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
1 Quotation from testimony to the committee, November 2010.
and effects on families reveals that data on pain are spotty and conflicting 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 understand 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 building 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 specialists, and researchers to enable more effective public dissemination of information (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 following 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.
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 implementing 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 developing 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 Excellence, 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, expanding 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
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 multifactorial 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.
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 examines 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.
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.
3 Schwann cells, satellite cells in the dorsal root ganglia, spinal microglia, and astrocytes.
- 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.
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).
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 diagnostic 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 physiological 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 growing 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.
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, 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 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.
5 The 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.
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.
Pain treatment needs to be individualized and often combined, [which] presents challenges to research design and statistical analysis; however, in reality, many who live with pain use a variety of pain management strategies simultaneously to achieve their goals.
—An advocate for people with chronic pain6
Numerous barriers impede the development of improved and innovative ways to treat chronic pain. Among them are the need for new diagnostic measures for pain and the need for improved clinical research methods to determine the efficacy of treatments. Comparative effectiveness research (CER), improved clinical trial designs, and the development of biomarkers and biosignatures (discussed previously) are among the strategies that can help overcome these barriers. They would be particularly useful if augmented by detailed pain-related information, such as the severity and sites of pain, pain-related disability, genetic profiles, and psychosocial information, collected in a systematic way through observational research and available through well-designed clinical databases and pain registries. Additionally, since pain can involve multiple sites and frequently is accompanied by a constellation of other symptoms and reported health- and mental health-related conditions (for example, sleeplessness, gastrointestinal discomfort, fatigue, and respiratory complaints, as well as psychosocial maladies), research is needed to document and assess this full spectrum of pain-associated problems. This information would enable the development of interventions that would address all aspects of the pain condition (Natvig et al., 2010).
Meta-analyses of RCTs of currently approved chronic pain treatments have found that they produce relatively small (less than 30 percent) improvements in pain intensity compared with placebo. Moreover, fewer than half of people treated
6 Quotation from response to committee survey.
have more than half their pain reduced (Turk, 2002). Efforts to demonstrate analgesic efficacy have repeatedly failed, even among commonly used analgesics, including opioids (Chapter 3), despite a long history of human experience with using various forms of these agents for pain control. According to Dworkin and colleagues (2011, p. S108), “the explanation for failures of RCTs of efficacious analgesic treatments is currently unknown.” Potential contributing factors include trial designs, methodological features, outcome measures, data analysis methods, and variations in populations studied, as well as the possibility that the drugs being studied are truly ineffective (Dworkin et al., 2011). These trials unfortunately have revealed little about the large number of nonresponders and what differentiates them from people in whom the tested drugs do make a difference.
Thus the search is ongoing not only for more effective and less risky treatments, but also for improved research methods. This section starts with a discussion of RCTs and their limitations for pain research and then describes initiatives to address those limitations. It then examines the potential usefulness in pain research of other research methods: CER; observational studies, databases, and registries; and psychosocial research. With respect to the latter, new, more sophisticated methods of data analysis are needed to build understanding of individual differences in pain and its psychosocial impact and to test causal or explanatory models of the role of psychosocial factors in the maintenance, magnification, and development of persistent pain.
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 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.
Assessment of Dimensions of Pain
Reliable and well-validated self-report measures are now available for assessing the experience of pain in adults and children, including pain intensity and other key dimensions. Valid and reliable self-report measures of emotional state and physical functioning also are available, including measures of pain’s impact on different levels and types of activity (e.g., Western Ontario-McMaster Osteoarthritis Scale [Bellamy et al., 1988]; Fibromyalgia Impact Questionnaire [Bennett et al., 2009]).
One limitation of self-report measures is that some people, because of developmental or cognitive limitations, are unable to describe their pain verbally. To address this limitation, standardized observation methods for assessing pain-related behavior are now available—for example, assessments of facial expressions related to pain in neonates and people with advanced dementia (Hadjistavropoulos et al., 2007; McGrath et al., 2008) or movement patterns connoting the presence of pain (Keefe, 2000).
Clinicians often find it helpful to understand how a person with pain rates noxious stimuli that are of a known intensity and duration. Reliable and well-standardized psychophysical protocols for testing reactions to controlled noxious stimuli (quantitative sensory testing) are being used to study differences in pain perception by sex and gender, race and ethnicity, age, and other important variables (Walk et al., 2009; Maier et al., 2010).
A significant barrier to improving the diagnosis, evaluation, and monitoring of pain is the need for new assessment methods that can be integrated more easily into clinical practice and used in epidemiological studies. Clinicians often view self-report measures as too time-consuming for routine use, especially in busy primary care settings. Many of these current measures are therefore employed primarily in interdisciplinary pain specialty practices. Even there, their use may be limited to a one-time administration prior to treatment. Reluctance to use these measures for periodic reassessment prevents learning about changes in the pain
experience and responses to treatment that could lead to treatment refinements and improved outcomes. It also inhibits development of the clinician–patient relationship so vital to effective pain treatment.
The Patient Report Medical Outcomes Reporting System (PROMIS), part of the NIH Roadmap for Medical Research, represents an important step (see http://www.nihpromis.org/). The goal of PROMIS is to develop and validate patient-reported measures that can be used to quantify clinical outcomes such as pain in adults and children (Fries et al., 2005; Revicki et al., 2009). Using sophisticated computer adaptive testing (CAT) methods, PROMIS will provide clinicians and researchers with short, valid, individually tailored, and easy-to-use methods for measuring pain in a wide variety of clinical and research settings. According to the PROMIS website, “Not only can the reports be used to design treatment plans, but also can be used by patients and physicians to improve communication and manage chronic disease” (NIH, undated-b).
Assessment of Psychological Traits and States Related to Pain Adjustment
Research conducted over the past two decades has led to a variety of reliable and valid self-report measures that can be used to assess psychological traits and states related to pain, as well as expectations, beliefs, and thoughts about pain and its impact (DeGood and Cook, 2011). These measures enable more precise characterization of how people adjust to their pain, and some of them can predict the development of pain-related disability and response to treatment (Linton and Hallden, 1998; Jensen et al., 2007).7 Incorporating self-report measures of psychosocial adjustment into clinical practice prevents overly simplistic thinking about adjustment to pain and can lead to a new appreciation of the impact of pain and the need to address its psychological and social contexts.
A number of psychological markers have been demonstrated to predict chronic pain and related disability. For example, Carragee (2005), Jarvik et al. (2005), and their colleagues have reported that psychological distress is a better predictor of the development of chronic back pain and pain-related disability than physical pathology up to a year following initial assessment. Similarly, Klenerman and colleagues (1995) found that fear of pain and further injury was a better predictor than injury-related variables of prolonged disability following back injuries.
Over the past decade, structured psychiatric interview methods have been shown to offer another standardized and reliable way of assessing adjustment to pain (Sullivan and Brennan-Braden, 2011). Although more time-intensive than self-report, these methods may provide more accurate and reproducible results
7 Examples include the Brief Pain Inventory, Multidimensional Pain Inventory, and Western Ontario and McMaster Universities Osteoarthritis Index: http://www.rheumatology.org/practice/clinical/clinicianresearchers/outcomes-instrumentation/WOMAC.asp (Kerns et al., 1985; Cleeland and Ryan, 1994).
when used in persons with persistent pain and potentially co-occurring and treatable emotional disorders, such as those involving mood, anxiety, posttraumatic stress, substance use, and sleep difficulties.
Ongoing Assessment and Monitoring of Pain and Pain-Related States
Pain and related psychosocial processes are dynamic and vary considerably over time. A key step in capturing these dynamic processes is to make greater use of newly developed daily diary methods (Stone et al., 2003; Broderick et al., 2008). Sophisticated data analysis methods then can be applied to the diary entries to assess how day-to-day changes in pain are related to changes in mood, stress, or cognition. Daily diary methods avoid problems with recall and capture potentially important pain-related processes closer to their real-time occurrence.
Although pain diaries often are used in clinical practice, new methods for collecting and analyzing the data are underutilized (Heapy et al., 2007; Turk and Melzack, 2011). As a result, major opportunities for understanding patients’ pain trajectories more fully and customizing treatment to their day-to-day adjustment to pain are being missed. Electronic methods for collecting, analyzing, and displaying data will make this activity less expensive and more widely available (Turk and Melzack, 2011).
I wouldn’t wish this on anyone, but if researchers could go through just one day of life as I live it, maybe they would understand how devastating this is. … There is no hope for people with R.S.D. [reflex sympathetic dystrophy]. “Just learn to live with it” is NOT acceptable! Please help us.
—A person with chronic pain8
In the future, many discoveries in pain research will require teams of researchers with diverse backgrounds who can integrate multilayered data into systems models. Increasingly, accomplishing this integration will require expertise in bioinformatics to help analyze and interpret massive data sets. Currently, a significant barrier to advances in pain research is the lack of scientists working in this arena. The field needs a larger and broader array of basic, clinical, behavioral, and social scientists from diverse disciplines, as well as veterinary clinical specialists, engineers, and researchers from the physical sciences.
8 Quotation from response to committee survey.
New training mechanisms are needed to make research on pain more accessible to scientists in many disciplines through exposure in graduate or medical school education and inclusion in comprehensive continuing education courses. The gathering of evidence on best practices in pain management for nurses is led at the federal level by the National Institute for Nursing Research, and pain is regarded as one of the most difficult challenges in health care for both nursing researchers and clinicians. Training models should better orient basic and applied pain researchers to the multidisciplinary nature of the development, amplification, and maintenance of chronic pain and pain-related disability. Along these lines, established curricula on pain are available (for example, the IASP curriculum), but they have not been widely used in the training of pain clinicians and researchers.
The population affected and the readiness of the science together should determine where the research money goes. Pain research needs investments to get from its infancy to adolescence. When a field is in its infancy and researchers think the chances of getting funding are very low, that discourages applications.
—Peter Reinecke, an advocate for people with chronic pain9
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.
9 Quotation from testimony to the committee, November 2010.
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,
10 In fall 2010, NIH Director Francis S. Collins accepted the NIH Scientific Management Review Board’s (SMRB) recommendation to merge the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism into a single new institute, thereby reducing the number of institutes and centers by one. Soon thereafter, he also decided, again based on an SMRB recommendation, to fill that slot with a new $722 million National Center for Advancing Translational Sciences, a proposal now before Congress.
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.
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).
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 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 of life for veterans (see Chapter 3). A key feature of the initiative is support for basic and applied research on pain management, especially for conditions prevalent among the nation’s 23 million military veterans.
The department’s Office of Research and Development and the Pain Management Program have collaborated to promote basic laboratory, clinical science, health services, and rehabilitation research and development services. The number of painrelevant projects increased from 10 in 2000 to 47 in 2007, while funding for pain-relevant research increased by 27 percent.
The expanded level of research continues, with numerous projects focused on the needs of veterans from the wars in Iraq and Afghanistan and the characteristic injuries they incur. Several of these projects involve collaboration between the Departments of Veterans Affairs and Defense. Painful musculoskeletal conditions are by far the most commonly diagnosed medical problems among this cohort of veterans.
In further support of the strategy, the department’s Health Services Research and Development Service has funded a Pain Research, Informatics, Medical Comorbidities, and Education Center to improve understanding of the complex interactions among pain, the associated chronic diseases, and various behavioral health factors, as well as to develop new, efficacious interventions. A national Pain Research Working Group comprising more than 50 representatives of the department and a few external collaborating investigators in pain and pain management focuses, in part, on disseminating research findings “with relatively direct practice and policy implications” (Kerns and Dobscha, 2009, p. 1162).
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.
If you think research is expensive, try disease.
—Mary Lasker (NIGMS, 2011)
Investigators seeking funds for pain research projects, at least in the past, have faced a number of significant hurdles, which the new funding opportunity program (Annex 5-1) may or may not help resolve. As discussed in Chapter 1 and earlier in this chapter, because pain is “everybody’s business,” in a sense it becomes no one’s. Although several NIH study sections review pain grant applications, the expertise is not focused and may be spread too thin to be effective. Nor is pain any institute’s or center’s primary agenda. As noted below, the study sections are working with a very small portion of the NIH budget, which is likely to shrink further as the funding for biomedical research becomes more constrained. Simply put, the current review and funding processes are suboptimal. The NIH Pain Consortium should to take steps to optimize the process for reviewing pain grants.
NIH provides about a third of all biomedical research funding in the United States. The agency’s interest in a topic has ripple effects, stimulating interest in laboratories and science training programs around the country. Between 1997 and 2004, when the NIH budget hit its high-water mark, funding nearly doubled, from $15.6 billion to $30.4 billion (in constant 2008 dollars). After 2004, funding declined slightly each year, reaching $28 billion in 2009. President Obama’s NIH budget request for fiscal year (FY) 2012 is just under $32 billion. Because of large past commitments requiring ongoing funding, little of that amount can support new efforts.
The reversal of annual growth in congressional appropriations for NIH during the mid-2000s affected funding for pain research, which has consistently represented a very small part of the NIH budget—0.61 percent in 2007. An analysis of NIH grant awards from 2003 to 2007 indicates that in the first year, 2003 to 2004, NIH funding allocated to pain research increased by 12 percent, but in the three succeeding years, it declined by an average of 9.4 percent per year, while overall NIH funding declined an average of only 1.9 percent per year (Bradshaw et al., 2008). Consideration needs to be given to expanding NIH funding of pain research, given the magnitude of the problem of pain (approximately 100 million adults affected by chronic pain alone) and its related costs (at least $635 billion per year) (see Chapter 2 for a full discussion). Research and innovation, including efforts focused on pain prevention, may be the most cost-effective approach to tackling the problem in all its dimensions.
Current pressures to reduce federal spending suggest that large NIH budget
expansions are unlikely in the foreseeable future. This trend will naturally encourage the institutes and centers to concentrate on their primary missions, which are not pain, meaning that money for new pain research will most likely be in increasingly short supply. As a result, this area of investigation may be a casualty of competing priorities. The impending merger of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism may further exacerbate the situation as their existing programs are consolidated.
According to the analysis by Bradshaw and colleagues (2008), in 2007 NIH awarded 586 grants for primary pain research. In most years examined, clinical research grants outnumbered basic research grants and exceeded them in dollars spent. Of the total funding for pain research in 2007 ($181 million), $78 million supported basic science and $102 million clinical research. In testimony provided to the committee, it was reported that NIH pain-related expenditures for 2009-2010 were approximately $320 million. Unfortunately, the increase over the 2007 funding level includes a one-time influx of economic stimulus funds from the American Recovery and Reinvestment Act, and therefore is unlikely to be sustained going forward. The NIH staff involved in pain research does not favor a specific dollar commitment for pain research lest it become an “entitlement,” not linked to quality benchmarks or measurable criteria. This point of view must be balanced against the magnitude of the pain problem and the need for prompt and sustained research efforts to address it.
Finally, although workforce development is not a primary focus of the committee’s work, the committee recognizes that new investigators can be attracted to the field—and current ones motivated to remain in it—only if funding for research and career development is predictable.
The kind of far-reaching progress anticipated for biomedical research in the 21st century will require even more research collaboration among public and private sectors.
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 anticancer 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,
12 A public–private partnership for biomarkers—the Biomarkers Consortium—has been developed. It involves the Foundation for the National Institutes of Health as the managing organization, NIH, the FDA, Pharmaceutical Research and Manufacturers of America, the Centers for Medicare and Medicaid Services, and the Biotechnology Industry Association, with a large number of for-profit companies and nonprofit organizations serving as contributing members (http://www.biomarkersconsortium.org/).
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 patho-
physiology 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;
13 Examples are the American Urological Association’s review of currently available treatments for interstitial cystitis (http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/ic-bps/diagnosis_and_treatment_ic-bps.pdf) and the American Academy of Neurology’s guideline on diabetic neuropathy (http://www.aan.com/go/practice/guidelines).
- 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.
Finding 5-1. Research to translate advances into effective therapies for pain is a continuing need. The committee finds that significant advances have been made in understanding the basic mechanisms of nociception and pain but that much remains to be learned, underscoring the importance of continued support for basic and clinical research. At the same time, the advances achieved to date have led to new potential targets for future pain assessment and treatment strategies. Furthermore, recent advances in the neurosciences, biomarkers, and the behavioral sciences have validated a comprehensive approach to the management of pain that includes the individual’s inherent biology, behavior, and psychological makeup and reactions, as well as environmental influences. However, data and knowledge gaps in pain research remain that have prevented such research advances from being translated into safe and effective therapies:
- There is a need for further understanding of the basic behavioral and environmental mechanisms and their interactions that cause, amplify, and maintain pain. Integration across the multiple layers of biological and behavioral sciences is needed to examine and develop systems models that can be used to improve the understanding and treatment of pain (i.e., across the domains of the gene, protein, synapse, neuron, circuit, network, brain, behavior, family/social/work/education environment, and culture).
- Advances in dissemination sciences could be used more effectively to help translate treatments found to be efficacious in clinical trials into clinical practice.
- The mechanisms and factors that lead acute pain to persist and become chronic are not understood.
- Gaps exist in basic, clinical, and epidemiological research on pain and pain management. Filling these gaps could help define the prevalence of recurrent and chronic pain conditions and populations at risk.
- Research is needed on the development, testing, and dissemination of effective psychoeducational interventions to support patients and their families.
- The long-term efficacy and safety of existing pain therapies (including chronic opioid therapy) are not well understood.
- Gaps exist in understanding of the influence of the role of the placebo group response and its impact on clinical pain management trials.
- Gaps exist in understanding the most effective ways of educating pain clinicians and researchers.
- Barriers in regulatory science prevent the efficient evaluation and approval of potentially effective therapies for clinical use.
- In the committee’s opinion, current processes within the National Institutes of Health for the review of grants pertaining to pain are suboptimal in that many topics in pain research do not fit within existing study sections, and expertise for the review of submitted proposals is inconsistent.
Addressing these gaps will require a cultural transformation in the view of and approach to pain research, involving basic, translational, and clinical researchers; federal funding and regulatory agencies; and private organizations. This cultural transformation is reflected in the following recommendations.
Recommendation 5-1. Designate a lead institute at the National Institutes of Health responsible for moving pain research forward, and increase the support for and scope of the Pain Consortium. The National Institutes of Health should designate a specific institute to lead efforts in advancing pain research and increase the support for and broaden the scope of its existing Pain Consortium. The committee recognizes that the primary physiologic processes that underlie pain involve the nervous system, which would make the National Institute of Neurological Disorders and Stroke a rational choice to take on this lead role, but also recognizes that the decision may depend on other factors best addressed by the organization’s leadership. The designated institute should
- Include pain as a major component of its mission.
- Assume leadership of the NIH Pain Consortium and the NIH Interagency Pain Research Coordinating Committee.
- Assume responsibility for assessing the effectiveness of the National Institutes of Health in moving pain research forward.
- Identify funding needs.
At the same time, the National Institutes of Health should increase financial resources and staffing support for and broaden the scope of the Pain Consortium and engage higher-level staff from the institutes and centers in the consortium’s efforts. The Pain Consortium should exert more proactive leadership in effecting the necessary transformation in how pain research is conducted and funded. The consortium should
• Hold more frequent, regular, structured, and productive meetings to advance interdisciplinary basic, translational, and clinical pain research.
• Take steps to improve the process for reviewing grant proposals related to pain. Study sections should be expanded to add individuals with pain expertise. The expansion effort should include
— identifying gaps in areas of pain research not met by existing study sections,
— ensuring that these gaps are filled by reviewers with appropriate expertise, and
— publishing on the Pain Consortium’s website a list of study sections that review pain research.
• Work with pain advocacy and awareness organizations to help identify public needs with regard to pain treatment and management.
• Work to improve and expand public–private partnerships between academia and the for-profit (e.g., pharmaceutical and device industries) and not-for-profit (e.g., foundations and professional organizations) entities that foster research, education, and treatment for pain.
Recommendation 5-2. Improve the process for developing new agents for pain control. Academia and industry should develop novel agents for the control of pain. This does not mean simply recycling current drugs. What is required is basic and clinical science research to discover new classes of pain therapeutics and more efficient ways of developing them. Also required is that regulatory agencies, especially the Food and Drug Administration, develop new and expeditious ways to evaluate and approve new pain therapies. Examples include new methods for patient stratification in clinical trials, as well as more
appropriately defined diagnostic and therapeutic endpoints (e.g., biomarkers and new surrogate markers of response).
Recommendation 5-3. Increase support for interdisciplinary research in pain. Federal agencies, such as the National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Disease Control and Prevention, Department of Defense, and Department of Veterans Affairs, as well as private funders of pain research, should increase support for interdisciplinary research and research training—across agencies and professions—on pain-related diseases and the deficiencies noted in Finding 5-1. This research should include teams of researchers comprising both traditional pain researchers and people from different fields (e.g., engineering, mathematical and computer modeling, systems biology, genomics, dissemination sciences, comparative effectiveness [or outcomes] research). It also should include teams with members from basic, translational, and clinical areas of expertise. Funding should focus on areas that represent gaps in pain knowledge and understanding.
Recommendation 5-4. Increase the conduct of longitudinal research in pain. Public and private funders should increase support for longitudinal research in pain, including comparative effectiveness research and novel randomized controlled trials, to help ensure that patients receive care that works best in both the short and long terms.
- The cohorts studied should include real-world patients with pain (i.e., those likely to have comorbid conditions in addition to pain, such as depression, anxiety, obesity, and hypertension) and not be restricted to overly homogeneous but atypical patient groups.
- The studies should use appropriate pain metrics and coding of the types of pain treatments tested.
- Public and private funders of pain research should collaborate with medical specialty and other health professions associations, federal agencies, and private industry to develop pain outcome registries involving real-world patients. Large prospective registries will enable investigators to identify more readily pain treatments and patient characteristics that result in beneficial outcomes or harms.
- Public–private partnerships could support a core infrastructure for interdisciplinary clinical trials in pain treatment (similar to that which exists in the children’s oncology field). Funding could be provided for a statistical and coordinating center, for some key investigative leaders, and for conduct of meetings at least yearly to identify and implement trials of new care models and interdisciplinary treatment strategies for specific pain populations.
- Studies also should evaluate the effectiveness or potential utility of interventions at the population health level, such as public policy initiatives, demonstration projects in the organization and reimbursement of care, and public education efforts.
Recommendation 5-5. Increase the training of pain researchers. With the support of training grants from the National Institutes of Health, academic institutions should increase the training of basic, translational, behavioral, population, and clinical pain researchers. Specific support should be provided for pre-and postdoctoral fellows and junior investigators to promote increased education in pain and collaborative research agendas for investigators. This training should recognize the interdisciplinary benefits of research on pain and pain management. Agencies such as the National Center for Health Statistics, the Agency for Healthcare Research and Quality, and the Centers for Medicare and Medicaid Services should support the training of researchers interested in secondary analysis of pain-related data collected by these agencies.
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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.
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.
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 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 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.
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.