5


Research Challenges

We want the best damn science this country can give us.

—Terrie Cowley, The TMJ Association, Ltd., an advocate for people with chronic pain1

The last several decades have seen remarkable strides in understanding of pain processes, as well as in assessment and, to some extent, treatment of pain, with new techniques and technologies being applied to one of humanity’s oldest problems. Important new insights into the basic science of pain—from genetics and molecular biology, to neural networks and neuroimaging, to the role of psychosocial factors—are unraveling pain’s mysteries. Some of these new insights have been highlighted earlier in this report. At the same time, the preceding chapters demonstrate that much remains to be learned. For example:

  • The section in Chapter 1 describing the current understanding of how pain works delineates the many physical and psychosocial attributes of pain and shows not only how far we have come but also how much more there is to learn about the biological, psychological, sociological, and environmental aspects of pain and its diagnosis, treatment, and prevention.
  • The description in Chapter 2 of the increasing prevalence of pain, the extent to which it affects various population groups, and its societal costs

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1 Quotation from testimony to the committee, November 2010.



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5 Research Challenges We want the best damn science this country can give us. —Terrie Cowley, The TMJ Association, Ltd., an advocate for people with chronic pain1 The last several decades have seen remarkable strides in understanding of pain processes, as well as in assessment and, to some extent, treatment of pain, with new techniques and technologies being applied to one of humanity’s oldest problems. Important new insights into the basic science of pain—from genetics and molecular biology, to neural networks and neuroimaging, to the role of psychosocial factors—are unraveling pain’s mysteries. Some of these new in- sights have been highlighted earlier in this report. At the same time, the preceding chapters demonstrate that much remains to be learned. For example: • The section in Chapter 1 describing the current understanding of how pain works delineates the many physical and psychosocial attributes of pain and shows not only how far we have come but also how much more there is to learn about the biological, psychological, sociological, and environ- mental aspects of pain and its diagnosis, treatment, and prevention. • The description in Chapter 2 of the increasing prevalence of pain, the extent to which it affects various population groups, and its societal costs 1 Quotation from testimony to the committee, November 2010. 217

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218 RELIEVING PAIN IN AMERICA and effects on families reveals that data on pain are spotty and conflict - ing and provide only a partial picture of pain’s impact. • The discussion of treatment approaches and system issues in Chapter 3 reveals a number of gaps and conflicting public policies regarding the management of pain. • Chapter 4’s discussion of shortfalls in education about pain with respect to promoting the application of even existing knowledge suggests the need for robust translational research and heightened efforts to under- stand how to educate and reach patients and the public more effectively with useful messages about pain and its management. This chapter focuses primarily on clinical and translational research opportunities—opportunities to fill the needs and gaps in pain research by build - ing on new discoveries. A number of prestigious organizations have been engaged in devising new strategies for pain research, and the committee did not attempt to readdress the specific recommendations of these groups. Rather, it focused its deliberations on what is needed to make pain research initiatives a reality and to enhance translational research—research based on interactions and feedback loops between researchers and clinicians on the one hand and between patients and researchers on the other—so as to bring new discoveries to patients more rapidly. Similar interactions are needed among educators, communication spe - cialists, and researchers to enable more effective public dissemination of infor- mation (with feedback) about pain and its management. The overall goals are to expedite the process of translating scientific findings into patient care in tandem with the development of new knowledge and to gain insights that will lead to future progress in diagnosis and treatment. Of note, the National Institutes of Health (NIH) recognized the breadth of areas for new knowledge development related to pain when it developed its 2011 request for “new and innovative advances . . . in every area of pain research.” Annex 5-1 at the end of this chapter reproduces NIH’s descriptions of these vital areas of research and the kinds of research questions of interest under the follow- ing broad topics: • molecular and cellular mechanisms of pain, • genetics of pain, • biobehavioral pain, • models of pain, • diagnosis and assessment of pain, • pain management, • epidemiology of pain, • health disparities, and • translational pain research.

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219 RESEARCH CHALLENGES The committee considered NIH’s specification of topics to be comprehensive, and instead of attempting to repeat the effort to identify specific topics for research, focused its deliberations on what is needed to optimize pain research initiatives. Nor did the committee address in detail overall workforce needs because NIH has stated plans for its own effort in that area later in 2011. The U.S. research establishment is not alone in placing increasing emphasis on the need for improvements in pain knowledge. The International Association for the Study of Pain (IASP) has made October 2010 to October 2011 the “Global Year Against Acute Pain,” highlighting a number of research-related problems that are barriers to better acute pain treatment, including • incomplete, sporadic, or nonstandard pain assessment; • limited transferability of results derived from randomized controlled trials (RCTs) to clinical practice; • other problems in evidence transfer, including general barriers to imple- menting evidence-based and outcome-driven practices; • failure to capture short- and long-term quality outcomes that might be correlated with the adequacy of acute pain control; and • disproportionately low expenditures for basic, translational, and clinical research relative to the burden of acute pain (IASP, 2010). In the United Kingdom, the British Pain Society is working toward develop- ing chronic pain patient pathways, and its efforts are proceeding in parallel with the interests of the U.K. Department of Health’s Chronic Pain Policy Coalition and experts working with the National Institute for Health and Clinical Excel - lence, with the aim of hosting a Pain Summit in November 2011. Additionally, the Royal College of General Practitioners has established pain as one of four new clinical priorities for the years 2011 to 2013 (Baranowski, 2011). The committee finds the new knowledge that may be developed under these international initiatives exciting but is aware that there also is a significant problem with respect to the appropriate use of currently available therapeutic modalities, and is concerned about the slow pace and unsystematic way in which important basic research results are adopted (or not) into medical practice. The concern is that “the current clinical research enterprise in the United States is unable to produce the high-quality, timely, and actionable evidence needed to support a learning health care system” (IOM, 2010, p. 7). Efforts are under way to address these issues by improving and diversifying research methods, ex- panding research targets, streamlining the organization and funding of research, encouraging collaboration among research teams and disciplines, and promoting public–private partnerships, but gains have been slow. Because of the biopsychosocial complexity of the pain process (Chapter 1) and the variable ways in which different individuals and population groups are affected, assessed, and managed (Chapter 2), and because of the lack of specific

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220 RELIEVING PAIN IN AMERICA scientific assessment tools and biomarkers with which to identify underlying processes, it is difficult to determine what treatment will work best for individual patients without a frustrating and debilitating period of trial and error. At this time, diagnostic tools, as well as treatment approaches for many chronic pain syndromes, are often empirical, and the metrics for defining pain, along with the endpoints for determining a therapeutic response, are not well measured or properly considered in the evaluation of therapeutic interventions. A more multi - factorial approach that takes into account the individual’s genetics, biology, social and cultural history, and psychological and environmental factors is needed, along with objective metrics for defining response. In this context, this chapter examines research challenges in the following areas: expanding basic knowledge, moving from research to practice, improving and diversifying research methods, building the research workforce, organizing research efforts, obtaining federal research funding, and fostering public–private partnerships. EXPANDING BASIC KNOWLEDGE The complexity of the “pain web” in the brain indicates the difficulty that comes with evaluating a multidimensional experience such as pain and pain affect. . . . Patients present with one or more actual pain generators, a wide range of past life experience in dealing with pain and suffering, and with their own natural proclivities and resources for handling their pain burden. Successful clinical and research outcomes must be capable of addressing or controlling for such wide variability. —Director of a pelvic pain specialty center2 Long-term investments in multiple basic science disciplines—physiological, cognitive, and psychological—are essential to the development of targeted pain therapies and safer, more effective pain management strategies. This section exam- ines in depth one promising basic research area—biomarkers and biosignatures— because results of this research could be useful in their own right and because other types of research could be strengthened by incorporating biomarker and biosignature data. This discussion is followed by a review of other active areas of basic research that may ultimately lead to improved pain management and a synopsis of opportunities in psychosocial research. 2 Quotation from response to committee survey.

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221 RESEARCH CHALLENGES Biomarkers and Biosignatures Biomarkers are used to identify individuals at risk for disease, diagnose a con- dition, assess its progress, or predict its outcome. They are “quantitative biologi - cal measurements that provide information about biological processes, a disease state, or . . . response to treatment” (IOM, 2008, p. 1). Two or more biomarkers used in combination are termed a “biosignature.” In the pain context, combining information from neuroimaging and circulating molecular markers, for example, can improve the sensitivity and specificity of diagnosis relative to that attainable from either method alone—vital information for treatment (Woolf, 2010). Promising biomarkers for pain research come from a broad range of rapidly expanding fields, including proteomics, metabolomics, immune modulation, in - flammatory processes, central neuroimaging, and neurocognitive processes, as well as new knowledge about the interactions among organ systems. Since up to half of the variation in the pain experience appears to be a result of individual biological factors, genetic markers are an obvious target for biomarker develop - ment (Kim and Dionne, 2005). Another active and needed area of research is the integration of biomarkers across the multiple dimensions of basic, behavioral, and environmental sciences to improve the understanding of what causes, amplifies, and maintains pain. To be sure, biomarker development faces a number of challenges. In gen- eral, biomarkers specific to neurological and psychiatric disorders have been difficult to identify, and clinical testing has been “plagued by factors such as patient heterogeneity, lengthy trial durations, subjective readouts, and placebo responses” (IOM, 2008, p. 11). The complexity of the brain, limited access to brain tissue, and the blood-brain barrier pose additional difficulties. An impor- tant nonphysiologic barrier to biomarker development is the lack of incentives for academic, industry, or government research programs to pursue promising biomarker candidates. Moving biomarkers from basic to clinical research also may be a challenge. As discussed in Chapter 1, the experience of pain involves the interaction of many different physical, psychological, and cognitive processes, and a person’s report of pain is inherently subjective. Clinicians seeking to use an objective measure of pain (a biomarker) risk implying to the patient that they do not believe the patient’s report. If biomarkers were validated (and perceived by patients) as aids in identifying promising beneficial treatments rather than “substantiating” or “verifying” patients’ pain reports, they might have a useful and accepted role in pain care. Most valuable would be their potential to obviate the need to conduct lengthy hit-or-miss trials of different therapies before identifying the one that works best for a given individual (Woolf, 2010). Finally, biomarkers potentially could play a role in pain prevention by iden - tifying individuals at high risk for whom special effort should be made to avoid triggering events or situations and to intervene promptly when they occur. This

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222 RELIEVING PAIN IN AMERICA function would be analogous to that of using genetic testing to identify people at elevated risk for heart disease or cancer. Other Promising Basic Research Knowledge about the way nociception and pain work at basic biological, genetic, and pathophysiologic levels has advanced rapidly in the past 20 years— knowledge that should facilitate the discovery of new analgesics through new approaches related to the following: • Genetics—The scientific understanding of the role of genes and gene polymorphisms in pain mechanisms is increasing. The potential exists to carry out genomewide screens for genes associated with pain in model organisms. • Ion channels—Research on ion channels has intensified over the last several years in an effort to explain their role in the development and maintenance of chronic pain syndromes. For instance, investigators have identified several subtypes of voltage-gated sodium channels—a substrate by which products of inflammation and growth factors trigger chronic pain states. These channels can be nonselectively blocked by lidocaine, mexiletine, lamotrogine, carbamazepine, and amytriptyline— all drugs used to treat chronic pain. Unfortunately, their nonselectivity results in significant side effects. Now, researchers and pharmaceutical companies are developing drugs that block more selectively those peripheral and central nervous system sodium channels that change their expression in chronic pain states. Similar efforts are under way to characterize the role of other transient receptor potential (TRP) ion channels. • Glial cells—The glial cell has traditionally played a supporting role to the neuronal cell in acute and chronic pain. More recently, investigators have reevaluated the glial cell’s importance as an initiator and maintainer of chronic pain states through its role in linking the immune, inflam - matory, and nervous systems. Researchers have discovered that some types of glial cells3 have a major impact on chronic neuropathic pain, challenging the old treatment paradigm of reducing neuronal activity to reduce pain. Indeed, targeting glial cells may result in a new class of therapies that are disease modifying rather than simply palliative. • Stem cells—Use of stem cells to create neurons might enable study of the response of human cells to new drugs, in vitro, early in the drug development process (Woolf, 2010). This field is in a nascent stage but holds promise. 3 Schwann cells, satellite cells in the dorsal root ganglia, spinal microglia, and astrocytes.

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223 RESEARCH CHALLENGES • Neuroimaging—Researchers have used neuroimaging tools—functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and magnetoencephalography (MEG)—to investigate the central nervous system correlates of the human pain experience. Although pain is a subjective experience, the brain regions and systems responsible for that experience can now be identified and characterized, including brain regions responsible for the pain-modulatory effects of attention/ distraction, anticipation, fear, anxiety, depression, placebo, and cogni- tive control. Neuroimaging also yields valuable information regarding central abnormalities in pain processing in chronic pain conditions and the effects of therapeutic agents on central neural systems. In short, neuroimaging opens windows into the brain’s functioning. • Veterinary science—Further opportunities should be sought to learn from the significant clinical veterinary studies of pain treatment in animals that experience conditions analogous to human pain disorders. Opportunities in Psychosocial Research In the psychosocial realm, there is a need for multidisciplinary research to develop and test novel theories that can explain how biological, psychological, and social factors interact to influence pain. Given the growing interest in tailor- ing of treatments, a particularly important research opportunity is to develop a way to subgroup patients (phenotyping) based on genetic and demographic factors, pain mechanisms, symptoms, and psychosocial adjustment to pain. Phenotyping studies should include measures that not only capture persistent psychological traits (e.g., personality traits) but also measure more dynamic processes, such as changes in mood, thoughts, beliefs, expectations, and coping efforts. Conclusion Focusing and integrating all of the above efforts would move pain research a step closer to personalized medicine. “Collectively, these [developments] will enable us to identify the mechanisms responsible for pain in each individual, the most appropriate treatment and the side effect hazards” (Woolf, 2010, p. 1246).

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224 RELIEVING PAIN IN AMERICA MOVING FROM RESEARCH TO PRACTICE Each condition is being researched separately, which dilutes the effort. We won’t understand any of them very well or why someone has one and not the other. Almost 80 percent of patients with vulvodynia also fit diag - nostic criteria for TMJ. They have allergies and chronic headache long before they have a TMJ problem. “You have this, and two years later you have that.” —Terrie Cowley, The TMJ Association, Ltd., an advocate for people with chronic pain4 A consistent, general direction of both basic and clinical and both physi - ological and psychological pain research is toward more personalized approaches to pain. Tailoring pain interventions to the specific makeup of the individual is attractive not only because it would presumably enable more effective treatment and avoid some of the serious downsides of current treatment options, but also because it might, finally, provide a viable strategy for prevention of pain. Further, personalized approaches might enable clinicians to address simultaneously the underlying causes of several pain syndromes, which sometimes cluster in a single individual. This section describes important challenges in moving from research to practice, including the difficulty of developing new analgesics, shortfalls in applying evidence-based psychosocial approaches in practice, and the need for interdisciplinary approaches. The Difficulty of Developing New Analgesics From 2005 to 2009, only a few of the nearly 100 new drugs approved by the U.S. Food and Drug Administration (FDA) were for chronic pain conditions, specifically arthritis and fibromyalgia (FDA and CDER, 2011). Furthermore, other than the recently introduced capsaicin patch for postherpetic neuralgia, no new therapeutic agents have been approved that represent truly novel approaches to pain management. Instead, most drugs approved recently are variations on existing molecules (e.g., pregabalin, duloxetine, nonsteroidal anti-inflammatory agents) or repackaged existing molecules (e.g., the many versions of extended- release opioids). It is ironic and concerning that “many major pharmaceutical companies are leaving the pain market” (Woolf, 2010, p. 1241), despite the grow- ing need for more diverse pain products and an increasing population of people with serious pain conditions (see Chapter 2). 4 Quotation from testimony to the committee, November 2010.

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225 RESEARCH CHALLENGES Current pharmaceutical-based treatments for acute, severe, and chronic pain commonly rely on two classes of drugs: opioids (which have major side effects and carry a large risk of abuse and misuse [Chapter 3]) and nonsteroidal anti- inflammatory drugs, such as the COX inhibitors (which carry the risk of renal failure, heart attack, and other serious complications). As advances in basic research raise the possibility of more personalized approaches to pain care, the “one-drug-fits-all” approach to treatment may finally be replaced by more tar- geted therapeutics. But personalized approaches will have profound implications for “changing the current analgesic drug development model” (Woolf, 2010, p. 1246). A significant challenge will be to rethink current regulatory strategies, which typically do not differentiate among the classes of patients for which a drug is approved. Rethinking also will be required with respect to treatment strategies. The appreciation that pain can become a chronic disease in and of itself through aberrant activity of the central nervous system should curtail the search for underlying disease pathology and redirect treatment efforts toward the mal- functioning nervous system itself—a “mechanism-based therapeutic approach” rather than a “strictly symptom-based approach” (Farrar, 2010, p. 1285). Thus far, however, “although considerable progress has been made in identifying pathophysiologic mechanisms of acute and chronic pain, this knowledge has not translated to the development of analgesic medications with improved efficacy, safety, and tolerability” (Dworkin et al., 2011, p. S107). In part this is because the very attributes that make personalized approaches to pain management pos - sible also may inhibit incentives for pharmaceutical companies to develop those approaches. The economics of developing a product akin to an “orphan drug” that would work in a small number of people are unfavorable in the extreme given the high cost of both bringing a drug to market and identifying the relatively few clinicians and individuals who can benefit from it. Recognizing the challenge to drug regulation posed by these expanding opportunities, the FDA has launched a Regulatory Science Initiative that includes a modernization of its evaluation and approval processes so as to give people ac- cess to innovative products when they need them.5 Specifically, one priority for this initiative is to accelerate the delivery of new medical treatments by “increas - ing the practical value of basic discoveries” so that “patients have access to the most cutting-edge medical treatment possible” (FDA, 2010b, p. 4). One of the reasons the FDA offers to justify accelerated drug development is the need for pain medications with less abuse potential than the opioids. A personalized drug ideally would work well for the intended person but have minimal effects on oth - ers and therefore would be less attractive as a drug of abuse. To make new pain treatments available expeditiously will require improved pain models, measure- ment tools (including patient-reported assessments), and clinical trial designs. 5The FDA defines “regulatory science” as the science of developing new tools, standards, and approaches for assessing the safety, efficacy, quality, and performance of FDA-regulated products.

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226 RELIEVING PAIN IN AMERICA Shortfalls in Applying Psychosocial Approaches in Practice Much of what is known about psychosocial factors and pain has come from studying patients in medical specialty clinics and specialized pain treatment pro - grams. Less is known about the psychosocial aspects of pain in general clinical practice. Although some large, nationally representative data sets (e.g., Medicare and Medicaid, the Department of Veterans Affairs, Kaiser Permanente, insurance industry claims data sets) include some measures of pain and its potential psycho- logical impact, these data sets have only recently begun to be explored (Zerzan et al., 2006; Haskell et al., in press), and their potential for yielding answers to questions regarding health services has yet to be realized. A variety of psychosocial treatment protocols for managing pain are avail - able, and evidence of their clinical and cost-effectiveness has continued to accu - mulate over time (Kerns et al., 2008, 2011). Paradoxically, these protocols are not widely used, in large part because third-party payers are unwilling to pay for them despite the positive evidence. Another reason these interventions have not been adopted more broadly is because too little is known about such basic questions as their optimal timing and dosing and their additive effects when combined with other treatments (Keefe et al., 2005). These evidence-based approaches cover a range of activities that are self-regulatory (e.g., hypnosis [Jensen, 2009] and biofeedback); • behavioral (e.g., weight loss [Sellinger et al., 2010], structured exer- • cises, and exposure to daily activities that patients fear will increase their pain or contribute to additional injury [Bell and Burnett, 2009]); and cognitive-behavioral (e.g., training in coping skills, cognitive restruc- • turing, problem-solving training [Morley et al., 1999; Hoffman et al., 2007]). Over the past decade, a major effort has been made to test the efficacy and cost-effectiveness of psychosocial approaches in patients with chronic pain conditions (e.g., chronic low back pain and migraine headaches) and persistent disease-related pain (Gatchel and Okofuji, 2006; Hoffman et al., 2007; Morley et al., 2008). In general, meta-analyses and systematic reviews of these approaches demonstrate modest short-term improvements in pain and functioning compared with standard care (pharmacological and medical interventions). (Longer-term studies are still to come.) However, the psychosocial interventions produce fewer adverse effects and often are carried out at lower cost (Turk, 2002). Meta-analysis of such interventions for chronic low back pain, for example, revealed a small and statistically significant effect for all the interventions across all outcome domains for as long as 5-year follow-up (Hoffman et al., 2007). Although meta-analyses of psychosocial interventions for pain often examine and comment on the methodological rigor of the studies they include, they give

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227 RESEARCH CHALLENGES relatively little attention to the quality of the intervention protocols (e.g., number and content of sessions, extent of therapist training, ongoing supervision, uptake and implementation of the techniques by the participant)—factors that may be critical to the success of treatment. Nevertheless, a number of studies included in these analyses have found that many, though not all, people exposed to these protocols show significant improvements in measures of pain, physical function- ing, and psychological distress (Gatchel and Okofuji, 2006; Dixon et al., 2007; Hoffman et al., 2007). The protocols themselves use various combinations of the types of activities listed above. Perhaps their most common feature is an emphasis on helping people with chronic pain learn to manage their pain and their lives despite residual discomfort. The public’s awareness and understanding of the nature of these interventions and their potential benefit, as well as such factors as patients’ motivation to engage in these treatments, are potentially important targets for further investigation (Jensen et al., 2003; Kerns et al., 2006). To date, relatively few studies have attempted to test the effectiveness of these protocols in primary care settings, where the vast majority of pain man - agement occurs, or with patients having comorbid conditions, such as obesity, diabetes, or depression. Furthermore, most studies have tested the efficacy of psychologist-delivered interventions, so that much less is known about the inter- ventions’ performance when delivered by physicians, nurses, physical therapists, social workers, or other health professionals (Keefe et al., 2005). To bridge the gap between current research knowledge and clinical applica- tion, more needs to be learned about the effectiveness of psychosocial protocols in primary care settings. Only recently have investigators begun to develop and test innovative strategies for delivering in the primary care setting psychosocial interventions designed to promote self-management of chronic pain. In two im - portant studies in this area, for example, psychologists or nurse care managers closely monitored patient symptoms and functioning and provided patient educa- tion and cognitive-behavioral therapy, and they encouraged adoption of a pain self-management approach in the context of more comprehensive care programs (Dobscha et al., 2009; Kroenke et al., 2009). In the study by Dobscha and col- leagues, the broader intervention involved provider education and training plus support in the application of a biopsychosocial model of chronic pain treatment. At the same time, it de-emphasized the medicalization of chronic pain. The Need for Interdisciplinary Approaches The team approach to care of people with complex chronic conditions envi - sioned in the development of medical homes and accountable care organizations may lead to new care delivery models. Although the physical mechanisms of some pain disorders may be identified and adequately treated medically, more comprehensive interdisciplinary treatment and related research are currently the best alternative for those with chronic pain when the underlying mechanisms are

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258 RELIEVING PAIN IN AMERICA Stone, A. A., J. E. Broderick, J. E. Schwartz, S. Shiffman, L. Litcher-Kelly, and P. Calcanese. 2003. Intensive momentary reporting of pain with an electronic diary: Reactivity, compliance, and patient satisfaction. Pain 104(1-2):343-351. Sullivan, M. D., and J. Brennan-Braden. 2011. Assessment of psychiatric disorders. In Handbook of pain assessment, 3rd ed., edited by D. C. Turk and R. Melzack. New York: Guilford Press. Pp. 399-414. Teutsch, S. M., and J. E. Fielding. 2011. Applying comparative effectiveness research to public and population health initiatives. Health Affairs 30(2):349-355. Turk, D. C. 2002. Clinical effectiveness and cost effectiveness of treatments for chronic pain patients. Clinical Journal of Pain 18(6):355-365. Turk, D. C., and R. Melzack. 2011. Trends and future directions in the assessment of people expe - riencing pain. In Handbook of pain assessment, 3rd ed., edited by D. C. Turk and R. Melzack. New York: Guilford Press. Pp. 489-506. Walk, D., N. Sehgal, T. Moeller-Bertram, R. R. Edwards, A. Wasan, M. Wallace, G. Irving, C. Argoff, and M.-M. Backonja, 2009. Quantitative sensory testing and mapping. A review of non- automated quantitative methods for examination of the patient with neuropathic pain. Clinical Journal of Pain 25(7):632-640. Wolfe, F., and K. Michaud. 2011. The national data bank for rheumatic diseases: A multi-registry rheumatic disease data bank. Rheumatology 50(1):16-24. Woolf, C. J. 2010. Overcoming obstacles to developing new analgesics. Nature Medicine 16(11):1241-1247. Zerzan, J. T., N. E. Morden, S. Soumerai, D. Ross-Degnan, E. Roughead, F. Zhang, L. Simoni- Wastila, and S. D. Sullivan. 2006. Trends and geographic variation of opiate medication use in state Medicaid fee-for-service programs. Medical Care 44(11):1005-1010. Zulman, D. M., J. B. Sussman, X. Chen, C. T. Cigolle, C. S. Blaum, and R. A. Hayward. 2011. Examining the evidence: A systematic review of the inclusion and analysis of older adults in randomized controlled trials. Journal of General Internal Medicine [Epub ahead of print].

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259 RESEARCH CHALLENGES ANNEX 5-1 MECHANISMS, MODELS, MEASUREMENT, AND MANAGEMENT IN PAIN RESEARCH FUNDING OPPORTUNITY ANNOUNCEMENT RESEARCH OBJECTIVES 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 re- mained 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-areas are not intended to be comprehensive or exhaus - tive. Synergistic studies that reach across two or more of these areas are encour- aged. Interdisciplinary and multidisciplinary research is especially encouraged, as is research that involves specific cooperation between basic and clinical scientists. These pain research areas also cut across Institutes and Centers (ICs) and pro - grams and should not be viewed as restricted to only one specific IC. 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 in - volved 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 signal - ing and in the development of hypersensitive pain states are important targets

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260 RELIEVING PAIN IN AMERICA 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: M echanisms that underlie sex differences in the pain experience. • C ellular and molecular mechanisms involved in pain processing, modu- • lation, and perception. M olecules and processes that target cellular mechanisms involved in sig- • naling, modulation, and perception of pain, as well as changes in these processes over the developmental life course, to enhance innovative therapeutic development. O ntogeny and neuropharmacology of the pain system. • E ndogenous and environmental factors that alter pain during the course • of development, in response to injury, and related to disease processes. M echanisms of hypersensitivity including both central and peripheral • mechanisms of hyperalgesia and allodynia. E ndogenous 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. Elucidat - ing 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: G enes and gene variants involved in the complex processes of pain • perception. U tilization of pharmacogenetics to identify gene variants with potential • to inform treatment providers which pain medications may be most ef- fective for the individual needing therapy, with the fewest side effects. U se of gene therapy to ameliorate chronic pain. • G ene polymorphisms and gene–environment interactions that predict • pain development or treatment response. E pigenetic mechanisms underlying chronic pain conditions. •

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261 RESEARCH CHALLENGES BIOBEHAVIORAL PAIN 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 individuals ability to self- manage pain. Research is encouraged but not limited to science in the following areas: A daptation to pain and ways to incorporate this adaptation into treatments. • M echanisms 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. B iobehavioral techniques for optimizing adherence to pain management. • Identify barriers to adherence to pain management strategies. S ensory, cognitive, and affective aspects of acute and chronic pain in • individuals across the developmental lifespan. D evelopment of methods for assessing relative contributions of bio- • logical, psychological, behavioral, and environmental predictors of the course of pain, pain dysfunction, and response to treatment for pain. I nteractions of pain and sleep, their combined impact on function and • illness recovery, and interventions that target these interactions. R elationships 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. I nteraction of biological markers, central nervous system mechanisms, • and drug, behavioral, and CAM interventions. M echanisms that underlie gender and cultural differences in the pain • experience.

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262 RELIEVING PAIN IN AMERICA 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 condi- tions 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 treat - ing 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: N ew animal models and refinement of existing animal models. • N ew measures of pain in animals that are noninvasive and objective, • and that permit a behavioral or functional assessment of pain and pain treatment outcomes. U se of transgenic animals in the study of pain mechanisms. • S tudies in patients with chronic pain conditions that develop, test, and • validate new models of these chronic disorders. C omputational models that predict development of pain and/or treatment • responses. C omputer simulations of pain that overcome ethical concerns and ex- • pand the range of studies possible. O bjective 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 physi - ologic 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.

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263 RESEARCH CHALLENGES Assessment should include diagnostic as well as outcomes measures. Research is encouraged but not limited to science in the following areas: R efinement of existing physiologic techniques for measuring pain for • greater sensitivity and specificity. N ew, outcome-specific techniques for different populations. • S ensitive assessment tools that are not language (neither receptive nor • production) dependent. R efinement of pain measurements that can account for or predict the • trajectory or course of pain, as well as the changes in pain over time. P redictive biomarkers of pain that are sensitive to rapid changes in pain. • D evelop 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. N ew technologies to improve pain assessment in all populations, but • especially in those persons with limited language abilities. PAIN MANAGEMENT The prevalence of pain and inadequate pain management in patients is well documented. It is estimated that 75 percent of patients with advanced cancer ex - perience moderate to severe pain; an IOM report states that 40 percent 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 medica - tions, 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. Health care provid- ers 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 nonpharmacologic ap- proaches. Research is encouraged but not limited to science in the following areas: I nterventions involving combinations and sequencing of pharmacologi- • cal, nonpharmacological, and behavioral interventions to manage pain in progressive, incurable diseases. I nterventions to reduce pain that are customized to the group (i.e., tar- • geted), as well as to the individual (i.e., tailored). N ew methods to manage pain in cognitively impaired individuals or • those unable to verbalize their pain.

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264 RELIEVING PAIN IN AMERICA I nterventions to manage co-occurring symptoms related to pain such as • depression and fatigue. R ole of pain and pain management approaches in improving rehabilita - • tion outcomes and preventing functional decline. M ethods for optimizing maintenance and stability of treatment in • patients with advancing disease or with pain from multiple contributing disease processes. N ovel interventions to manage pain in progressive, incurable, non- • malignant diseases. I nterventions to improve management of side effects related to pharma - • cological pain therapy. N ew techniques for managing pediatric pain. • M odels of therapy in those with uncontrolled pain and/or breakthrough • pain. P ain management strategies at the end of life. • L ong-term (i.e., physiologic, behavioral, or developmental) effects of • pharmacologic treatment during the neonatal period and childhood. C linical 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, epide - miologic information concerning pain disorders is not well developed. Research is encouraged but not limited to science in the following areas: I ncidence and natural history of pain disorders and their correlates over • time. I nterplay of environmental (e.g., familial and/or neighborhood quality and • resources), physical (e.g., comorbid medical disorders that are a result of, or a cause of pain), behavioral (e.g., comorbid mental and substance use disorders), and social or socioeconomic (e.g., loss of employment— including issues of secondary or tertiary gain, social isolation, lack of mobility, dependence on others for basic caretaking) factors. R isk factors, including age, ethnicity, family history, gender, genetic pre - • disposition, lifestyle, occupation, pre- or coexisting mental and physical disorders, and socioeconomic status (SES); and the mechanisms that are associated with the occurrence, maintenance, and remission of pain conditions. I mpact of pain on an individual’s SES and the resulting health con - • sequences (e.g., obesity, deconditioning, mental disorders, substance

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265 RESEARCH CHALLENGES abuse) controlling for the effect of the cultural and socioeconomic influ- ence of the community. P revalence 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. T he 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. C reation and adoption of innovative epidemiologic and statistical meth- • odologies and study designs to further the understanding of pain dis- orders. Also use these techniques to maximize the analytic yield from new and existing data sets. I nterrelationship of psychiatric disorders (e.g., borderline personality, • histrionic, antisocial) and chronic pain, and relate these findings to pharmacological and behavioral therapies. C omorbid disorders and pain, including descriptive studies of risk and • protective processes, and interventions aimed at relieving adverse con- sequences associated with comorbid disorders and pain. HEALTH DISPARITIES 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 announce - ment 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: D ifferences in care for various types of pain, acute postoperative pain, • treatment-related pain, cancer pain, or chronic nonmalignant pain, in various settings (i.e., health clinics, physician and dental offices, in - stitutional settings including long-term care facilities, assisted living

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266 RELIEVING PAIN IN AMERICA facilities, or emergency departments), and management of pain at the end of life. D ifferences 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. D ifferences in perceptions of pain and responses to pain and how these • differences impact appropriate treatment management of pain. T he nature and extent of disparities in the delivery of pain treatment in • diverse populations. E xisting 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. N ovel, evidence-based interventions to improve training for health care • providers and educational interventions for minority patients. M easures of pain perception for those with cognitive impairment, or • limited health literacy and from varied cultures. A ssessment of the global impact, including societal and medical conse - • quences, of pain related disparities on both individuals and society, and the potential impact of pain-related disability. D iverse cultural beliefs about and actions taken for pain and its manage- • ment including self-care and that of lay caregivers. T reatment and management strategies for chronic pain in diverse • populations. M eans to identify population differences in pain perception and process- • ing by addressing the incidence, severity, and consequences of pain in these and the general populations, and in specific disease states. N ew diagnostic tools for different pain mechanisms, and objective mea- • sures of treatment response that have validity in diverse populations. T he prevalence and effectiveness of the use of nonpharmacological and • novel (e.g., virtual reality) therapies for pain treatment in diverse popula- tions such as ethnic minority groups and persons with disabilities. P ain 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.,

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267 RESEARCH CHALLENGES 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: N ovel pharmacological and non-pharmacological pain treatments. • I mproved treatment protocols and adjunctive therapies that promote • greater effectiveness, patient adherence, or patient tolerance. C haracteristics (e.g., gender, race, age, type of pain) that predict • which patient populations will benefit most or least from various pain treatments. B arriers to effective pain treatment. • N ew technologies for use in the study and treatment of pain in the natu - • ral environment of the patients daily living. C linical studies to inform, develop, and validate new animal models of • chronic pain conditions; i.e., a bedside-to-bench approach. D esign and development of small molecule mimics and other advanced • pharmacological approaches.

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