transmission of sensory signals to the brain. But, as more powerful analytical molecular tools have emerged in recent years, scientists now realize that glial cells play a far more important role in pain than was previously appreciated.

The NIH recently launched an effort to stimulate needed research into the basic biology of glial cells and their interactions with neurons in causing orofacial pain disorders. The initiative encourages multidisciplinary studies in a variety of areas to define more broadly than ever the important aspects of the pain process. Based on this broad investigative approach, key aspects of the pain process will be more clearly defined, pointing the way to unique and highly specific molecular targets for drug development. Without identifying these additional targets, it will be impossible to ever adequately control or treat pain, particularly among Americans who suffer from chronic pain.

One example of such targets is fractalkines. It is clear how neurons detect and process pain. Primary neurons have pain-detecting receptors, and these receptors are distributed throughout the body. When a pain receptor is activated, a pain signal is conveyed via neurons to various areas of the brain. However, it has not been so clear how glial cells receive information from neurons that pain is present. NIH researchers have recently discovered that fractalkines are released from neurons during pain states, and these fractalkines activate receptors on glial cells which cause the glial cells to release chemicals that exacerbate the pain state. Stopping the ability of fractalkines to activate glial cells has been shown in animals to greatly reduce signs of pain. Accordingly, fractalkines are seen as a potential novel target for pain treatment in humans.

GENE THERAPY/GENOMICS
Our current knowledge of pain transmission has led researchers to identify many of the molecules involved in transforming acute pain to the chronic state. Regulating the production of these molecules through genetic approaches has great potential for pain management. Using viral vectors to deliver a neurotransmitter-related gene to the spinal cord, NIH researchers have been able to alleviate pain over a long period of time in dogs and rats with various types of pain, including pain from nerve damage. Some scientists have used gene therapy to cause neurons to increase the levels of endogenous opioids or endorphins (chemicals that naturally occur in the body that have similar characteristics to drugs like morphine). When these levels of endogenous opioids are increased, pain is decreased for long periods of time. Other NIH researchers have used gene therapy to increase the number of mu-opioid receptors (the sites where opioids like morphine act) in the brain and spinal cord. This not only results in endogenous opioids producing more analgesia, but when drugs like morphine are administered to these animals, the drugs are more effective at relieving pain. A further gene therapy approach is to target glial cells in the brain and spinal cord. Glial cells have been found to be critically involved in many types of pain. Using gene therapy, the signals that glial cells send to produce pain can be dampened, thus resulting in long-term analgesia in animals.

GENDER AND PAIN
It is now widely believed that pain affects men and women differently. NIH research in this area is yielding fascinating and important results. For example, NIH researchers have shown that male experimental animals injected with estrogen, a female sex hormone, appear to have a lower tolerance for pain. Similarly, the presence of testosterone, a male hormone, appears to elevate tolerance for pain in female mice. Female mice deprived of estrogen during experiments react to stress similarly to male animals. Estrogen, therefore, may be acting as a sort of pain switch, turning on the ability to recognize pain.

Investigators know both males and females have strong natural pain-killing systems, but these systems operate differently. Continued research may result in a better understanding of how pain affects women differently from men, enabling new and better pain medications to be designed with gender in mind.

NIH supported scientists are conducting research on several aspects of chronic pain, including a number of investigations on vulvodynia, a complex and multifactorial chronic pain syndrome. While the exact prevalence remains unknown, several million women in the United States are estimated to have vulvodynia. Investigators are currently studying the basic aspects of pain in this condition as well as treatment modalities. An announcement communicating the intent to continue supporting research efforts aimed at reducing the burden of this disease and improving the quality of life for women affected with this disorder is soon to be released. In addition, NIH funds several projects on endometriosis, another condition in women that often causes severe, chronic pain.

In other NIH-supported research, scientists have observed that at matched levels of pain intensity, men and women differ in the degree and direction of the mu-opioid response in distinct areas of the brain. In particular, men had greater activation of certain receptors in specific regions of the brain. Conversely, when women experienced pain, they had reductions in the resting levels of these receptors when they experienced pain in an area of the brain previously associated with hyperalgesic responses to the blockage of these receptors. Similarly, researchers found that women experienced pain relief using another class of drugs known as kappa-opioids, whereas men reported little benefit. Scientists also have focused on possible genetic predisposition to pain and have found that people who inherit an extremely common variation in a particular gene have a lower natural threshold of pain than those who were born without the variation. The scientists speculated that the variant gene encodes a slightly altered enzyme that functions somewhat differently than the normal enzyme, leading to lower brain levels of pain-killing endorphins. This finding highlights the growing recognition that pain treatment should be customized to meet the specific needs of individual patients.

IMPROVING QUALITY OF LIFE AND SYMPTOM MANAGEMENT
NIH is sponsoring research that examines and tests interventions to overcome the barriers that impede 1) communication between patients and clinicians about cancer-related pain and their symptoms, 2) clinician utilization of clinical practice guidelines, and 3) patient and caregiver understanding of and adherence to effective pain management strategies. In one study, researchers developed an assessment questionnaire that would teach patients how to report their symptoms. The study's goal is to determine the most effective method that enables patients and doctors to broach the discussion of pain, resulting in improved symptom management.

Another NIH-supported study dealing with cancer pain found that side effects, such as lack of mental clarity and constipation, could discourage patients from adhering to their pain management regimen. These symptoms often can be easily and effectively managed. The NIH also is working to dispel myths about cancer and pain and helping clinicians ask specific questions to determine how well pain medications are working and how well patients are coping.

In the field of pain management, NIH is funding the development of new clinical interventions that allow patients of all ages to better cope with chronic pain, from adolescents being treated for cancer, to the elderly self-managing chronic pain to maintain a high quality of life. Other studies focus on the caregivers of those with chronic pain, and how they can best care for their loved ones while dealing with the added burdens and stresses of their new roles.

PROMISING NEW APPROACHES
NIH researchers may be on the trail of a new and more targeted treatment for severe chronic pain. A team of NIH scientists have recently established, in a series of animal studies, the therapeutic potential of selectively deleting specific nerve cells from the nervous system that convey severe chronic pain. Some have referred to this approach as a �molecular scalpel,� because the technique uses a drug called resiniferatoxin, or RTX, to selectively delete certain neurons that transmit pain signals, but leaves other neurons untouched. As a result, the nervous system functions normally, but a certain spectrum of pain responsiveness is eliminated. Currently, doctors have no way of selectively eliminating nerve cells involved in chronic pain. Researchers also have applied the technique to dogs, whose owners had brought them into nearby veterinary hospitals with severe pain from arthritis and cancer. In these dogs, pain was safely and effectively ameliorated. The ultimate goal is to move the treatment into early stage clinical trials in the near future for people with severe chronic pain.

NIH researchers also are using virtual reality technologies to reduce pain and stress during acute medical procedures. Virtual reality employs computers, which are used to generate simulated environments with which people can interact. The patient views these worlds through special goggles and earphones. While patients are deeply distracted within the virtual world, various procedures were performed on them with little stress or pain (i.e. dental procedures, burn wound care).

Well-defined cognitive-behavioral approaches to headache management are being developed and may be particularly effective for children with headache pain. Interactive programs that focus on understanding pain and its triggers, teach relaxation, biofeedback and cognitive techniques help to reduce headache frequency and improve quality of life.

Conclusion
NIH hopes that the above information has provided an overview of the diverse and multi-faceted work on pain that is being supported by a coordinated effort of its Institutes and Centers. The Consortium looks forward to continuing its work to alleviate the pain of many Americans, as a significant contribution toward fulfilling NIH�s efforts to reduce the burden of illness and disability.

APPENDIX 1
Members of the NIH Pain Consortium
National Cancer Institute (NCI)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of General Medical Sciences (NIGMS)
National Institute of Child Health and Human Development (NICHD)
National Institute on Aging (NIA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Mental Health (NIMH)
National Institute on Drug Abuse (NIDA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Nursing Research (NINR)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Center for Research Resources (NCRR)
National Center for Complementary and Alternative Medicine (NCCAM)
John E. Fogarty International Center (FIC)
Warren Grant Magnuson Clinical Center (CC)
Office of the Director

• Office of Behavioral and Social Sciences Research (OBSSR)
• Office of Technology Transfer (OTT)
• Office of Rare Diseases (ODP/ORD)
• Office of Research on Women�s Health

APPENDIX 2
NIH Initiatives to Promote Pain Research

Current Initiatives
Prescription Opioid Use and Abuse in the Treatment of Pain
Sponsors: NIDA, NIA, NIDCR
RFA-DA-06-005
$5,700,000
RELEASE DATE: November 18, 2005
This collaboration between three Pain Consortium Institutes is intended to solicit research that will examine the risk and protective factors regarding the onset of opioid abuse and addiction in the context of pain, develop pain treatment protocols that are tailored to reduce the probability of these negative health consequences, and develop ways to ameliorate these problems when they occur. The most powerful treatments available for most forms of pain are opioids. However, opioid treatments can produce negative health effects, such as intoxication and physical dependence, and may result in opioid abuse and addiction. In a recently announced solicitation, NIH is requesting applications for research that will provide a scientific foundation to help inform health care providers on how to treat pain successfully while minimizing the risks of abuse and addiction to opioids.

Neurobiology of Persistent Pain Mediated by the Trigeminal Nerve Sponsors: NINDS, NIDCR
PAS-03-173 RELEASE DATE: September, 2003/EXPIRATION DATE: July, 2006. $1,500,000 This PAS is sponsored in collaboration between NINDS and NIDCR and contributes to the goals of the NIH Pain Consortium. These ICs invite applications to advance understanding of the neurobiology of persistent pain mediated by the trigeminal nerve and to develop effective therapeutic strategies to alleviate pain associated with disorders of myofascial, nervous, or skeletal tissues of the head and face, which are innervated by this nerve. The purpose is to foster research that addresses the mechanisms of pain onset, chronic pain conditions, and responsiveness to pain therapy through novel basic and clinical research. Current knowledge of the neurobiology and neurochemistry of nociception, pain modulation and pain perception needs to be further developed and correlated with clinical manifestations of craniofacial pain to improve therapeutic strategies.

Prescription Drug Abuse
Sponsor: NIDA
PA-04-110
RELEASE DATE: June, 2004/EXPIRATION DATE: Feb, 2008
NIDA encourages research aimed at understanding and reducing prescription drug abuse while supporting appropriate medical use of therapeutic agents with abuse liability. To promote the Nation�s health, research is needed to understand the factors contributing to prescription drug abuse, to characterize the adverse medical, behavioral, and social consequences associated with this abuse, and to develop effective prevention and service delivery approaches and behavioral and pharmacological treatments. Applications to address this issue are encouraged across a broad range of experimental approaches including basic, clinical, epidemiological, prevention, and treatment studies.

Joint Degeneration: Mouse Models
RELEASE DATE: August, 2004/EXPIRATION DATE: November, 2007.
PA NUMBER: PA-04-139 Sponsors: NIAMS, NIA, NIDCR
This announcement solicits proposals of research employing genetically defined and genetically modified mouse models to explore the biological mechanisms underlying non-inflammatory joint degeneration, or osteoarthritis.  Inflammatory processes are evident in late stages of osteoarthritis, and are likely to be major contributors to the chronic pain that is the most common symptom of the condition. Increasing knowledge of molecular mechanisms in cartilage and bone biology, along with advances in the genetic manipulation of mice, have yielded new concepts and new animal models that may be relevant to osteoarthritis in humans. This Program Announcement is intended to accelerate the characterization of new models and the testing of hypotheses that could lead to improved diagnosis and treatment of osteoarthritis.

Biobehavioral Pain Research
Sponsors: NINR, NIA, NIAMS, NCI, NICHD, NIDCR, NIDA, NIMH, NINDS, NCCAM
RELEASE DATE: July, 2003/XPIRATION DATE: July, 2006
PA NUMBER: PA-03-152 The purpose of this biobehavioral pain research program announcement is to inform the scientific community of the interests of the various institutes at the NIH and to stimulate and foster a wide range of basic and clinical studies on pain as they relate to the missions of these Institutes. Applications are encouraged to study individual differences in pain responses that may be due to factors such as genetic differences, endocrine activity, neural activity, immune function, psychological state, developmental stage, cognitive capacity, disability state, age, gender, social context and cultural background. The pain experience needs to be examined at all levels of research including the gene, molecule, cell, organ, and individual with the goal of developing biobehavioral interventions to manage or prevent pain.

Collaborative Neurological Sciences Award
Sponsors: NINDS, NIDA, NIMH
RELEASE DATE: Aug, 2005/Expiration Date: Oct, 2008
PAR-04-149
The CNS award will support an investigator-initiated research project in which the applicant and collaborating neuroscientist(s) work in a clearly defined area of mutual research interest. The intent of the award is to develop competitive neuroscience research programs at minority institutions leading to successful competition for traditional research project grants (e.g., R-series and/or equivalent NSF grants) by the applicant investigator during the performance period of the award. The project should consist of a thematic research plan that involves an efficacious collaborative effort among the participating investigators, each of whom will be conducting a portion of the total research project in his/her own laboratory. Examples of the collaborative interactions include the sharing of ideas, data, and exchanging of research techniques and expertise. It is anticipated that interactions between the laboratories of the collaborating investigators will also provide further training opportunities for predoctoral and postdoctoral fellows at both institutions.

Development of Recombinase-Expressing (�Driver�) Mouse Lines for Studying the Nervous System
Sponsors: NIH Blueprint for Neurosciences Research
RELEASE DATE: Nov, 2005/Expiration Date: Feb, 2006
RFA-MH-06-007
This RFA is an initiative of the NIH Blueprint for Neuroscience Research, a trans-NIH partnership to accelerate neuroscience research. This funding opportunity supports the design, creation, and characterization of recombinase-expressing C57BL/6 mouse lines to aid in studies of nervous system development and/or function.  These so-called "driver lines" should specify expression in distinct cell types and/or other useful temporospatial expression patterns in the nervous system.  Drivers with the greatest utility (such as inducibility) and relevance to neuroscience research will be given priority.

Recent Initiatives
The Role of Neuronal/Glial Cell Interactions in Orofacial Pain Disorders
Sponsors: NIDCR
RFA-DE-06-005
RELEASE DATE: May 10, 2005
$2,000,000
The goal of this initiative is to stimulate basic research on the role of glial cells in pain disorders of the orofacial complex and in particular, studies on the interactions between glial cells and neurons that lead to pathological pain states. This initiative will encourage molecular, cellular, and animal studies on 1) the mechanisms by which stimulation of primary afferent nociceptors lead to activation of spinal cord, brain, and peripheral glial cells; 2) the influence of activated glial cells on nociceptive neuron function in experimental pain models; 3) the identification of glial cell proteins and signaling pathways important in maintaining chronic pain states; 4) the identification of the neuronal proteins and signaling systems regulated by activated glial cells; and 5) the role of activated microglia as antigen presenting cells influencing systemic immune cell interactions with the CNS. The knowledge gained from these approaches will lead to rapid and new advances in the identification analgesic targets for chronic pain disorders.

Neurobiology of Complex Regional Pain Syndrome/Reflex Sympathetic Dystrophy
RELEASE DATE: May, 2003/EXPIRATION DATE: April, 2005.
Sponsors: NINDS
$1,500,000
This initiative is to promote research designed to advance our understanding of the neurobiological mechanisms and epidemiology of Complex Regional Pain Syndrome (CRPS)/Reflex Sympathetic Dystrophy (RSD). A major goal is to facilitate the development of novel collaborative research programs among physiologists, neuroscientists, behavioral neuroscientists, imaging specialists and clinicians in order to develop integrative research programs to accelerate progress in CRPS/RSD research. This PA is intended to encourage cross-disciplinary research focused on a mechanism-based diagnostic classification of CRPS/RSD, which might lead to mechanism-based therapeutic strategy for this chronic condition. Prospective Studies on Craniofacial Pain and Dysfunction Sponsor: NIDCR RFA-DE-05-007 RELEASE DATE: November 17, 2004 $2,500,000 The NIDCR invites applications for a Cooperative Agreement (U01) to support a multi-site prospective cohort study of craniofacial pain and dysfunction. For the purpose of this RFA, craniofacial pain and dysfunction will be defined as one or a combination of symptoms such as pain in the muscles of mastication, pain in the temporomandibular joint, facial neuropathies, locking and/or limitation of jaw opening. The purpose is to encourage experienced and established investigators in the area of epidemiology to submit proposals for a prospective cohort study that will identify the incidence of craniofacial pain and dysfunction and its risk factors. Mechanisms of Orofacial Pain: Anatomy, Genomics, and Proteomics Sponsors: NIDCR, NINDS RFA Number: RFA-DE-05-004 RELEASE DATE: November 19, 2003 $1,700,000 This Request for Applications contributes to the goals of the NIH Pain Consortium. The NIDCR and the NINDS invited applications to stimulate and support innovative, interdisciplinary research studies to elucidate the molecular mechanisms underlying orofacial pain, particularly the discovery of proteins and protein networks critical to processing nociceptive information. The purpose of this RFA is to encourage the use of genomic and proteomic approaches and imaging techniques to clarify the molecular events involved in acute orofacial pain, the transition from unrelieved acute to chronic pain and neuronal hyperexcitability as manifested by hyperalgesia and allodynia, and chronic orofacial pain disorders of inflammatory and neuropathic origins. This improved understanding could lead to new therapeutic interventions to effectively treat chronic pain conditions.

Reducing Barriers to Symptom Management and Palliative Care
Sponsors: NCI, NINR, ORWH
RFA Number: CA-05-013
RELEASE DATE: May 26, 2004
$5,200,000
The purpose of this RFA is to solicit grant applications for research directed at developing and testing interventions to reduce or overcome barriers to the delivery of appropriate symptom management and palliative care to patients suffering from disease and/or treatment-related sequelae. Historically, the cancer symptom management research community has focused largely on describing symptom prevalence and testing new interventions to ameliorate one or more symptoms. Many of these studies have shown efficacy, yet, because of a number of patient, clinician, and health system-related barriers, the larger cancer community is not adopting these findings. Research is needed to discover new or innovative way to implement evidenced based practices into routine clinical care. We must expand and accelerate our potential to address the problems of inadequate symptom management and palliative care among diverse populations in the United States. Given NCI�s challenge goal of eliminating the suffering and death due to cancer by 2015, efforts must be directed to improving the delivery of treatments to prevent or ameliorate the adverse physical and psychosocial consequences associated with the diagnosis and treatment of cancer.

APPENDIX 3
DRAFT AGENDA

The NIH Pain Consortium First Annual Symposium
Advances in Pain Research
April 16, 17, 2006
Natcher Auditorium
NIH Clinical Center

Morning I
Session 1: Genetics of Pain
Alan Basbaum, University of California, San Francisco: Mouse Models and Pain Circuits
Jeff Mogil, McGill University: Genes Mutations Underlie Variations in Analgesic Response
Session 2: Cancer Pain/Basic Research and Interventions
Pat Mantyh, University of Minnesota: Animal Models for Cancer Pain
Christine Miaskowski, University of California, San Francisco: Advances in Cancer Pain Management Posters and lunch

Afternoon I
Session 3: Neuronal/Glial Interactions in Chronic Pain
Linda Watkins, University of Colorado: Glia and Pain Management
Joyce DeLeo, Dartmouth-Hitchcock Medical Center: Glia and the Analgesic Response
Session 4: Cognitive/Emotional Aspects of Pain
Cathy Bushnell, McGill University: The Effects of Attention and Emotion on Pain Perception
Roger Fillingim, University of Florida: Ethnic and Gender Variations in Pain Perception
Jennifer Haythornthwaite, Johns Hopkins University: Cognitive Approaches to Pain Management Posters and Reception

Morning II
Session 1: Headache Pain
Michael Moskowitz, Massachusetts General Hospital: Cortical Spreading Depression and Migraine
Rami Burstein, Harvard University: Central Sensitization of the Trigeminal System in Migraine
Andrew Hershey: Childrens Hospital, Cincinnati, Gene Expression Profiles in Migraine Break
Session 2: The Role of Imaging in Pain Research and Therapy
Nouchine Hadjikhani, Massachusetts General Hospital: Imaging Migraine Auras
David Borsook, McLean Hospital and Harvard University: Imaging the Trigeminal Pathways
Robert Coghill, Wake Forest University: Imaging as a Biomarker for Pain Lunch

Afternoon II
Session 3: Novel Therapies for Chronic Pain
Baldomero Oliver: University of Utah: Targeted Toxins � Prialt
Christopher DeCharms: Biofeedback therapy; FMRI
James Eisenach: Preoperative Treatment for Postoperative Pain Management
David Fink, University of Michigan: Gene Therapy for Pain Management Break
Session 4 Three brief talks selected from poster submissions plus advocate talk

APPENDIX 4
Current NIH Training Opportunities in the area of Pain and Neurobiology
Training in Translational Research in Neurobiology of Disease
RFA-DA-06-008
Sponsors: This is an initiative of the NIH Blueprint for Neuroscience research involving the collaboration among NIH Institutes and Centers that include: NCCAM, NCRR, NEI, NIA, NIAAA, NIBIB, NICHD, NIDCD, NIDCR, NIDA, NIGMS, NIEHS, NIMH, NINDS, NINR and OBSSR.

Course Development in the Neurobiology of Disease
R F A-MH-06-006.
Sponsors: The Blueprint Institutes
Diseases of the nervous system pose a significant public health and economic challenge, affecting nearly one in three Americans at some point in their life, with a cost exceeding $500 billion per year.  The National Institutes of Health (NIH) Blueprint for Neuroscience Research ( http://neuroscienceblueprint.nih.gov) is a collaborative and coordinated effort across 16 Institutes and Centers that supports research on the nervous system to accelerate the pace of discovery in neuroscience research.  The ultimate goal of the Neuroscience Blueprint is to translate this new understanding into clinical interventions that will reduce the public health burden of nervous system disorders and help to maintain a healthy nervous system throughout life.   Over the past decade, driven by the emerging science, the NIH Institutes and Centers with an interest in neuroscience have increasingly joined forces through initiatives and through working groups on specific disorders.  By pooling resources and expertise, the Neuroscience Blueprint can take advantage of economies of scale, confront challenges too large for any single Institute or Center, and develop research tools and infrastructure that will serve the entire neuroscience community.

Last Revised: December 23, 2005

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