Biomarkers and Biosignatures

Biomarkers are used to identify individuals at risk for disease, diagnose a condition, assess its progress, or predict its outcome. They are “quantitative biological 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, inflammatory 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 development (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 general, 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 important 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 identifying 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 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, inflammatory, 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.
• 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 cognitive 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 tailoring 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).

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 growing need for more diverse pain products and an increasing population of people with serious pain conditions (see Chapter 2).

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 targeted 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 malfunctioning 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 possible 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 access to innovative products when they need them.⁵ Specifically, one priority for this initiative is to accelerate the delivery of new medical treatments by “increasing the practical value of basic discoveries” so that “patients have access to the most cutting-edge medical treatment possible” (FDA, 2010b. 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 others and therefore would be less attractive as a drug of abuse. To make new pain treatments available expeditiously will require improved pain models, measurement tools (including patient-reported assessments), and clinical trial designs.

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 programs. 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 psychological 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 available, and evidence of their clinical and cost-effectiveness has continued to accumulate 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 exercises, 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 restructuring, 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 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 functioning, 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 management 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 interventions’ 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 application, 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 important studies in this area, for example, psychologists or nurse care managers closely monitored patient symptoms and functioning and provided patient education 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 colleagues, 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 envisioned 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 unclear or those for whom demonstrated medical treatments do not exist. Interdisciplinary research can provide insight into the combinations of treatments— pharmacological, physical, psychosocial—most likely to achieve the optimal result (Dobscha et al., 2009; Kroenke et al., 2009).

Collaborative research is essential if pain care is to become truly interdisciplinary, multidimensional, and multimodal. Involvement of primary care clinicians will facilitate the translation of new pain assessment and management protocols, including psychosocial protocols, into clinical practice.

Randomized Controlled Trials: The Gold Standard

RCTs have long been regarded as the gold standard for understanding the safety and efficacy of health care interventions, especially drugs. RCTs have a number of strengths, and they continue to play an important role in the development, evaluation, and regulatory approval of new treatments and interventions. Compared with alternative research methods, they carefully control for potentially confounding factors (internal validity)—hence their ability to provide specific answers to questions related to the efficacy of new treatments, compared with alternatives and with placebo, as well as questions about appropriate dosages of the treatment being tested.

However, there are significant problems with RCTs as used in the pain field, including their limited ability to predict effectiveness (external validity)—that is, how well a drug will perform in real-life populations (Dworkin et al., 2011). In particular, older adults—the age group in which pain is most prevalent—are often excluded from RCTs (Zulman et al., 2011). Yet this may be the age group for which predicting the effects of pain medications may be most important and difficult because of age-related organ system dysfunction, coexisting chronic conditions, and the probability that elders are taking multiple other medications. RCTs typically also have excluded people with comorbid psychological disorders, those with pain conditions other than that being studied, and those taking other medications. The clinical reality is, of course, that many people with chronic pain also have psychological symptoms (Chapter 1), have multiple types of pain, and take various medications for these conditions. As a result of these tight exclusion criteria, people enrolled in clinical trials are unlikely to represent the typical population of people with pain seen in a primary care clinic or pain center.

Some RCTs enroll relatively few subjects, and as a consequence, adverse outcomes (which may prove to be important) may go undetected. Moreover, comparator treatments included in RCTs often do not represent current best practices in care. For example, combinations of medications are common in clinical practice but rarely used in RCTs. RCTs have other disadvantages as well:

• They are expensive and administratively cumbersome and suffer from difficulties in recruiting sufficient numbers of subjects.
• Many RCTs are of relatively short duration (typically 4 to 14 weeks), whereas people with chronic pain may need to use a medication for many months to years. This is a critical shortcoming in trials of analgesics. Perhaps nowhere is this latter issue more of a problem than with prescription opioids. To date, there still has been no accurate assessment of the long-term safety and effectiveness of chronic opioid therapy (Martell et al., 2007).
• RCTs may be terminated early if initial results suggest serious toxicity (in which case termination is probably appropriate), but also if they indicate potentially dramatic benefits that researchers believe should be made available to everyone in the study. When trials are terminated early, less is known about the drug and its potential usefulness over the longer term.

In short, RCTs generally manage their study population very closely, but given the diverse biological, psychological, demographic, social, and clinical characteristics of people with pain, such trials may not be the best or the only way to evaluate new analgesic agents or therapeutic approaches. In the future, answering the many research questions about pain treatment likely will require novel research designs that can better align the strengths of RCTs with the design requirements of pain studies. What is needed is a balance of different, complementary research approaches.

Initiatives to Address Limitations of Clinical Trials

According to the FDA (2010a), “Many experts in analgesic drug development believe that it is the design of the clinical trials that is at fault in [the disappointing results in trials of new analgesics] and that better trial designs will yield more successful results.” As discussed in Chapter 1, the slow translation of basic science findings into novel therapeutics is a major problem, and there is growing concern about the lack of innovation in the design and conduct of clinical trials that could improve the testing of potential therapies. Specific initiatives focused on pain have been making important contributions toward improving the consistency of pain outcome measures and resolving study design issues and problems inherent in the conduct and reporting of clinical trials. An important target of future research is a better understanding of how to increase the sensitivity of clinical trials, as well as new approaches to regulatory science that could enhance the efficiency of product approval while continuing to emphasize safety.

Over the last 20 years, several initiatives have been undertaken to address issues in the design of RCTs for pain-related disorders. Starting in 1992, the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) project was developed as an international organization of experts in outcome measurement for rheumatoid arthritis and osteoarthritis. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and function scale grew out of this collaboration and has become the standard for most arthritis studies.

Since 2002, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), with industry funding, has been developing “consensus reviews and recommendations for improving the design, execution, and interpretation of clinical trials of treatments for pain” (IMMPACT, undated, website home page). Participants include representatives from academia, industry partners, U.S. government agencies (the FDA, NIH, the Department of Veterans Affairs), and consumer support and advocacy groups. IMMPACT has created databases to assist researchers in evaluating methods used in past RCTs related to osteoarthritis and neuropathic pain; in development are additional databases on fibromyalgia, back pain, and acute postsurgical pain. IMMPACT’s recommendations and systematic reviews, as with those of its pediatric counterpart, Ped-IMMPACT, have helped guide the design of trials, clinical research, and a national survey, and its research reports and articles are widely published and cited in both specialty and general journals.

With its pivotal role in the approval of safe and effective therapies for pain, the FDA has undertaken new initiatives to support research on how to improve clinical trials. The Clinical Trials Transformation Initiative, a public–private partnership founded by the FDA’s Office of Critical Path Programs and Duke University, now involves more than 50 organizations in efforts to identify practices that will “increase the quality and efficiency of clinical trials” (https://www.trialstransformation.org/).

Recently, the FDA provided seed money for a new effort—the Analgesic Clinical Trials, Innovations, Opportunities, and Networks (ACTION) initiative— described as “a collaborative effort designed to bridge gaps in the discovery and development of safe and efficacious analgesics” (FDA, 2010a). It has two key objectives: to initiate and foster collaborations among stakeholders in pain research in order to share data, best practices, and innovative thinking; and to leverage resources to speed the development of analgesic drugs. Its goal is to seek new ways of analyzing and standardizing trial data and to establish public–private partnerships to support projects aimed at improving trial design.

The initial activities of ACTION involve developing a standardized data submission template to facilitate analysis of clinical trial data; initiating analyses of factors, such as placebo group response rates, that may influence assay sensitivity using group data available through the FDA; and conducting a scientific workshop focused on improved efficiency of clinical trials. Future research objectives are to

• conduct analyses of databases created from clinical trials of analgesics from all available sources, including those submitted to the FDA as part of the drug approval process;
• develop and test novel methods for analyzing endpoints of analgesic trials;
• improve methodologies for the standardization of data collected in clinical trials and harmonization of data from completed trials of pain treatments; and
• establish an ACTION public–private partnership to provide an infrastructure for ongoing support of additional projects to inform analgesic development and trial design (Dworkin et al., 2011).

The sustainability of ACTION will depend on its ability to secure additional funding from a variety of public and private sources.

In short, the intent of all these initiatives is to enable improvements in trial design that may reduce the level of confounding results and speed the development of improved pain treatments. Ongoing support for these efforts will have an important impact on improving the availability of evidence-based therapeutic options for pain care.

Comparative Effectiveness Research, Observational Studies, and Psychological Research

CER is the generation and synthesis of evidence that can be used to compare the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care (IOM, 2009). Research on both existing and novel forms of pain management might benefit from using CER techniques to assess the relative effectiveness of various treatments overall and in specific populations. The results of CER are intended to assist consumers, clinicians, purchasers, and policy makers in making informed decisions that will improve health care at both the individual and population levels (IOM, 2009). Most gaps in the literature on chronic pain involve uncertainties regarding treatments for specific types of patients—those with comorbidities, specific genotypes, different disease stages, and so on.

In some countries, formal CER programs have been established to help national health authorities decide whether to reimburse for particular procedures (Satvat and Leight, 2011). That is explicitly not the goal of CER in the United States, although in a constrained economic environment, disallowing payment for treatments that clearly are ineffective or for costly treatments that clearly are of limited or questionable benefit may be an inevitable future step.

CER uses a number of different research methodologies, including RCTs, but also observational studies, as no single research approach can answer all questions about interventions and outcomes. CER that involves analyses of archival data from electronic health care databases and electronic health records holds great promise (see below). Such data are currently used extensively in pharmacoepidemiology and health services research. Although they are not as well controlled as RCTs, observational studies have a number of potential advantages: (1) they often use databases having large sample sizes with extended follow-up over long periods of time; (2) they can identify and track specific study populations; (3) they reflect routine, community-based clinical practice and can measure actual medication use; (4) subjects are managed according to standards of community practice, in academic health centers, or with clinical protocols; (5) the data may be sufficiently rich to allow researchers to focus on informative drug–drug and dosage-level comparisons; (6) they may include historical, demographic, disease-related (e.g., duration of symptoms), comorbidity, and psychosocial variables that may affect treatment response; and (7) they have the potential to capture information on important adverse effects treated by clinicians.

Increasingly, genomic and pharmacokinetic data can be included in health care databases and used to identify patient characteristics and treatments associated with better and more cost-effective outcomes. With these approaches, patient care and research needs can be collected in a common data set. By providing valid information about what works and in whom, CER serves as a key to individualized care and future innovation in personalized therapies (Garber and Tunis, 2009).

Not only pain management but also pain prevention and public health strategies can be investigated and enriched through CER. For example, population-based approaches can be used to assess targeted public education; regulatory mechanisms; and changes made to physical environments to prevent injuries in workplaces, schools, homes, athletic fields, and roadways. The use of CER to assess public health approaches usually requires a comprehensive research design that relies on observational studies or modeling approaches rather than RCTs partly because it is difficult to isolate a single social variable to determine the causes of changes in rates of illness or injury (Teutsch and Fielding, 2011).

CER also holds promise for informing pain-related public policy. To date, however, it has been used almost exclusively to test medical and surgical treatments for pain. For these studies to be useful in informing policy decisions at both the individual and population levels, their focus needs to be expanded so as to test the effects of psychosocial interventions for pain relief relative to one another and to other medical, rehabilitative, and complementary and alternative medicine (CAM) approaches.

Observational Studies, Databases, and Registries

Many databases can be used for the observational studies that support CER research, but three are particularly useful: large administrative databases, principally the Medicare database, which covers tens of millions of people; databases from health plans that use electronic medical records (for example, the Department of Veterans Affairs and the 16 organizations in the HMO Research Network); and the FDA’s Sentinel Initiative on drug safety, which has access to millions of patient records. A growing area of importance is the emphasis on personal electronic medical records and the collection of specific data in carefully planned registries, such as those used for cancer patients. Large databases can be used to evaluate comparative safety as well as comparative effectiveness. They also can aid in comparing postintervention expenditures and utilization across different treatments, a topic of interest to insurers. Each has advantages, such as those cited above, as well as disadvantages. For example, large administrative databases contain limited information on the severity of the patient’s illness and details on patient and treatment characteristics often available only in text form and are not easily exportable.

Condition-specific pain registries have been created—such as PainCAS^™ (http://www.pain-cas.com/) and the National Data Bank for Rheumatic Diseases (http://www.arthritis-research.org/)—that contain various amounts of detail on patients, treatments, and outcomes (Wolfe and Michaud, 2011). This type of database usually contains details limited to one condition or syndrome and may not contain other valuable and important information, such as patient comorbidities and signs, symptoms, and physical findings that might affect the effectiveness and clinical outcomes of pain treatment.

Harnessing the growing amounts of clinical data currently stored within isolated health care systems and provider offices clearly holds potential for expanding the evidence base on the effectiveness of pain treatments. The development of systems to allow individual patients and physicians to access important medical information independently of any specific medical care system holds promise for the future. It offers the possibility of evaluating treatments and outcomes using observational study designs across the full spectrum of patients and practice settings and identifying heterogeneity in treatment effects among subpopulations. Wide geographic variation in the use of therapies (for example, joint replacement surgery) and new analgesics creates natural experiments that can reduce the biases usually associated with observational studies. These data sources also may provide efficient sampling frames for recruitment to large practical clinical trials or cluster randomized trials.

A relatively recent approach, practice-based evidence (PBE), was developed to overcome some of the limitations described above and has been used to determine which interventions are associated with better outcomes for specific types of patients in the actual practice of care (Horn et al., 2005; Horn and Gassaway, 2010). PBE uses the Comprehensive Severity Index (CSI^®, http://www.isisicor.com/CSI_Flyer_p1.html), which is based on objective clinical findings rather than diagnostic codes to control for patient differences (Ryser et al., 2005).

A Chronic Pain PBE Registry^© is being created in New York City, based initially on detail on thousands of patients treated in four pain clinics in three academic institutions (the Weill Cornell Medical College-New York Presbyterian Hospital, the Memorial Sloan-Kettering Cancer Center, and the Hospital for Special Surgery). In addition to the advantages cited above, this registry includes longitudinal scoring of severity of illness for all conditions for each patient, a wealth of detail on treatments, and information on outcomes that are measured by both patients and their providers.

If this type of registry proves useful, expansion to other locales or even nationally would be useful, although expensive. There is a need for greater development and use of such patient outcome registries that can support point-of-care treatment decision making, as well as for aggregation of large numbers of patients to enable assessment of the safety and effectiveness of therapies. These registries could help create “learning systems” that would provide clinicians with information about treatment success or failure on an ongoing basis, along with probability “filters” for information that might be particularly useful in the care of an individual patient.

The large databases and diverse populations offered by health system-wide research, combined with biosignature data on patients’ individual characteristics, could contribute to the development of personalized medicine approaches that would take into account the wide variability in people’s responses to pain and pain treatment. At present, researchers cannot differentiate among the various potential pain processes that may be occurring in a given person. Expecting a population of people whose pain etiology is heterogeneous to respond in the same way to a potential new analgesic in a clinical trial is a likely cause of some of the disappointing results that have been seen. In many cases, moreover, several biological processes are in play simultaneously, making it difficult to detect benefits from a treatment that has an impact on only one or a few of those processes (Farrar, 2010).

A principal reason why targeted therapy, based on genomic and other factors specific to individuals, has not become more widespread is the absence of clear, reproducible evidence for both its predictive power and its impact on patient outcomes. However, genomic approaches as applied to pain treatments are still in an early stage of investigation. As such information becomes increasingly available, the opportunity to test its usefulness across larger populations will depend on the quality and availability of individual-level data. The development of standardized approaches to collection, recording, storage, and access for such data, designed so that the privacy of the individual is carefully protected, is essential to achieving the goal of improved individualized pain care.

Psychosocial Research

Psychosocial research holds promise for greatly increasing the ability to understand and treat people with pain. Over the past several decades, significant progress in the development of research methods for assessing and treating pain has closed important gaps in understanding of how individuals perceive, react to, and adjust to pain, as well as how they respond to treatment. These approaches are relatively new and have not yet influenced health policy significantly or been widely adopted in clinical practice.

A Road Not Taken

Although there is much more to be learned about pain from many research perspectives, much of what we already know is not applied well or consistently in clinicians’ day-to-day interactions with people in pain. As noted earlier, because pain is a feature of so many health conditions, no one “owns” it in the same way that a large cadre of cardiologists or oncologists and national research institutes focuses on heart, lung, and blood conditions or cancer. The relatively small group of physician pain specialists, although acquiring increasing coherence, has not been concentrated in one field, but spread across the disciplines of anesthesiology, physiatry, psychiatry and neurology, occupational medicine, and palliative care. Nor are there large numbers of generous funders and foundations supporting pain research, or patient advocacy groups with the visibility, national network, and financial resources of the American Heart Association or American Cancer Society to press for more research and training and public awareness of what quality pain care should be.

For these reasons, it might appear logical for the committee to have suggested creation of a pain institute within NIH that could develop a research strategy and coordinate the disparate pain-related efforts currently spread across various institutes and centers, which are not working as quickly or effectively as the opportunities being created by new science might allow. In not making such a recommendation, the committee was guided by several factors:

• The National Institutes of Health Reform Act of 2006 (PL 109–482) caps the number of institutes and centers at 27, its current complement.¹⁰ Effecting a change in that legislative rule would be difficult.
• The 2006 act also gives the NIH director expanded authority to manage the agency, and he recently approved a new National Center for Advancing Translational Sciences. The goal of that center, which is to speed the translation of therapies from the laboratory to the bedside, is certainly compatible with committee’s views with respect to advances in pain assessment and treatment.
• In a 2003 report on the organization of NIH, a National Research Council and Institute of Medicine (NRC/IOM) committee commented, “An organization’s ability to make effective changes is influenced by a multiplicity of factors, including structure, strategy, and systems” (p. 4), encompassing both its formal and informal processes. The goal of increased and better coordinated pain research is not necessarily dependent on having a unique institute or center, but could result from a stronger strategy and systems to support that goal. With respect to establishing new institutes or centers, the NRC/IOM committee recommended that a public process be established “to evaluate scientific needs, opportunities, and consequences of the proposed change and the level of public support for it. For a proposed addition, the likelihood of available resources to support it should also be assessed [emphasis added]” (p. 7). The Scientific Management Review Board is designed to carry out that public process. The committee acknowledges elsewhere in this chapter the high probability of declining funds for pain research.
• The potential for a more robust set of pain-related research activities does exist, coordinated across NIH institutes and centers by the NIH Pain Consortium and across NIH and other federal agencies by the Interagency Pain Research Coordinating Committee, currently in formation. Further, the NIH request for proposals (“Mechanisms, Models, Measurement, and Management in Pain Research Funding Opportunity Announcement”), included at the end of this chapter as Annex 5-1, provides a thorough and thoughtful overview of the breadth of research opportunities in the pain field.

Therefore, instead of recommending the creation of a pain institute, a proposal the committee believed would not produce either a pain institute or any other desired result, the committee focused on ways to reenergize and strengthen current activities, a goal the committee believed was both more practical and achievable. The committee’s recommendations to this end are designed to ensure clearer responsibility and accountability for pain research, working within the existing organizational structure.

Organizational Alternatives

A number of efforts are under way to organize research efforts, particularly clinical trials, differently to make them logistically easier to mount, more economical, and more useful. A number of these efforts involve interorganizational networks and cooperation (see Box 5-1 for an example).

BOX 5-1

The Department of Veterans Affairs’ Pain Research Program. Since 1998, the Department of Veterans Affairs has had a National Pain Management Strategy intended to develop a systemwide approach to reducing pain and suffering and improving the quality (more...)

An important example is the NIH Common Fund, housed within the office of the NIH director. It supports cross-cutting, trans-NIH programs that involve the participation of at least two NIH institutes or centers, encouraging collaboration among researchers who have worked on similar problems in the past. Previously, NIH researchers worked exclusively in their organizational silos, missing opportunities for shared insights and for the development of common, best methods (NIH, undated-c). Indeed, an early Common Fund science advance described by NIH is one that involves the development of “new tools to correct brain activity,” which is expected to contribute to new treatments for several brain disorders, including chronic pain.

Programs the Common Fund supports are known collectively as the NIH Roadmap for Medical Research. Roadmap programs are generally short-term, 5- to 10-year programs that are “expected to have exceptionally high potential to transform the manner in which biomedical research is conducted” (NIH, undated-c). They are developed through a strategic planning process that involves multiple stakeholders. This process has led to the identification of three themes under which Roadmap projects fall: New Pathways to Discovery, Research Teams of the Future, and Reengineering the Clinical Research Enterprise. Funded initiatives respond to one or more of these major themes and attempt to

• foster high-risk/high-reward research,
• enable the development of transformative tools and methodologies,
• fill fundamental knowledge gaps, or
• change academic culture to foster collaboration.

The PROMIS initiative, described previously, is a good example of how the general Roadmap purposes can be adapted and applied to the needs of pain patients and the clinicians who serve them.

Pain is a topic of interest for virtually every NIH institute and center and should benefit from this type of collaboration. The NIH Pain Consortium was established in an effort to make this happen. The consortium has identified the following goals:

• to develop a comprehensive and forward-thinking pain research agenda for NIH that builds on past efforts;
• to identify key opportunities in pain research, particularly those that provide for multidisciplinary and trans-NIH participation;
• to increase visibility for pain research within and outside NIH, such as among pain advocacy and patient organizations; and
• to pursue the pain research agenda through public–private partnerships, wherever applicable (NIH, 2007).

Participating in the NIH Pain Consortium are 15 institutes, four centers, and four offices under the Office of the NIH Director. The committee commends the efforts of the NIH Pain Consortium to foster pain research. However, the committee believes there needs to be a transformation in how pain research is conducted and that the Pain Consortium should take an even more proactive leadership role in effecting that transformation. NIH should increase staffing support for the Pain Consortium and engage higher-level staff from the institutes and centers, and the consortium should hold more frequent, regular, structured, and productive meetings to advance basic, translational, and clinical pain research and to monitor funding levels and the overall portfolio of pain research funding. One possibility, reflected in the committee’s recommendations, is the identification of a single lead institute or center to coordinate this work, establish a consistent strategy, and maintain momentum. The National Institute of Neurological Disorders and Stroke is one strong lead-agency candidate, but not the only one.

In 2004, NIH created a Blueprint for Neuroscience Research, in which 13 institutes, two centers, and one office participate (NIH, undated-a). One of the priorities for the blueprint is the Grand Challenge on Pain, which supports research “to understand the changes in the nervous system that cause acute, temporary pain to become chronic nerve pain (neuropathic pain).” The blueprint is encouraging collaboration among researchers in the pain field and those nonpain experts with expertise in neuroplasticity. The committee recognizes the importance of the NIH blueprint and encourages NIH to increase collaborative pain research through this mechanism.

With or without the participation of one of the above NIH initiatives, the development of clinical research networks (CRNs) to conduct RCTs or other types of clinical research is one approach that can be used to spread the costs of trials across institutions, gather larger pools of patients to participate in studies, and otherwise achieve economies and accelerate the drug development process (IOM, 2010). Encouraging clinicians who work with people with pain to participate in clinical research might improve rates of integration of new findings into everyday medical care and help focus projects on issues of immediate clinical need and potential application, such as more usable psychosocial evaluation tools.

Current Partnership Activities

Efforts to promote public–private partnerships will likely be important in building and sustaining the capacity for pain-relevant research. There are several examples of existing important partnerships that could be expanded. One particularly effective collaboration over the past decade has been IMMPACT (described earlier in this chapter), which has yielded multiple consensus reports designed to foster improvements in clinical trial design and execution and in interpretation of pain treatment studies. Recently, the FDA supported the creation of ACTION, a public-private partnership (also described earlier) that will expand the efforts initiated by IMMPACT. Although the goals and objectives of IMMPACT and ACTION relate directly to promoting the development of analgesics, their indirect effect has been to promote knowledge and consensus on a broad array of methodological, measurement, and trial design issues relevant to research more broadly.

Another partnership example can be found within the Department of Veterans Affairs. A majority of the department’s facilities are closely affiliated with schools of medicine and nursing and associated health professionals, and the strong public interest in veterans and their known high prevalence of painful disorders encourages an explicit focus on pain and pain management. Collaborative funding opportunities involving the Department of Veterans Affairs, the Department of Defense, and NIH, among other public agencies, should be explored.

A few private foundations, notably the Mayday Fund, have long supported research, including psychological research, related to pain. In the past year, Mayday partnered with the Patrick and Catherine Weldon Donaghue Medical Research Foundation to sponsor Project STEP, which systematically examines the efforts of the Department of Veterans Affairs to implement a stepped pain care model. Most recently, Mayday provided partial support for an examination of efforts to enhance pain care in a federally qualified health center (FQHC). In addition, a recent Mayday Fund report (The Mayday Fund, 2009) includes a number of forward-thinking recommendations relevant to pain research involving

• the need for coordinated health information technology systems across payers and providers to permit tracking of pain conditions, treatments, and outcomes and to facilitate improvements in quality of care;
• the need for increased funding for pain research “to a level that is commensurate with the size of a public health problem that affects millions of people” (p. 10); and
• the need for studies to determine best practices in treating specific types of chronic pain.

Recommendations such as these inherently involve cross-sector partnerships and multiple constituencies.

Public–private partnerships are especially appropriate when problems fall outside the normal scope of activities of either the basic sciences or industry. Basic scientists may develop candidate biomarkers, for example, but lack the resources and incentives to proceed with the intensive effort involved in translating them into “practical, reliable, and well-characterized tools ready for clinical use” (IOM, 2008, p. 11). At the same time, the scanning efforts necessary to produce candidate entities may be too far removed from industry’s search for marketable products.¹²

NIH launched its own agency-wide program for public–private partnerships (the PPP Program) in 2005 within the Office of the NIH Director as a result of work on the NIH Roadmap, in collaboration with the Foundation for the NIH. The Roadmap is focused on areas in which NIH institutes and centers can build on existing strengths and create synergies through cross-cutting projects. The PPP Program is a logical extension of that approach, expanding the techniques and goals of collaboration outside the walls of NIH.

According to the home page for the PPP Program website, public–private partnerships will “provide additional models for conducting biomedical research in an increasingly complex world.” The PPP Program’s mission is to be a central resource within NIH to facilitate collaborations—that is, to aid in establishing, sustaining, coordinating, and advising NIH and potential public- and private-sector partners with respect to, as the home page says, the “formation of partnerships that leverage NIH and non-NIH resources” (NIH, 2010).

NIH already has almost 30 years’ experience with public–private partnerships, dating from creation of the National Cooperative Drug Discovery Group within the National Cancer Institute (NCI) in 1982, an approach subsequently adopted by four other institutes. The NCI program aims to

• support multidisciplinary team research to discover new targeted anti-cancer therapies;
• address the need for new therapies with greater selectivity;
• use new technologies to speed discovery (i.e., molecular targets, compound libraries, high-throughput screening, imaging);
• protect intellectual property; and
• foster high-risk, translational research with a potentially high payoff.

Although the makeup of multidisciplinary teams for pain would, of course, be different and perhaps more diverse than that of such teams for cancer, the above list provides a good summary of what public–private partnerships in the field of pain management might hope to accomplish.

A new opportunity for enhancing public–private partnerships to improve pain care can be found in the new Patient-Centered Outcomes Research Institute, established by the Patient Protection and Affordable Care Act of 2010 (Public Law 111-148, Secs. 6301 and 10602). This independent, nonprofit organization is intended to support CER projects and other investigations that will help patients and clinicians make better health care decisions. Its board of governors includes physicians, industry representatives, public officials, consumer representatives, and others appointed by the Comptroller General of the United States. Its processes are required to be transparent and to involve substantial public input. The institute will be more likely to make pain-related research a priority if advocates for improved pain care reach out to this agency and make a strong case for such research.

Potential Projects for Public–Private Partnerships

The discussion in this chapter points to a number of areas ripe for public– private partnerships, whereby different parties can bring their strengths to the table. One is the concept of multicenter clinical trials to enable the involvement of sufficient numbers of participants with specific pain pathologies; a second is involvement of private clinicians in the trial process to facilitate knowledge transfer to daily practice; a third is the FDA’s desire to develop new regulatory science approaches through which it can work more closely with the scientific community and industry; and a fourth is to balance the pharmaceutical industry’s market-driven process for determining research priorities with a process driven by consumer needs, which could take greater account of the pain treatment needs of children, the elderly, and disease or population groups that are too small to attract industry. (The FDA’s effort to encourage pediatric studies is an example of how this is being done [Politis, 2005].)

New public–private partnerships could help leverage resources to target high-priority, if not expensive, research questions and initiatives. CER is another high-priority research need that almost certainly will require public–private partnerships and the combining of financial and other resources. Partnerships could expedite the development of treatment approaches that employ advanced technologies, such as web-based treatment and support programs or the use of cell phone applications to enhance maintenance of treatment of regimens. Finally, the development and dissemination of provider and patient/family educational resources (see Chapter 4) is another obvious target for such partnerships.

Other potential partnerships could involve

• working with international research organizations on epidemiologic and human behavior studies in an attempt to understand the reasons for the apparent increased prevalence of chronic pain in many countries, including the United States;
• working with the pharmaceutical industry and the pain research community to increase understanding of genetic or other variations in pathophysiology that affect individual responses to nociception and pain treatment and the biomarkers or biosignatures that characterize those responses;
• working with industry, clinicians from multiple disciplines, and pain advocacy and awareness organizations to apply knowledge about individual differences in pain perception, persistence, and responses to treatment to support the development of personalized strategies for pain management, including pharmacogenomic approaches;
• working with proprietors (public or private) of large health care and pharmacy databases to determine what information they can provide to inform research on the comparative effectiveness of pain treatments, as well as additional data elements that could feasibly be added, and where there are gaps in information, supporting multiorganizational pain patient registries;
• working across NIH institutes and centers, the Agency for Healthcare Research and Quality (AHRQ), the Centers for Medicare and Medicaid Services (CMS), clinicians treating pain patients, and patient advocacy groups to produce and publicize evidence-based reviews of currently used pain treatments (including surgery) and their effectiveness¹³ in order to discourage unnecessary or ineffective treatments that delay appropriate care, encourage greater use of treatments known to be effective, and address barriers to more effective pain care;
• working with the pharmaceutical industry, the FDA, and patient advocates to ensure that accurate information about pain and its self-management is included in drug inserts and on appropriate NIH websites in order to foster public education;
• working with private foundations, voluntary health organizations (e.g., the Arthritis Foundation, the American Cancer Society), or other funders to provide full or partial funding for promising grant applicants that miss NIH cutoff points or for new investigators, workshops or training experiences targeting promising new pain investigators, and more forceful advocacy for additional pain research funding;
• working with the above groups and with academic institutions to develop a national network that would support and encourage ongoing mentoring, including such activities as laboratory visits and ongoing e-mail/ telephone contact, and fostering new collaborations between successful senior and midcareer investigators and younger investigators;
• researchers in health care, health policy, and health economics working with CMS, NIH, the FDA, the Department of Veterans Affairs, the Department of Defense, private insurers, health professions associations, consumer groups, integrated health care systems, accountable care organizations, and academic medical centers to compare outcomes of care for various pain treatments and assess which are most effective for specific groups of patients and under what circumstances (use of these more effective treatments should be encouraged, while use of ineffective treatments should be discouraged); and
• investigators working with public health entities, pain advocacy and awareness organizations, physicians, and others to explore the effectiveness of alternative public health strategies, approaches to public and patient education and clinician–patient communication, and ways in which system changes could support better pain care.

Each of the above examples suggests a somewhat different mix of partners. Such variation is highly desirable, not only because it engages a wider range of organizations in thinking about pain care but also because it avoids overreliance on a small group of industry partners.

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 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-areas are not intended to be comprehensive or exhaustive. Synergistic studies that reach across two or more of these areas are encouraged. 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 programs 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 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.

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:

• 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 noninvasive 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.

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 experience 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 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. Health care providers under treat 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 approaches. Research is encouraged but not limited to science in the following areas:

• Interventions involving combinations and sequencing of pharmacological, nonpharmacological, 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., 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.
• Risk factors, including age, ethnicity, family history, gender, genetic predisposition, 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.
• 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 socioeconomic 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.
• Comorbid disorders and pain, including descriptive studies of risk and protective processes, and interventions aimed at relieving adverse consequences 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 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 nonmalignant 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 nonpharmacological 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 patients 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.