The purpose of this Funding Opportunity Announcement (FOA), "Mechanisms, Models, Measurement, & Management in Pain Research," is to inform the scientific community of the pain research interests of the various Institutes and Centers (ICs) at the National Institutes of Health (NIH) and to stimulate and foster a wide range of basic, clinical, and translational studies on pain as they relate to the missions of these ICs.
New advances are needed in every area of pain research, from the micro perspective of molecular sciences to the macro perspective of behavioral and social sciences. Although great strides have been made in some areas, such as the identification of neural pathways of pain, the experience of pain and the challenge of treatment have remained uniquely individual and unsolved. Furthermore, our understanding of how and why individuals transition to a chronic pain state after an acute insult is limited. Research to address these issues conducted by interdisciplinary and multidisciplinary research teams is strongly encouraged, as is research from underrepresented, minority, disabled, or female investigators.
Pain is a critical national health problem. It is the most common reason for medical appointments and costs this country over $100 billion each year in health care and lost productivity. Chronic pain affects more than 50 million Americans per year. Pain often results in disability and, even when not disabling, it has a profound effect on the quality of life. Its deleterious effects have been demonstrated in morbidity, immune function, sleep, cognition, eating, mobility, affective state, psychosocial behaviors, and overall functional status. In the hospitalized patient, pain may be associated with increased length of stay, longer recovery time, and poorer patient outcomes, which in turn have health care quality and cost implications.
The NIH Pain Consortium was established in 1996 to enhance pain research and promote collaboration among researchers across the many NIH ICs that have programs and activities addressing pain. Currently, the research interests of twenty-one NIH Institutes, Centers, and Offices are represented in the Consortium. Although these combined efforts have resulted in great scientific progress, the understanding and treatment of pain remains incomplete. Congress declared 2001 to 2010 the Decade of Pain Control and Research. NIH continues to be responsive to and in alignment with the focus of this declaration. At the Annual NIH Pain Consortium Symposia, "Advances in Pain Research," speakers present new pain research findings and reiterate the need for an ongoing multidisciplinary research agenda that will lead to the prevention or effective treatment of unwanted pain.
The NIH Pain Consortium supports research on all conditions in which pain is a prominent feature. Of interest are diseases, such as cancer, that of themselves or their treatment may result in pain. Many primary conditions, whether acute (such as injury), recurring (such as migraine), or chronic (such as arthritis) are significantly complicated by co-morbid pain disorders. Some pain conditions are unassociated with other primary diagnoses. Chronic pain is widely believed to represent a disease itself, causing long-term detrimental physiologic changes and requiring unique assessments and treatments. The areas of research detailed below and the following acute and chronic pain conditions are of special interest but do not comprise a comprehensive or complete listing of research areas relevant to this FOA.
- Inflammatory Pain
- Visceral pain
- Chronic urologic pelvic pain syndromes
- Neuropathic pain
- Spinal cord injury pain
- Musculoskeletal pain, including back pain
- Cancer Pain
- Bone pain secondary to cancer
- Cardiovascular pain disorders
- Chemotherapy-induced neuropathies and other malignant disorders
- Temporomandibular joint and muscle disorders
- Pain associated with HIV/AIDS
- Pain associated with osteoporosis
- Pain associated with communication disorders (e.g., otitis media, tinnitus, burning mouth syndrome, dysphagia)
- Pain at the end of life
- Pain in older persons with multiple contributing morbidities
- Pain in people with drug and alcohol addictions
- Pain in persons with neuromuscular conditions
- Pain in preterm neonates exposed to multiple medical interventions
- Skin disorders and pain
New and innovative advances are needed in every area of pain research, from the microperspective of molecular sciences to the macro perspective of behavioral/social sciences. Although great strides have been made in some areas, such as the neural pathways of pain, chronic pain and the challenge of its treatment have remained uniquely individual and largely unsolved. Proposals that seek to improve the understanding of the causes, costs, and societal effects of both acute and chronic pain and the relationships between the two are highly encouraged. Studies on the mechanisms underlying the transition from acute to chronic pain are also needed. Additionally, proposals that link such understandings to the development of better approaches to therapeutic interventions, including complementary and alternative medicine (CAM) interventions, and management of acute and chronic pain are in keeping with the current translational focus of NIH and are encouraged.
The following topic
MOLECULAR AND CELLULAR MECHANISMS OF PAIN
Improved treatments of acute and chronic pain conditions require a thorough understanding of the processes underlying the transmission and perception of painful stimuli. Discovery of the molecules, cells, and neuronal pathways involved in nociception/pain perception and affective aspects of pain are critical. Molecular and cellular studies, when coupled with studies in animal models and clinical research, will provide a comprehensive basis for the development of new pharmacological, behavioral, and technology-based treatments for chronic pain disorders, and/or research on the mechanisms of action of therapies effective for chronic pain. Hormones, neurotransmitters and their receptors, ion channels, G-protein coupled receptors, neuropeptides, and neurotrophic factors are just a few of the molecules of interest in pain studies. Molecular mechanisms and nervous system circuitry involved in facilitation and inhibition of pain signaling and in the development of hypersensitive pain states are important targets of pain research. Neurons, glial cells, and keratinocytes all play important roles in pain sensation and approaches examining their individual functions and their interactions are vital for understanding pain processes. Research is encouraged but not limited to science in the following areas:
- Mechanisms that underlie sex differences in the pain experience.
- Cellular and molecular mechanisms involved in pain processing, modulation, and perception.
- Molecules and processes that target cellular mechanisms involved in signaling, modulation, and perception of pain, as well as changes in these processes over the developmental life-course, to enhance innovative therapeutic development.
- Ontogeny and neuropharmacology of the pain system.
- Endogenous and environmental factors that alter pain during the course of development, in response to injury, and related to disease processes.
- Mechanisms of hypersensitivity including both central and peripheral mechanisms of hyperalgesia and allodynia.
- Endogenous molecules that modify pain perception and analgesic treatments.
GENETICS OF PAIN
Clinical studies have identified polymorphisms at several gene loci that are associated with differential sensitivity to experimental pain. Inbred strains of mice also show differential pain responses in models of neuropathic and inflammatory pain. These studies strongly suggest that genetics plays an important role in pain mechanisms. Chronic pain conditions are complex disorders where environmental and genetic influences interact to affect sensitivity to noxious stimuli and relief from pain. Polymorphisms and mutations in mitochondrial DNA may also play a role in modulating pain, especially in muscles and peripheral nerves. Elucidating the genetic contributions to the individual variability in pain sensitivity and perception is of much interest. Research is encouraged but not limited to science in the following areas:
- Genes and gene variants involved in the complex processes of pain perception.
- Utilization of pharmacogenetics to identify gene variants with potential to inform treatment providers which pain medications may be most effective for the individual needing therapy, with the fewest side effects.
- Use of gene therapy to ameliorate chronic pain.
- Gene polymorphisms and gene-environment interactions that predict pain development or treatment response.
- Epigenetic mechanisms underlying chronic pain conditions.
The experience of pain is a complex interaction of biological, cognitive, behavioral, sociocultural, spiritual, and environmental factors. Pain etiology, severity, tolerance, exacerbation, maintenance, and treatment are all significantly influenced by this complex of acknowledged but poorly understood interactions. Comorbid conditions that alter affect, such as mood disorders, can induce or exacerbate pain. Although it is recognized that psychological factors, such as expectation or stress, significantly contribute to pain tolerance and treatment efficacy, the physiological mechanisms of these effects are poorly understood. Physiologic responses such as autonomic arousal, muscle tone and activity, skin thermal receptor activation, and cardiopulmonary reactivity, are perceived as painful in some behavioral and sociocultural environments, but not in others. The elucidation of these complex interactions will enable better assessment of pain in clinical settings, more effective therapeutic approaches, greater ability to prevent pain onset, and potentially will increase the individual's ability to self-manage pain.
Research is encouraged but not limited to science in the following areas:
- Adaptation to pain and ways to incorporate this adaptation into treatments.
- Mechanisms and process variables that are responsible for the efficacy of behavioral and CAM interventions for pain. This research includes studies to better understand the effect of patients' expectations and beliefs, psychophysiological states (e.g., anxiety, relaxation, stress), adherence, and specific cognitive (e.g., imagery) and sociocultural (e.g., support systems) components in behavioral and CAM interventions to treat pain.
- Biobehavioral techniques for optimizing adherence to pain management. Identify barriers to adherence to pain management strategies.
- Sensory, cognitive, and affective aspects of acute and chronic pain in individuals across the developmental lifespan.
- Development of methods for assessing relative contributions of biological, psychological, behavioral, and environmental predictors of the course of pain, pain dysfunction, and response to treatment for pain.
- Interactions of pain and sleep, their combined impact on function and illness recovery, and interventions that target these interactions.
- Relationships among a variety of emotional states (e.g., anger, fear, anxiety and depression), which are associated with acute and chronic pain conditions, and how these affective states modify the experience of pain and treatment outcomes.
- Interaction of biological markers, central nervous system mechanisms, and drug, behavioral, and CAM interventions.
- Mechanisms that underlie gender and cultural differences in the pain experience.
MODELS OF PAIN
There are many factors responsible for pain experienced by patients. Current animal models of pain have been useful in understanding the mechanisms of pain and developing interventions that target these particular mechanisms. However, many of the existing animal models do not adequately reflect clinical pain conditions and, in particular, chronic pain disorders. The development of new animal models is necessary in order to discover the underlying mechanisms of pain perception as well as the mechanisms of analgesia that will prove useful in treating patients. Innovative clinical modeling studies are also needed to advance our understanding of these underlying mechanisms. Research is encouraged but not limited to science in the following areas:
- New animal models and refinement of existing animal models.
- New measures of pain in animals that are non-invasive and objective, and that permit a behavioral or functional assessment of pain and pain treatment outcomes.
- Use of transgenic animals in the study of pain mechanisms.
- Studies in patients with chronic pain conditions that develop, test, and validate new models of these chronic disorders.
- Computational models that predict development of pain and/or treatment responses.
- Computer simulations of pain that overcome ethical concerns and expand the range of studies possible.
- Objective Measures of spontaneous pain in validated animal models of chronic pain conditions.
DIAGNOSIS AND ASSESSMENT OF PAIN
Most healthcare system interactions are initiated by persons with complaints of pain. To date, direct patient report is the basis of most pain assessments. Yet many patients, including the very young, persons with cognitive, sensory, psychiatric, or physical disabilities, those rendered unresponsive by their physiologic state (e.g., drug intoxication, severe brain injury), and those persons who by culture, education, language, or communication skills may be unable to effectively respond using currently validated assessment tools. To study, model, predict, prevent, diagnose, treat, or manage pain effectively, sensitive multimodal measurement tools are needed. Pain assessment techniques must be valid and reliable and provide sensitivity, both with single and repeated measurements, and allow for the assessment of acute, chronic, persistent, and breakthrough pain. Severity/intensity, type/location/source (i.e., somatic, visceral, neuropathic), and duration (acute, chronic, persistent, breakthrough) are key components to assess. Assessment should include diagnostic as well as outcomes measures. Research is encouraged but not limited to science in the following areas:
- Refinement of existing physiologic techniques for measuring pain for greater sensitivity and specificity.
- New, outcome-specific techniques for different populations.
- Sensitive assessment tools that are not language (neither receptive nor production) dependent.
- Refinement of pain measurements that can account for or predict the trajectory or course of pain, as well as the changes in pain over time.
- Predictive biomarkers of pain that are sensitive to rapid changes in pain.
- Develop pain assessments that are sensitive across both developmental and cognitive spectrums, especially assessments of pain in children and in older adults with declining cognitive function.
- New technologies to improve pain assessment in all populations, but especially in those persons with limited language abilities.
The prevalence of pain and inadequate pain management in patients is well documented. It is estimated that 75% of patients with advanced cancer experience moderate to severe pain; an IOM report states that 40% of people at the end of life have severe, unrelieved pain. A number of advances have been made in the treatment of chronic pain, most notably the neuroactive medications, counter-stimulation methods, and cognitive-behavioral therapies. However, adoption of these advances remains modest. Many patients report that they are reluctant or afraid to report their pain, are unaware of available pain management modalities, or do not adhere to pain treatment when available. Healthcare providers undertreat pain, fearing patient addiction, drug interactions, or adverse events. In addition, research findings consistently show the heterogeneity of response to treatment, even for pain of the same type and etiology.
Due to the biobehavioral nature of pain, pain management should engage interdisciplinary teams and involve both pharmacologic and non-pharmacologic approaches. Research is encouraged but not limited to science in the following areas:
- Interventions involving combinations and sequencing of pharmacological, non-pharmacological, and behavioral interventions to manage pain in progressive, incurable diseases.
- Interventions to reduce pain that are customized to the group (i.e., targeted), as well as to the individual (i.e., tailored).
- New methods to manage pain in cognitively impaired individuals or those unable to verbalize their pain.
- Interventions to manage co-occurring symptoms related to pain such as depression and fatigue.
- Role of pain and pain management approaches in improving rehabilitation outcomes and preventing functional decline.
- Methods for optimizing maintenance and stability of treatment in patients with advancing disease or with pain from multiple contributing disease processes.
- Novel interventions to manage pain in progressive, incurable, nonmalignant diseases.
- Interventions to improve management of side-effects related to pharmacological pain therapy.
- New techniques for managing pediatric pain.
- Models of therapy in those with uncontrolled pain and/or breakthrough pain.
- Pain management strategies at the end of life.
- Long-term (i.e., physiologic, behavioral, or developmental) effects of pharmacologic treatment during the neonatal period and childhood.
- Clinical trials to establish best pain management practices.
EPIDEMIOLOGY OF PAIN
One goal of this FOA is to stimulate innovative investigations that enhance our understanding of the incidence, prevalence, and correlates of pain within and across populations. Epidemiology is one of the fields of science recognized for its contribution to understanding of physical and mental disorders. However, epidemiologic information concerning pain disorders is not well developed. Research is encouraged but not limited to science in the following areas:
- Incidence and natural history of pain disorders and their correlates over time.
- Interplay of environmental (e.g., familial and/or neighborhood quality and resources), physical (e.g., co-morbid medical disorders that are a result of, or a cause of pain), behavioral (e.g., co-morbid mental and substance use disorders), and social or socio-economic (e.g., loss of employment-including issues of secondary or tertiary gain, social isolation, lack of mobility, dependence on others for basic caretaking) factors.
- Risk factors; including age, ethnicity, family history, gender, genetic predisposition, lifestyle, occupation, pre- or co-existing mental and physical disorders, and socio-economic status (SES); and the mechanisms that are associated with the occurrence, maintenance, and remission of pain conditions.
- Impact of pain on an individual's SES and the resulting health consequences (e.g., obesity, deconditioning, mental disorders, substance abuse) controlling for the effect of the cultural and socio-economic influence of the community.
- Prevalence of and methods for self-management of pain within and across cultural, racial, ethnic populations, and populations of special interest such as persons with disabilities, across developmental age groups.
- The effect changes in practice or policy have on the measures of pain, e.g., effect of the increase in the amount of opioid prescriptions on the natural course of pain using aggregate population measures.
- Creation and adoption of innovative epidemiologic and statistical methodologies and study designs to further the understanding of pain disorders. Also use these techniques to maximize the analytic yield from new and existing data sets.
- Interrelationship of psychiatric disorders (e.g., borderline personality, histrionic, antisocial) and chronic pain, and relate these findings to pharmacological and behavioral therapies.
- Co-morbid disorders and pain, including descriptive studies of risk and protective processes, and interventions aimed at relieving adverse consequences associated with co-morbid disorders and pain.
The Institute of Medicine reported significant racial and ethnic disparities with regard to the socioeconomic, health, and quality-of-life impacts of pain. Racial and ethnic minorities tend to be under treated for pain when compared with non-Hispanic Whites. There is also evidence for racial/ethnic differences in pain care for various types of pain. Persons with disabilities report greater levels of pain and less benefit from treatment than do those without disabilities. Little other data exists as to pain disparities in persons with disabilities, the homeless, or persons living in frontier/extremely rural areas. It is clear that many factors contribute to these health disparities, including patient preferences, differences in attitudes toward and response to treatments, access to and accessibility of health care providers, and health care system factors. This program announcement invites research applications that seek to address the underlying causes of these disparities and suggest ways to address and remedy them. In particular, clinical investigations and appropriate clinical trials relevant to health disparity issues are of interest. Research is encouraged but not limited to science in the following areas:
- Differences in care for various types of pain, acute postoperative pain, treatment-related pain, cancer pain, or chronic non-malignant pain, in various settings (i.e., health clinics, physician and dental offices, institutional settings including long-term care facilities, assisted living facilities, or emergency departments), and management of pain at the end of life.
- Differences in the factors contributing to pain disparities including patient-related (e.g., communication, attitudes), health care provider-related (e.g., decision making), and health care system-related (e.g., access to pain medication) factors.
- Differences in perceptions of pain and responses to pain and how these differences impact appropriate treatment management of pain.
- The nature and extent of disparities in the delivery of pain treatment in diverse populations.
- Existing and potential barriers to quality pain care and management including patient-related barriers, health care provider-related barriers, health care system-related barriers, and sociocultural barriers.
- Novel, evidence-based interventions to improve training for health care providers and educational interventions for minority patients.
- Measures of pain perception for those with cognitive impairment, or limited health literacy and from varied cultures.
- Assessment of the global impact, including societal and medical consequences, of pain related disparities on both individuals and society, and the potential impact of pain-related disability.
- Diverse cultural beliefs about and actions taken for pain and its management including self-care and that of lay caregivers.
- Treatment and management strategies for chronic pain in diverse populations.
- Means to identify population differences in pain perception and processing by addressing the incidence, severity, and consequences of pain in these and the general populations, and in specific disease states.
- New diagnostic tools for different pain mechanisms, and objective measures of treatment response that have validity in diverse populations.
- The prevalence and effectiveness of the use of non-pharmacological and novel (e.g. virtual reality) therapies for pain treatment in diverse populations such as ethnic minority groups and persons with disabilities.
- Pain management for special populations including infants, children, elderly, cognitively impaired, disabled, chronically and/or terminally ill, and patients with psychiatric diagnoses.
TRANSLATIONAL PAIN RESEARCH
The translation of laboratory-based, scientific discoveries into practical, clinical applications is a current priority for NIH. Such translational research has a reasonable probability of leading to practical outcomes within the foreseeable future and likewise resultant clinical findings should stimulate new areas of basic research. Inherent in translational research is the recognition of both efficacy (i.e., does the intervention work in a controlled setting) and effectiveness (i.e., does the intervention work in the natural environment) research. Effective translational research is extremely important in pain research and is needed to bridge the inherent differences in approach between basic studies of pain and the clinical study of pain conditions. Accordingly, proposals directed toward translational pain research are of particular interest. Research is encouraged but not limited to science in the following areas:
- Novel pharmacological and non-pharmacological pain treatments.
- Improved treatment protocols and adjunctive therapies that promote greater effectiveness, patient adherence, or patient tolerance.
- Characteristics (e.g., gender, race, age, type of pain) that predict which patient populations will benefit most or least from various pain treatments.
- Barriers to effective pain treatment.
- New technologies for use in the study and treatment of pain in the natural environment of the patient's daily living.
- Clinical studies to inform, develop, and validate new animal models of chronic pain conditions; i.e. a bedside to bench approach.
- Design and development of small molecule mimics and other advanced pharmacological approaches.